Energey Balance and Cancer

Energy Balance and Cancer
Volume 5
Series Editor:
Nathan A. Berger,
Case Western Reserve University,
Cleveland, OH, USA
For further volumes:

http://www.springer.com/series/8282
Steven D. Mittelman ●
Nathan A. Berger
Editors
Energy Balance
and Hematologic
Malignancies
Editors
Steven D. Mittelman, M.D., Ph.D. Nathan A. Berger, M.D.
Keck School of Medicine Case Western Reserve University
Los Angeles, CA, USA Cleveland, OH, USA
ISBN 978-1-4614-2402-4 e-ISBN 978-1-4614-2403-1

DOI 10.1007/978-1-4614-2403-1
Springer New York Dordrecht Heidelberg London
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Preface
The Many Roles of Obesity in Hematologic Malignancies:

Predisposing Factor, Treatment Confounder, and Long-Term
Complication
When Dr. Harold Varmus, the head of the National Cancer Institute, was recently
asked about what research should be getting more attention, he responded, “The
contribution that obesity makes to cancer is a very important feature of public health”
[1]. Obesity is known to increase the risk of developing and dying from most cancers,
and is singly responsible for ~20% of cancers in the USA. Despite these chilling
statistics, little is known about how obesity contributes to this cancer risk.
Hematological malignancies, including leukemias, lymphomas, and multiple
myeloma, represent ~9% of new cancers in the USA, and leukemia is the most com-
mon childhood cancer [2]. The incidences of these cancers are also increased in
obese individuals. In addition, recent evidence shows that obesity is associated with
a poorer outcome from some of these malignancies.
Some cancers, including breast and colorectal, are located in close proximity to
adipose tissue, which could contribute to the observed relationships with obesity.
Others, such as esophageal, gastric, and gall bladder, are likely affected by dietary
lifestyle factors, which could explain part of their link with obesity. Hematological
cancers, however, have no obvious connection to the obese state, making their con-
sistent link with obesity intriguing and provocative. Perhaps, a clue lies in the fact
that hematopoietic tissue in the bone marrow resides in very close proximity to mar-
row adipocytes, though whether these fat cells are altered in obesity remains unclear.
In any case, uncovering the connections between obesity and hematologic malig-
nancies will likely tell us something important about cancer, in general, and how it
interacts with its host to proliferate, metastasize, and resist treatment.
In this textbook, we explore the relationships between obesity and the incidence,
treatment, and outcome of hematologic malignancies. We have been fortunate to
amass top leaders and pioneers in the field to share their expertise on these issues.
v
vi Preface
In Chap. 1, Lauren R. Teras and Alpa V. Patel, from the American Cancer Society in
Atlanta, GA, discuss the known links between obesity and the epidemiology of
hematologic malignancies. In Chap. 2, Jeffrey M. Gimble from Tulane University
provides a detailed overview of the bone marrow microenvironment, focusing on
the interactions between adipocytes and hematopoietic cells. Chapter 3, written by
Steven D. Mittelman and Anna Butturini, from Children’s Hospital Los Angeles,
Keck School of Medicine, University of Southern California, provides insight into
the potential mechanisms linking obesity and adipose tissue with leukemia develop-
ment and treatment resistance. The effects of obesity on multiple myeloma inci-
dence and treatment are covered in Chap. 4, by Tracey Beason and Graham Colditz
from Washington University School of Medicine, St. Louis. In Chap. 5, the impact
of obesity on the pharmacokinetics of antileukemia drugs is described by Jennifer
Kendrick, Dawn Warkentin, and Mary H.H. Ensom, from the Children’s and
Women’s Health Centre of British Columbia and Vancouver Coastal Health. Chap. 6,
by Fausto R. Loveriza Jr. of the University of Nebraska Medical Center and Willis
Navarro of the National Marrow Donor Program, details the role of obesity on stem
cell transplantation complications and outcome. Obesity as a complication of can-
cer treatment is covered in Chap. 7, written by Emily Tonorezos and Kevin Oeffinger
of Memorial Sloan-Kettering Cancer Center, while physical activity interventions to
prevent this outcome is discussed in Chap. 8, by Luisa Soares-Miranda, from the
University of Porto, Portugal, and Carmen Fiuza-Luces and Alejandro Lucia, from
the Universidad Europea de Madrid.
In all, this textbook presents the current state of understanding of how obesity
can impact hematologic malignancies. This information should provide a founda-
tion for researchers in the obesity–cancer field, and we hope that this information
will help them to develop new ideas and innovations to combat this important
national health problem. In addition, this text should highlight, for clinicians, phar-
macists, and ancillary caregivers, the importance of considering body weight and
energy balance in the care plans for patients with these diseases.
Los Angeles, CA, USA Steven D. Mittelman

Cleveland, OH, USA Nathan A. Berger
References
1. Kaiser J (2011) Piloting cancer research with a shrinking budget. Science 333, 397.
2. Anonymous Surveillance, Epidemiology, and End Results (SEER) Program (2006) (http://
www.seer.cancer.gov) SEER*Stat Database. In: Anonymous.
Contents
1 The Epidemiology of Obesity and Hematologic

Malignancies ............................................................................................. 1
Lauren R. Teras and Alpa V. Patel
2 Adipocytes, Lipid Metabolism, and Hematopoiesis .............................. 31
Jeffrey M. Gimble
3 Mechanisms Linking Obesity and Leukemia Prognosis ...................... 47
Steven D. Mittelman and Anna Butturini
4 Obesity and Multiple Myeloma .............................................................. 71
Tracey Beason and Graham Colditz
5 The Impact of Obesity on Pharmacokinetics and Dosing
of Leukemia Chemotherapy.................................................................... 97
Jennifer Kendrick, Dawn Warkentin, and Mary H.H. Ensom
6 The Impact of Obesity on Stem Cell Transplant................................... 129
Willis H. Navarro and Fausto R. Loberiza Jr.
7 Obesity Following Childhood Cancer:
Mechanisms and Consequences .............................................................. 141
Emily S. Tonorezos and Kevin C. Oeffinger
8 Physical Activity and Recovery from Hematological
Malignancy ............................................................................................... 159
Luisa Soares-Miranda, Carmen Fiuza-Luces,
and Alejandro Lucia
Index ................................................................................................................ 177
vii
Contributors
Tracey Beason Division of Public Health Sciences, Department of Surgery,

Washington University School of Medicine, St. Louis, MO, USA
Anna Butturini Agensys Inc, Santa Monica, CA, USA
Graham Colditz Chief Division of Public Health Sciences,
Department of Surgery, Alvin J. Siteman Cancer Center,
Washington University School of Medicine, St. Louis, MO, USA
Mary H.H. Ensom Clinical Pharmacy Specialist, Children’s and Women’s
Health Centre of British Columbia, Vancouver, BC, Canada
Faculty of Pharmaceutical Sciences, The University of British Columbia,
Vancouver, BC, Canada
Carmen Fiuza-Luces Exercise Physiology, Universidad Europea de Madrid,
Madrid, Spain
Jeffrey M. Gimble Stem Cell Biology Laboratory, Pennington Biomedical
Research Center, Louisiana State University, Baton Rouge, LA, USA
Jennifer Kendrick Clinical Pharmacist–Pediatrics, Children’s and Women’s
Health Centre of British Columbia, Vancouver, BC, Canada
Fausto R. Loberiza Jr. Department of Internal Medicine,
University of Nebraska Medical Center, Omaha, NE, USA
Alejandro Lucia Exercise Physiology, Universidad Europea de Madrid,
Madrid, Spain
Steven D. Mittelman Center for Endocrinology, Diabetes & Metabolism,
Children’s Hospital Los Angeles, Los Angeles, CA, USA
Willis H. Navarro National Marrow Donor Program, Minneapolis, MN, USA
ix
x Contributors
Kevin C. Oeffinger Department of Pediatrics, Memorial Sloan-Kettering Cancer

Center, New York, NY, USA
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York,
NY, USA
Alpa V. Patel Epidemiology Research Program, American Cancer Society,
Atlanta, GA, USA
Luisa Soares-Miranda Research Center in Physical Activity, Health and Leisure,
University of Porto, Porto, Portugal
Lauren R. Teras Epidemiology Research Program, American Cancer Society,
Atlanta, GA, USA
Emily S. Tonorezos Department of Medicine, Memorial Sloan-Kettering Cancer
Center, New York, NY, USA
Dawn Warkentin Leukemia/Bone Marrow Transplantation, CSU Pharmaceutical
Sciences, Vancouver Coastal Health Authority, 12th and Oak Site, Vancouver, BC,
Canada
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver,
BC, Canada
Chapter 1
The Epidemiology of Obesity and Hematologic
Malignancies
Lauren R. Teras and Alpa V. Patel
Abstract Evidence from epidemiologic studies suggests that excess body fat may
influence risk for hematologic malignancies including multiple myeloma, Hodgkin
lymphoma, non-Hodgkin lymphoma (NHL), and leukemia. Mechanisms related to
adiposity and its effects on energy metabolism, immune function, and the endocrine
environment are thought to act in the pathways that give rise to these malignancies.
The research literature on this topic, however, is as yet insufficient for conclusion,
and much more data may be required before any association between excess weight
and this diverse group of cancers can be reliably established. Existing data to sup-
port such an association are compelling nonetheless and, given the extent and mag-
nitude of the obesity epidemic and its implications for human health, deserve an
exhaustive scientific evaluation. The aims of this chapter are to summarize the cur-
rent state of research on obesity and hematologic malignancies in adults and children,
and provide a focus for future study in this area.
1 The Epidemiology of Obesity
Obesity in the United States (US) is now universally recognized as epidemic.

According to the National Health and Nutrition Examination Survey (NHANES),
including the latest data from 2007 to 2008, the prevalence of overweight among
adults, defined as body mass index (BMI: weight (kg)/height (m)2) of ³25 kg/m2), is
currently estimated to be 68% [1]. This includes the 33.8% of those with BMI
L.R. Teras, Ph.D. (*) • A.V. Patel, Ph.D.

Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
e-mail: lauren.teras@cancer.org
S.D. Mittelman and N.A. Berger (eds.), Energy Balance and Hematologic Malignancies, 1
Energy Balance and Cancer, DOI 10.1007/978-1-4614-2403-1_1,
2 L.R. Teras and A.V. Patel
40
Adult Overweight
30
Percent
Adult Obese
20
Adolescent Overweight
10
Adolescent Obese
0
1960-62 1971-74 1976-80 1988-94 1999-00 2003-04 2007-08
2001-02 2005-06
Fig. 1.1 Prevalence of overweight and obesity in the US, NHANES 1976–2008
³30 kg/m2 (obese) and the 5.7% of the population whose BMI is ³40 kg/m2
(extremely obese), according to the current accepted system for classification of
adult weight status, which is summarized as follows:
BMI (kg/m2) BMI Class

<18.5 Underweight
18.5–24.9 Normal weight
25.0–29.9 Overweight
³30.0 Obese
³40.0 Extremely obese
Nearly one-third (31.7%) of the US children aged 6 through 19 years are considered
to be either overweight or obese according to the accepted clinical definitions for high
BMI as set forth by the Centers for Disease Control and Prevention (CDC) sex- and
age-specific growth charts for the US, which label obesity as BMI in the 95th and
higher percentiles and overweight as BMI in the 85th to <95th percentiles [2].
These numbers represent sharp increases in prevalence since the 1970s (Fig. 1.1).
Among adults aged 20 years and older, obesity prevalence changed little during the
1960s and 1970s. From that time, however, and continuing up to 1999–2000, rates
more than doubled, from 15.1 to 31% [3–5]. Over the past decade, rates among US
women remained relatively stable, from 33.4 in 1999–2000 to 35.5% in 2007–2008;
among men during this period, however, obesity increased from 27.5 to 32.2% [1].
In addition, the portion of adults classified as extremely obese has increased over the
past 25 years, from 1.4% in 1976–1980 to 5.7% in 2007–2008 [1]. Similar patterns of
1 The Epidemiology of Obesity and Hematologic Malignancies 3
increase have been observed among children and adolescent girls and boys.
Between 1976–1980 and 1999–2000, prevalence of obesity among adolescents aged
12–19 years tripled from 5 to 15.5%, with rates stabilizing thereafter, except among
boys aged 6–19 in the heaviest (97th) percentiles, where rates continued to rise [2].
The increases in obesity among adolescents and adults have occurred across race,
ethnicity, and gender, with the highest rates now observed in non-Hispanic Black
Americans, followed by Mexican Americans, followed by non-Hispanic Whites [1, 2].
The problem of obesity is not confined to the US. Parallel trends of increasing
prevalence have been observed in Canada, Europe, Australia, China, and many
other developing and low-income countries [6–16]. Worldwide obesity has more
than doubled since 1980 [17]. In the developing world, where overweight and obe-
sity are a more recent phenomenon, increases in prevalence are occurring much
more rapidly than the rate of increase observed in the US [18, 19]. Along with the
rising prevalence in these countries, is a concomitant change in the population dis-
tribution of obesity along socioeconomic lines; whereas the obesity epidemic began
as a phenomenon of higher income people, the burden has shifted, and is now greater
among lower and middle income groups. For example, over a 10-year period in
Brazil, the highest prevalence of obesity shifted from the highest to the lowest
socioeconomic group [20]. These dynamics have resulted in a seemingly paradoxi-
cal situation where overweight adults and malnourished children are found together
within the same population strata or community and, in some instances, the same
household, presenting a “dual burden” of disease [17, 21, 22].
By the year 2000, for the first time in human history, the number of adults
worldwide who were overweight or obese exceeded the number of those who were
underweight [23]. As of 2008, the World Health Organization (WHO) estimated
that 1.5 billion adults (aged 20 years and older) were overweight; of these, over 200
million men and nearly 300 million women were obese [17]. In 2010, approximately
43 million children under the age of 5 were overweight, as defined by a weight-
for-height >2 SD over the WHO median [8].
The implications of these trends for human health are far-reaching. Obesity is a
major contributor to premature mortality in the US and globally, and a major risk
factor for type 2 diabetes, heart disease, hypertension, and stroke [24, 25]. Excess
weight also contributes to many other chronic conditions including gallbladder
disease, osteoarthritis, reproductive abnormalities, sleep apnea and respiratory
problems, and depression [26]. It is an established risk factor for cancers of the
breast (postmenopausal), colon, endometrium, esophagus (adenocarcinoma), pan-
creas, and kidney (renal) [27, 28], and observational evidence suggests that excess
adiposity may also increase risk for cancers of the gallbladder, liver, thyroid, ova-
ries, as well as multiple myeloma, leukemia, Hodgkin and NHL [28, 29]. Some of
these are cancer sites for which no screening and few early detection tools exist,
underscoring the need to better understand the role of potentially modifiable risk
factors such as body weight in their etiology.
Scientific research into the determinants of obesity, along with its associated
health outcomes, increasingly supports a life-cycle perspective, which recognizes the
importance of the nutritional and physical environments beginning in the prenatal
period, continuing from infancy through every stage of development and into old
age [30–32]. Childhood and particularly adolescent BMI status tends to persist into
adulthood, and is not amenable to treatment once established [33–35]. Therefore,
understanding the factors that influence adiposity in the early stages is essential to
identify those in the population who are at the greatest risk of overweight and obe-
sity-related illnesses later in life.
Etiologic factors which give rise to obesity are numerous and complex. Clearly, a
positive energy balance over time is the key determinant of excess weight gain at any
age. But while overeating and lack of physical activity are the primary causes of a
positive energy balance, their biologic, environmental, and cultural antecedents are
rather ambiguous. There is consistent epidemiologic evidence, for example, that
parental, particularly maternal, obesity is strongly associated with childhood over-
weight, perhaps reflecting a genetic predisposition [36, 37]. Yet, while heredity may
contribute a portion of an individual’s overall risk, the greater impact comes from
shared environmental conditions and lifestyle habits that may be adverse to good health
[38]. Parental socioeconomic, educational, and marital status are also associated with
obesity in childhood [39–41], likely because these demographic characteristics tend to
drive the day to day dietary choices and habits that influence the growth and develop-
ment of children, including the quality and timing of meals and snacks, proximity to
and availability of healthy food options, sleep duration, and time spent in sedentary
activities such as video-gaming, computer use, and watching television. Television
viewing habits have emerged as important determinants of weight status in children
[42, 43] and adults [44–47], not only because they are indicators of physical activity
level and sedentary behaviors but perhaps also due in part to cultural aspects of TV
programming, advertising, and snacking patterns related to TV viewing [41, 48, 49].
Birth weight, an indicator of the gestational nutritional environment, is associated
with BMI in childhood, adolescence, and adulthood. Consistently higher risk of
overweight and obesity at various points in life have been observed among those
with higher than normal birth weight (>4,000 g) [50]. The effect of low birth weight
(<2,500 g) is unclear, but has been associated with increased risk of later abdominal,
as opposed to general, obesity [51]. Epidemiologic, clinical, and experimental
evidence support the hypothesis that physiologic and metabolic changes that occur
in response to a poor nutritional environment in utero may predispose a person to
central adiposity, glucose intolerance, type II diabetes, and cardiovascular disease
[52]. These relationships have potential etiologic implications for cancers that may
develop through insulin pathways, such as colon, pancreatic, liver, and breast. It is
important to note that the observed associations between birth weight and obesity
are likely modified by genetic and maternal characteristics and postnatal growth
trajectories. Babies, especially those born small for gestational age, who experience
rapid or “catch-up” growth in infancy or early childhood, may be at increased risk
for excessive weight gain and subsequent obesity [53, 54].
A feature of modern society that contributes substantially to overweight and obesity
in the population is the “built” environment, where urban planning that promotes
automobile use and restricts opportunities for walking and/or outdoor recreational
physical activities, has led to a substantial reduction in manual activity and energy
expenditure associated with basic survival activities of past generations [21, 55].
Moreover, the wide availability, affordability and convenience of energy-dense
“fast” food further contribute to the problem as part of an increasingly “obesogenic”
environment [56].
The importance of a comprehensive and coherent approach to health research,
policy, and education, with a focus on nutrition across the lifespan, cannot be over-
stated. Public health efforts are underway at the community, national, and international
levels, and there are data to suggest that rates of overweight and obesity may be
stabilizing in some countries and among some demographic groups in the US [1, 2,
57–60]. Notwithstanding, the general trend of rising obesity around the world
continues. Our ability to prevent and treat obesity-associated diseases in the vast
numbers of individuals affected will depend upon a clear understanding of the
effects of excess weight and adiposity on the initiation and progression of disease in
the human body.
2 Anthropometric Measures and Adult Non-Hodgkin

Lymphoma
Adult NHL is a complex disease composed of several histologic subtypes, and over
time, the classification of NHL has been variable. In 2007 [61], the InterLymph
Consortium Pathology Working Group described and categorized NHL histologic
subtypes based on the International Classification of Disease for Oncology, Second
and Third Editions (ICD-O-2 and -3) to provide a more standard definition that has
since been used in epidemiologic studies. The most common histologic subtypes in
adults include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL),
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and
plasma cell multiple myeloma (multiple myeloma). For the purpose of this text,
multiple myeloma will be discussed separately. The etiology of NHL is thought to
differ by histologic subtype, but factors related to immune function or inflammation
have been hypothesized to be important risk factors across all subtypes of the disease.
Anthropometric measures, most notably height and weight, may be associated
with NHL risk through various biologic pathways. Obesity is associated with a
chronic proinflammatory state, hyperinsulinemia, and the bioavailability of steroid
hormones, all of which have been shown to stimulate cell proliferation and inhibit
apoptosis [62]. Both early-life BMI and taller stature also may represent nutritional
status in childhood and a greater availability of food [63, 64], resulting in increased
exposure to growth hormones, such as insulin-like growth factor-1 (IGF-1). IGF-1
is a major regulator of childhood growth [65], and has been shown to stimulate
B-cell proliferation [66] and inhibit apoptosis [67]. Furthermore, because height is
influenced by both genetic and environmental factors, it may represent additional
exposures that could affect the development of NHL. For example, frequent infections
during childhood have been associated with shorter stature as well as with stronger
immune function into adulthood [68], and stronger immune function is hypothesized
ADULT BMI AND LYMPHOMA-NHL
Women Overweight
Zhang, 1999
Zhang, 1999
Cerhan, 2002
Cerhan, 2002 Obese
Calle, 2003
Calle, 2003
Skibola, 2004
Skibola, 2004
Pan, 2004
Pan, 2004
Rapp, 2005
Rapp, 2005
Lukanova, 2006
Lukanova, 2006
Engeland, 2006
Engeland, 2006
Chiu, 2006
Chiu, 2006
Reeves, 2007
Reeves, 2007
Fernberg, 2007
Fernberg, 2007
Maskarinec, 2008
Study (First Author, Year)
Maskarinec, 2008
Lu, 2009
Lu, 2009
Men Calle, 2003
Calle, 2003
Skibola, 2004
Skibola, 2004
Pan, 2004
Pan, 2004
Rapp, 2005
Rapp, 2005
Oh, 2006
Oh, 2006
Samanic, 2006
Samanic, 2006
Lukanova, 2006
Lukanova, 2006
Engeland, 2006
Engeland, 2006
Chiu, 2006
Chiu, 2006
Fernberg, 2007
Fernberg, 2007
Maskarinec, 2008
Maskarinec, 2008
Combined Willett, 2005
Willett, 2005
Chang, 2005
Chang, 2005
Cerhan, 2005
Cerhan, 2005
Bosetti, 2005
Bosetti, 2005
Chiu, 2007
Chiu, 2007
Morton, 2008
Morton, 2008
Troy, 2010
Troy, 2010
Geyer, 2010
Geyer, 2010
Pooled, Total Overweight
Pooled, Total Obese
0.1 1.0 10
Relative Risk
Fig. 1.2 Previous epidemiologic studies of recent or late adult BMI and NHL
to lower NHL risk. As a result, it is plausible that obesity at various points throughout
life and height may play a causal role in lymphomagenesis, although the critical
time period of exposure is unclear.
2.1 Recent Adulthood Body Mass Index
The most extensively studied anthropometric factor in relation to NHL risk is recent
or adult BMI. To date, more than 25 observational epidemiologic studies, prospective
cohort and case–control [45, 69–100], have examined BMI at study entry or 1–5
years prior to diagnosis, respectively (Fig. 1.2). The largest prospective studies of
NHL incidence to date include the NIH-AARP Diet and Health Study with 1,381
cases, the Prostate, Lung, Colon, and Ovary Trial (PLCO) with 1,264 cases [84],
and the European Prospective Investigation of Cancer (EPIC) cohort with 1,219
NHL cases [69]. The NIH-AARP Study and PLCO both reported approximately
30% higher risk of NHL among obese individuals compared to normal weight. In
contrast, EPIC found no statistically significant association between BMI and NHL
risk overall. Additionally, the large American Cancer Society Cancer Prevention
Study-II, a prospective study of mortality that included approximately 2,400 incident
Fig. 1.3 Previous epidemiologic studies of recent or late adult BMI and DLBCL
NHL deaths, reported a 55% increased risk of NHL mortality among obese men
and 40% increased risk among obese women compared to normal weight men and
women, respectively [45]. Among the case–control studies, the largest study to date
is actually the international pooling effort called InterLymph which includes
approximately 10,000 NHL cases and 16,000 controls from 18 case–control studies
[95]. This study examined BMI in general within 5 years prior to diagnosis, but
found no associations with NHL overall.
Individual study results have been somewhat inconsistent as indicated by the
Q-test showing heterogeneity between studies (p < 0.0001), and the random effects
summary risk estimate across all epidemiologic studies to date suggests a 6% statis-
tically significant higher NHL risk among overweight men and women compared to
normal weight (Fig. 1.2). Furthermore, obese men and women were 1.19-fold more
likely (95% CI 1.11–1.27) to develop NHL compared to normal weight men and
women. Fewer studies further examined the association between recent adult BMI
and NHL risk among specific histologic subtypes (Figs. 1.3–1.5). Among these
studies, the majority reported that the association between recent BMI and NHL
was strongest for the DLBCL subtype compared to the other major subtypes examined,
with a fixed effect summary risk estimate indicating that obese men and women
have approximately 30% statistically significant higher risk of DLBCL compared to
Fig. 1.4 Previous epidemiologic studies of recent or late adult BMI and CLL/SLL
normal weight men and women (Fig. 1.3). However, summary results in relation to
overweight or obesity indicate a modest 15% higher risk of CLL/SLL (Fig. 1.4) and
a nonstatistically significant approximate 10% higher risk of FL (Fig. 1.5) among
obese men and women, suggesting that recent adult BMI may be more important in
the etiology of DLBCL compared to other subtypes. Since the results of recent BMI
have not been consistent in relation to NHL overall and have been relatively sparse
but suggestive of differences when examining specific NHL subtypes, interest in
exploring other anthropometric risk factors in relation to adult NHL has ensued.
Furthermore, the latency period for NHL is not well established, thus many studies
have explored earlier life anthropometric exposures in relation to NHL risk.
2.2 Early Adulthood Body Mass Index and Height
Both early-life BMI and taller stature may represent genetic or environmental
factors that can affect NHL risk, but fewer studies have examined these factors
compared to later life or recent adult BMI. Results have more consistently shown a
positive association between early adult BMI, at age 18 or age 20 years, compared
Fig. 1.5 Previous epidemiologic studies of recent or late adult BMI and FL
to later adulthood BMI in relation to NHL risk. In fact, of the studies that have
examined early life BMI [70, 75, 78, 80, 84, 89], only one [70] did not observe a
positive association with BMI at age 18 or 20 years. The largest prospective study
to date reported a statistically significant positive dose–response relationship
(trend p = <0.001) for BMI at age 20 years [84]; however, not all individual relative
risk estimates reached statistical significance. Results of other studies have been of
similar magnitude. Even fewer of these studies examined associations by major
histologic subtypes with varying results [75, 78, 80, 84, 89]. However, there appears
to be a modest suggestion that associations with early adulthood BMI may be
slightly stronger for CLL/SLL and possibly FL, and less strongly associated with
DLBCL, but results are too sparse and varied to draw clear conclusions.
Additional support for an association between earlier life anthropometric factors
in relation to NHL risk comes from the consistent positive associations observed
between taller stature and NHL risk. Similar to early adulthood BMI, height is
thought to be influenced by early life nutritional factors, growth hormones, or chronic
infections, where children with a greater number of infections can also have shorter
stature. A small number of previous studies have examined height in relation to NHL
risk, and this includes all of the studies that also examined early adulthood BMI
[69, 70, 74, 75, 78, 80, 84, 87, 88, 90]. Consistent with results for early adulthood
BMI, only one study reported no association with height in relation to NHL risk
overall [70], and all others support a positive association between increasing height
and NHL risk. Studies that examined associations among major histologic subtypes
suggest that associations may be stronger for FL and CLL/SLL compared to other
histologic subtypes [69, 74, 75, 78, 80, 84, 87, 88, 90]. Given the slightly stronger
associations among FL and CLL/SLL subtypes compared to DLBCL with height
and possibly earlier adulthood BMI, it is possible that earlier life exposures may be
more relevant for those subtypes, and the relevant time period for exposure may dif-
fer by subtypes of disease. However, there remains a limited number of studies
examining associations by histologic subtypes to draw any definitive conclusions.
2.3 Summary and Future Directions
It is plausible that obesity at various points throughout life and height may play a
causal role in lymphomagenesis, although the critical time period of exposure is
unclear. Recent or late adulthood obesity is associated with a modest increased risk
of NHL overall, and may be more strongly associated with the DLBCL subtype.
Early adulthood BMI (at age 18 or 20 years) and height have been more consistently
associated with NHL risk overall compared to later adulthood measures, and asso-
ciations may vary by subtype. Few studies have examined other measures of body
size such as change in weight or BMI, waist circumference, or waist-to-hip ratio in
relation to NHL risk [69, 75, 87, 89, 90], and none of these studies reported consis-
tent associations with any of these measures and NHL risk, overall or within any
histologic subtype.
In addition to better understanding the relevant time frame of exposure, there is
a need to clarify the relationship between these various anthropometric measures by
histologic subtypes of disease. Given the continued rise in the prevalence of obesity
in the United States and worldwide, clarifying these relationships are of etiologic
interest and may have potentially substantial public health impact.
3 BMI and Hodgkin Lymphoma
Relatively little research has been done on obesity and Hodgkin lymphoma. This is
likely due to the rarity of this cancer (2.8 cases per 100,000 men and women) [101].
The studies that have examined this relationship have generally done so with rela-
tively small sample sizes [72–74, 79, 83, 86, 88, 98, 102–105]. Only one study had
more than 1,000 Hodgkin lymphoma cases [72]. An association between obesity
and Hodgkin lymphoma is biologically plausible because body size has been shown
to influence immune function [106] and altered immune function is thought to be
critical to Hodgkin lymphoma etiology. Interleukin-6 (IL-6) may be one of the
important players as associations of both IL-6 single nucleotide polymorphisms and

serum levels with Hodgkin lymphoma have been observed [107]. The precise mech-
anisms, however, are not known.
Epidemiologic studies on obesity and Hodgkin lymphoma have yielded inconsis-
tent results. A population-based case–control study from England observed a two-
fold higher risk of Hodgkin lymphoma for obese men compared to men with a BMI
in the normal range [103]. Two other studies have reported a positive association
between obesity and risk of Hodgkin lymphoma [104, 105] in men but the sample
sizes in both studies were extremely limited. Wolk et al. [104] observed a standard-
ized incidence ratio (SIR) of 3.3 (95% CI: 1.4–6.5) in a study that included 8 men
diagnosed with Hodgkin lymphoma, and Paffenbarger et al. [105] reported that
among 45 college students, obese students were almost twice as likely than nonobese
classmates to develop Hodgkin lymphoma. Several other studies, however, did not
detect an association between BMI and Hodgkin lymphoma [73, 74, 79, 86, 88] in
men. Two studies to date have observed an association between body weight and
Hodgkin lymphoma in women [72, 102]. The largest study to date [72] found a 47%
higher risk among women with BMI 30.0–34.9 kg/m2 and a greater than 2.5-fold
higher risk among women with BMI ³40.0 kg/m2 compared to normal weight women.
Keegan et al. observed a statistically significant 74% higher risk of Hodgkin lym-
phoma when comparing women in the fourth (BMI ³ 24.5 kg/m2) to the first quartile
(BMI < 19.9 kg/m2) of BMI, but only among younger women (aged 19–44 years)
[102]. This study also found an association between high birth weight (>3.63 kg) and
risk of Hodgkin lymphoma in the younger women only. On the other hand, the
authors observed an association between Hodgkin lymphoma and adult height
(thought to reflect genetic and environmental growth factors as well as early life
nutritional status) in all women in the study, though it was only statistically signifi-
cant in the younger women. Likewise, Engeland et.al. found a positive association
with height in both women and men [72]. An additional study found an association
[108] between height and Hodgkin lymphoma in men, but a third did not [103].
Based on the epidemiologic literature to date, it is unclear if there is a relation-
ship between obesity and Hodgkin lymphoma. The few studies that have observed
an association have reported relatively large magnitudes of effect (two- and three-
fold higher risk among the obese relative to normal weight); however, sample size
was extremely limited in these studies and the role of chance cannot be ruled out.
The discrepant findings between men and women may reflect a true sex difference
but it may also be due to limited power in existing studies given that Hodgkin lym-
phoma is even less common among women [101]. Evidence against a prominent
role for obesity in Hodgkin lymphoma etiology includes the fact that while rates of
obesity have been greatly increasing over time, rates of Hodgkin lymphoma have
not been increasing and, in fact, appear to have been slightly decreasing since 1975.
Given the limited number of epidemiologic studies to date, potential heterogeneity
by sex, and the possibility of variation in associations by age of diagnosis or subtypes,
additional studies are needed to address these issues.
4 BMI and Adult Leukemia
Leukemias are a group of cancers that are characterized by increased numbers of

leukocytes. Historically, leukemias were defined as malignancies originating in the
blood and classified by type of leukocyte affected (myeloid or lymphoid) and
characteristics of the cancer (chronic or acute). The four resulting subtypes were as
follows: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (also known
as acute myelogenous leukemia; AML), chronic lymphoid leukemia (also known as
chronic lymphocytic leukemia; CLL), and chronic myeloid leukemia (also known
as chronic myelogenous leukemia; CML). However a widely accepted new classifi-
cation scheme created by the World Health Organization in 2001 [109] puts greater
emphasis on cell lineage to define types of hematologic malignancies. As a result,
CLL and SLL are now thought to be the same disease entity and CLL is considered
a type of NHL. Therefore, CLL is discussed with NHL (Sect. 2) of this text.
There are few well-established risk factors for leukemia. High levels of radiation
[110] and chemicals such as benzene [111] have been linked to some types of leu-
kemia, but these risk factors are thought to account only for a small fraction of all
leukemia cases. A role for BMI in the etiology of leukemia is plausible through
similar biologic mechanisms as NHL. Elevated levels of serum IGF-1 are thought to
increase cell proliferation and inhibit apoptosis as well as increase propagation of
bone marrow progenitor cells. In addition, IGF-1 receptors have been detected in
explanted leukemic cells [112]. Chronic inflammation and impaired immune func-
tion caused by high levels of adiposity may also link obesity to leukemia [113].
Most [45, 72, 82, 89, 91, 100, 114–116] but not all [79, 83, 97, 98, 104, 117]
studies that have examined overweight and obesity in relation to overall leukemia
have found a positive association. In a prospective mortality study of over 900,000
adults, Calle et al. [45] found a positive dose–response relationship between BMI
and leukemia mortality rates in men only. The rate ratio comparing men with a BMI
of 35+ kg/m2 to men with a BMI 18.5–24.9 kg/m2 was 1.70 (95% CI: 1.08–2.66).
However, there was no association observed among women. In the Chicago Heart
cohort of approximately 40,000 adults, Chiu et al. [89] observed higher mortality
rates for both men and women with higher compared to lower BMI levels. Incidence
studies of BMI and leukemia have also generally observed a positive dose–response
relationship between BMI and leukemia risk for both men and women. Pooled esti-
mates show a statistically significant 12% higher risk for overweight adults and a
39% higher risk for obese adults compared to normal/underweight adults. It should
be noted, however, that the p-values for the Q-test of heterogeneity suggest some
heterogeneity among the findings. Studies that stratified analyses by sex observed
similar point estimates for men and women for overweight and a slightly stronger
association for men than women for obesity (Fig. 1.6).
Ten studies [72, 77, 83, 98, 114–116, 118–120] examined the association between
BMI and subtypes of leukemia and results were inconsistent. Two population-based
case–control studies observed a strong association between obesity and CML
(Fig. 1.7) and a weaker association with overweight [115, 118]. Results from
cohort studies, however, were collectively inconclusive. In a cohort of 40,000
Australian adults, MacInnis et al. reported a fivefold increased risk of a myeloid
Fig. 1.6 Previous epidemiologic studies of BMI and overall adult leukemia
Fig. 1.7 Previous epidemiologic studies of BMI and adult CML

Fig. 1.8 Previous epidemiologic studies of BMI and adult AML
leukemia for overweight and obese adults [77]. Though sample size was limited, the
authors report an even stronger effect for CML specifically. A Norwegian cohort
study observed a positive association between obesity, but not overweight, and CML
in men and the opposite for women (a positive association between CML and over-
weight but not obesity) [72]. Two other cohort studies found no association between
obesity and CML [116, 119].
Four [72, 114–116] of eight [72, 83, 98, 114–116, 119–120] studies that examined
BMI and AML observed a positive association (Fig. 1.8). In a cohort of US women
in Iowa, Ross et al. found a statistically significant approximately twofold increased
risk of AML for overweight and an almost 2.5-fold increased risk for obesity and
AML [114]. A cohort study of US veterans found a similar magnitude of association
between hospital-diagnosed obesity and AML risk in black men (RR = 2.64, 95% CI:
1.80–3.85) and a statistically significant but weaker association in white men
(RR = 1.59, 95% CI: 1.33–1.90) [116]. One [72] of three [72, 116, 119] studies that
examined BMI and ALL observed a statistically significant association (among men
only) with authors reporting a positive dose–response relationship (Fig. 1.9).
There is some evidence that overweight and obesity increase risk of adult leukemia
but the literature on this topic is relatively sparse. In addition, previous studies
have some limitations that may impact the interpretation of the results. Case–control
studies are at risk of recall bias and in all studies measured or reported BMI may, at
Fig. 1.9 Previous epidemiologic studies of BMI and adult ALL
least in part, reflect undiagnosed disease when BMI was ascertained close to the
time of diagnosis. More research is needed in large prospective studies, particularly
those that can separate out leukemia subtypes, to fully understand the relationship
between BMI and adult leukemia.
5 Birth Weight and Childhood Lymphoma
Few studies have examined birth weight and childhood lymphoma. A recent meta-
analysis including nine published studies (seven case–control and two cohort) found
no association between high or low birth weight and any type of lymphoma [121].
The pooled random effects estimate for the six studies that examined high birth
weight (4+ kg) compared to all other infants (i.e., <4 kg) and risk of NHL was 1.18
(95% CI: 0.84–1.67). The pooled effect estimate for the same birth weight compari-
son and Hodgkin lymphoma was 0.92 (95% CI: 0.66–1.24). Studies that presented
estimates for high vs. normal (2.5 to <4 kg) birth weight reported similar null results
for both NHL and Hodgkin lymphoma. Low (<2.5 kg) birth weight and NHL was
examined in five of the nine studies [121]. The summary odds ratio for risk of NHL
and low compared to normal birth weight was 1.07 (95% CI: 0.71–1.62). Only three
studies have published odds ratios on low compared to normal birth weight and
Hodgkin lymphoma, and the summary estimate was also null: 0.94 (0.54–1.65).
The limited number of studies that have examined this association do not support an
association between birth weight and childhood lymphoma.
6 Birth Weight and Childhood Leukemia
At least 40 studies have examined birth weight in relation to risk of overall leukemia,
ALL, or AML, and pooled estimates for all three show statistically significant
increased risks of leukemia with “high” (usually defined as 4 kg) relative to “normal”
(definitions range from <2.5 to <4 kg) birth weight. Fewer studies have examined
“low” (usually defined as <2,500 g) birth weight and leukemia, and thus far an asso-
ciation is suggested for AML but neither ALL nor overall leukemia risk. Likely
birth weight per se is not causally linked to leukemia but instead factors that deter-
mine or are associated with both birth weight and leukemia risk likely explain this
association. This section reviews the published literature to date on birth weight and
childhood leukemia and discusses some of the methodological issues and biological
explanations of this association.
6.1 Overall Leukemia
Despite different birth weight cutpoints, studies have been extremely consistent in
showing an association between risk of childhood leukemia (all types combined)
and high birth weight (Fig. 1.10). Nineteen studies have been published on this topic
and the Q-test indicated little heterogeneity between the studies (p = 0.19). The fixed
effects summary estimate from these 19 studies [122–140] was 1.39 (95% confi-
dence interval (CI): 1.28–1.50). The strongest associations were observed for very
young children. Birth weight was associated with a 56% (95% CI: 1.34–1.84) higher
risk of overall leukemia in studies of children ages 5 years or younger.
Although most studies did not report birth weight measured as a continuous
variable, a recent meta-analysis [141] estimated the dose response from studies with
either continuous or three or more categories of birth weight information. The meta-
analysis reported an 18% (95% CI: 1.13–1.20) higher risk of overall leukemia per
kilogram of birth weight. This linear increase in risk of overall leukemia for high
birth weight was not found for low birth weight. In fact, the authors reported a lack
of evidence of any association between low birth weight and overall leukemia.
6.2 Acute Lymphoblastic Leukemia
ALL is the most common type of childhood leukemia and accounts for almost a
third of all childhood cancers. At least 30 studies have examined the association
Fig. 1.10 Previous epidemiologic studies of high birth weight and childhood leukemia
between birth weight and ALL and, almost all have detected a higher risk for babies
born at least 4 kg compared to smaller babies (the definition of the reference cate-
gory has varied among studies) (Fig. 1.11). Not surprisingly, the summary estimate
for ALL (31% higher risk for high birth weight) is similar to that of overall leuke-
mia, since ALL is by far the most common childhood leukemia subtype. A recent
study using the National Registry of Childhood Tumors in Europe to study risk of
childhood leukemia reported a statistically significant eight percent increase in risk
of lymphoid leukemia (most of which are ALL) per half kilogram of birth weight,
which is consistent with the 18% per kg increased risk reported from the meta-
analysis above [142].
Several recent studies [140, 143–145] of birth weight and ALL have calculated
weight-for-gestational-age measures in an effort to determine if accelerated intra-
uterine growth is actually the more relevant exposure for leukemia. Using these
measures, babies that are small because they are born early but large for their gesta-
tional age are classified as heavy babies. Johnson et al. [143] conducted a case–
cohort study in Minnesota and found an 80% higher risk of ALL for the highest
category of birth weight (>4,309 g) compared to small babies (<2,496 g), but only a
30% higher risk of ALL for large-for-gestational-age (LGA) babies compared to
appropriate-for-gestational age (AGA) babies. However, a case–control study using
Fig. 1.11 Previous epidemiologic studies of high birth weight and childhood ALL
birth certificate data in Texas found a similar, slightly stronger association between
LGA and ALL (OR = 1.66) as between high birth weight and ALL (OR = 1.50)
[140]. Finally, in two studies conducted by Milne et al. in Western Australia: a
registry-based cohort study [144] and a population-based case–control study [145],
the authors observed a 25% and 18% higher risk of ALL per one standard deviation
increase in proportion of optimal birth weight (a ratio of reported birth weight and
calculated optimal birth weight, respectively). The optimal birth weight calculation
was done using a regression equation including terms for gestational age, maternal
height, parity, and infant sex. The source population for this calculation was a cohort
of singleton births without any recorded risk factors for intrauterine growth restriction.
Though the authors report that model fit statistics suggest these corrected gesta-
tional-age measures are more appropriate than birth weight alone, the magnitude of
effect does not appear to be greatly different using these calculated measures.
6.3 Acute Myeloid Leukemia
Although AML is the second most common type of childhood leukemia, it is

considerably less common than ALL [101]. As a result, individual studies of birth
Fig. 1.12 Previous epidemiologic studies of high birth weight and childhood AML
weight and AML have had very limited sample sizes, making the interpretation of
results from any one study difficult (Fig. 1.12). Many of the confidence intervals
were relatively wide and some included the null value; however, the majority of
studies observed a higher risk of AML for children born heavy compared to lighter
babies, and the random effects pooled estimate was 1.42 (95% CI: 1.12–1.79).
However, it should be noted that the random (rather than fixed) effects model was
used because the Q-test indicated heterogeneity among the study results (p = 0.016).
Unlike overall leukemia and the ALL subtype, the Caughey et al. [141] meta-
analysis of nine studies comparing risk of AML for low birth weight (usually
defined as 2.5 kg) babies to AML risk in normal birth weight babies reported a
statistically significant summary estimate (1.50, 95% CI: 1.05–2.13) but similarly
the Q-test of heterogeneity for this result was of borderline significance (p = 0.05).
In studies that examined birth weight corrected for gestational age, these mea-
sures were not shown to be more predictive for AML than raw birth weight data.
However, as mentioned previously, sample size in all these studies was extremely
limited and the results should be interpreted with caution.
7 Other Considerations in Childhood Hematologic

Malignancies
7.1 Methodological Considerations
Methodological differences may explain some of the inconsistency in measured

magnitude of effect and, in some cases, conflicting findings. Some studies used
leukemia mortality rather than incidence as the endpoint, and sources of birth weight
information varied (e.g., birth certificate, birth registry, interview) among the studies.
There were also different cutpoints used to define high, normal, and low birth
weight, and some used a dichotomous variable while others attempted to define a
specific comparison group. In addition, odds ratios for three studies were not
provided by the authors and were, therefore, calculated by Caughey et al. [141] in a
previous meta-analysis using the data provided by the original studies. Finally,
covariate sets differed from study to study. Although the point estimates did not
appear greatly changed, studies that used birth weight corrected for gestational age
information reported model fit statistics that suggested weight for gestational age
was a better measure than birth weight. Several maternal characteristics (e.g., BMI,
pregnancy weight gain, diabetes, smoking or drug use, mother’s birth weight)
adjusted for by some but not other studies may be important. The impact of these
and other potential confounders is unknown. Perhaps the most important method-
ological limitation, particularly for AML, was small sample size.
7.2 Biologic Mechanisms
Several explanations have been postulated for the observed association between
high birth weight and leukemia. One current hypothesis is that circulating IGF-1 is
playing an important role in this relationship. IGF-1 plays a role in normal
hematopoiesis formation (e.g., regulation of normal B-lymphocytes) and can stimu-
late both myeloid and lymphoid leukemia cells in vitro [146]. Circulating IGF-1
levels have also been positively correlated with birth weight [146], and it has been
hypothesized that the higher levels of IGF-1 that accompany higher birth weights
may be causing increased proliferation of cells that are already predisposed to leu-
kemia. In other words, cells that already have one or more “hit” (genetic or other
change), are rapidly dividing and subject to the copying of additional somatic muta-
tions that may ultimately lead to leukemia. There is also evidence that IGF-1 may
be involved in reduction of apoptosis. Alternatively, a reverse causation hypothesis
has been proposed: preleukemic cells secrete IGF-1 which causes higher birth
weight. The additional production of IGF-1 produced by an autocrine loop coupled
with endogenous IGF-1 may increase birth weight and stimulate the preleukemic
cells. However, the evidence for this hypothesis is more limited [146] and a 2004
analysis [147] conducted in a Nordic population found that families of children with
leukemia (not just the child with leukemia him/herself) tended to have higher birth
weights than families with no child diagnosed with leukemia making this reverse
causality hypothesis seem less likely.
Other growth factors and hormones may play a role as well. The IGF-II gene is
involved in controlling the supply of maternal nutrients to the fetus [148], and the
loss of normal genomic imprinting of IGF-II has been implicated in leukemogene-
sis. Some support for a possible U-shaped relationship between birth weight and
childhood leukemia comes from Lei et al. [149] who found that extreme (both high
and low) levels of thyroid stimulating hormone (involved in normal growth and dif-
ferentiation and previously found to be inversely correlated with birth weight) have
been associated with a decreased risk of childhood leukemia. Further support for a
possible role for growth factors in the pathogenesis of childhood leukemia comes
from two studies that found an association between height and ALL [150, 151].
There is also some evidence that bone marrow volume is associated with birth
weight [152]. Therefore, another possible explanation for the association between birth
weight and childhood leukemia is that infants born with a heavier birth weight merely
have more cells at risk for malignant transformation [153]. Similar hypotheses have
been presented for several malignancies including brain tumors in children [154].
7.3 Maternal Weight
Maternal characteristics have also been studied in relation to childhood hematopoi-

etic cancers. Two studies examined maternal pregnancy weight gain and risk of
offspring ALL and AML, and they reported conflicting results. One observed an
association with AML [143] while the other observed an association with ALL
[155]. Although McLaughlin et al. did not find an association between AML and
pregnancy weight gain, they did find a higher risk of AML (and ALL) in offspring
of women who were heavier before getting pregnant than of leaner women. Though
the sample size was limited for stratified analyses of AML risk, the authors found
that the higher risk of ALL for children with high birth weights was only observed
in mothers who were leaner before pregnancy. Given the limited but suggestive
associations with maternal weight, more research on this topic is needed to better
understand this relationship.
7.4 Conclusions and Future Directions
In summary, the research conducted to date supports a 30–40% higher risk of

childhood leukemia for babies born 4 kg or heavier compared to lighter babies.
The relationship between low birth weight and leukemia is less clear. Large (for
efficiency of time and resources, likely consortial) studies will be required to con-
firm these findings and determine if there is a dose–response relationship. Future
considerations include understanding the biology of the association between birth
Table 1.1 Summary of associations between anthropometric measures and hematologic

malignancies
Likelihood
Malignancy Anthropometric measure assessed of association a
Adult
NHL Recent adulthood BMI Likely
Early adulthood BMI Probable
Height Likely
DLBCL Recent adulthood BMI Likely
Early adulthood BMI Possible
Height Possible
CLL/SLL Recent adulthood BMI Probable
Height Possible
FL Recent adulthood BMI Possible
Height Possible
Hodgkin lymphoma Recent adulthood BMI Possible
Leukemia overall Recent adulthood BMI Likely
CML Recent adulthood BMI Probable
AML Recent adulthood BMI Probable
ALL Recent adulthood BMI Probable
Childhood
Leukemia overall Birth weight Likely
Maternal weight Possible
ALL Birth weight Likely
AML Birth weight Probable
NHL Birth weight Unlikely
Hodgkin Birth weight Unlikely
a
Categories for likelihood of association based on the following criteria:
Likely: More than ten observational studies have examined the association with indi-
vidual study results consistently suggestive of an association
Probable: Six to ten studies have examined the association with individual study results
consistently suggestive of an association, or more than ten studies have examined the
association with individual study results suggestive of an association, but inconsistent
Possible: Five or fewer studies have examined the association with individual study results
consistently suggestive of an association, or six to ten studies have examined the asso-
ciation with individual study results suggestive of an association, but inconsistent
Unlikely: No consistent association observed
(and maternal) weight and childhood leukemia. If birth weight itself is not causal,
then understanding the related factors that are responsible for the association is
needed. In addition, a better understanding of the biology behind this association
could help explain why it has been consistently observed for childhood leukemia
but not lymphoma.
8 Summary of Obesity and Hematologic Malignancies
Numerous studies have examined anthropometric measures in relation to adult and

childhood hematologic malignancies with several measures suggestive of associations.
The strength of association varied by the anthropometric measures studied, and type
and subtypes of hematologic malignancies. The likelihood of an association was
assessed and reported in Table 1.1 based on the following criteria (1) Likely: more
than ten observational studies have examined the association with individual study
results consistently suggestive of an association; (2) Probable: six to ten studies
have examined the association with individual study results consistently suggestive
of an association, or more than ten studies have examined the association with indi-
vidual study results suggestive of an association, but inconsistent; (3) Possible: five
or fewer studies have examined the association with individual study results consistently
suggestive of an association, or six to ten studies have examined the association
with individual study results suggestive of an association, but inconsistent; (4)
Unlikely: no consistent association observed.
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Chapter 2
Adipocytes, Lipid Metabolism,
and Hematopoiesis
Jeffrey M. Gimble
Abstract The physiology and pathology of adipogenesis and hematopoiesis are

interconnected. Hematopoietic stem cells (HSC) rely on bone marrow mesenchy-
mal stromal/stem cells (BMSC) with pre-adipocyte properties for paracrine factors
directing their proliferation and differentiation. The lineage commitment of these
BMSC along the adipocyte vs. osteoblast pathways modulates the “stem cell niche”
within the bone marrow microenvironment, and similar relationships exist within
the thymus. These relationships are regulated directly as a function of biological
aging since adipose stores in the marrow and thymus increase at the expense of
hematopoietic cell proliferation, differentiation, and/or function. Furthermore, the
interaction between adipocytes and hematopoietic cells is not limited to medullary
adipocytes within the marrow cavity. There is a growing appreciation that adipose
stromal/stem cells (ASC) and their differentiated progeny within extramedullary
(peripheral) adipose depots direct hematopoietic function through their endocrine
production of adipokines and cytokines, such as adiponectin, leptin, and interleukin
6. Indeed, such adipose depots may be underappreciated reservoirs of HSCs. The
feedback loops ASC, BMSC, and HSC merit increased attention in light of the
comorbidities associated with the looming international obesity and type 2 diabetes
epidemic.
1 Introduction
The body contains multiple forms of adipose tissue closely connected to hematopoietic
cells. Subcutaneous and visceral white adipose tissues (WAT) act as energy reser-
voirs and function as an endocrine organ through the release of systemically acting
J.M. Gimble, M.D., Ph.D. (*)

Stem Cell Biology Laboratory, Pennington Biomedical Research Center,
Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA 70808, USA
e-mail: gimblejm@pbrc.edu
32 J.M. Gimble
adipokines such as adiponectin, leptin, and resistin as well as hematopoietic/

inflammatory cytokines (IL-6, TNFa) [1]. Pathological conditions reveal ties
between WAT and hematopoiesis. In subjects with diabetes and/or obesity, mac-
rophages and T-lymphocytes infiltrate visceral WAT to create a sterile inflammation
[2–6]. Far less common is progressive osseous heteroplasia (POH), an inborn mutation
of the G protein a stimulatory subunit [7]. In children with this disease, subcutane-
ous WAT converts into ectopic bone tissue complete with a hematopoietic marrow
[7–10]. Brown adipose tissue (BAT) is a mitochondrial-rich thermogenic organ
capable of high levels of fatty acid oxidation that is most prominent in newborns,
although recent nuclear imaging studies have documented its presence in adults
[11–14]. Mammary adipose tissue contributes to lactation after parturition while
mechanical fat pads, located in weight-bearing joints and retro-orbitally, provide
structural support. Additionally, adipose depots exist within the bone marrow, and
these increase in size with advancing age and, possibly, reduced body temperatures
[15–20]. Marrow adipocytes first appear soon after birth, progressing from the distal
to proximal skeletal elements [18, 21]. In recent years, new tools, such as noninva-
sive nuclear magnetic resonance imaging (MRI) methods, transgenic mice, and flow
cytometry, have been used to address older questions concerning the metabolic
interface between adipose tissue and hematopoietic cells [21–23]. This chapter
will review our current understanding of relationships between adipocytes and
hematopoietic cells within the bone marrow and peripheral adipose depots; however,
literature concerning the role of adipogenic marrow in hematological malignancies
will be deferred to Chap. 3.
2 Adipogenesis: Cellular Mechanisms
2.1 Cellular Progenitors at the Stromal Level
Bone Marrow Mesenchymal Stem Cells: Due to the wealth of literature focusing on
hematopoietic stem cells (HSC), readers are referred to the following reviews for
additional information [24–26]. Instead, this chapter will focus on the adipogenic
stromal progenitor or stem cells. In the bone marrow, adipocytes, osteoblasts, and
hematopoietic-supporting stem cells derive from a common precursor first described
by Friedenstein as mechanocytes and now known as bone marrow mesenchymal
stromal (or stem) cells (BMSC) [27–32]. The BMSCs differentiate along either the
adipocyte or osteoblast pathways and an inverse relationship exists between these
lineages [33–37]. While osteoblasts are associated with hematopoietic support,
adipocytes have been classified by some as hematopoietic inhibitors [22, 23, 36,
38–40]. Transplantation studies of “red” marrow have induced both osteogenesis
and hematopoiesis in animal models [41–43]. In vitro studies show that human and
murine stromal cells with osteoblast features have the ability to support the prolif-
eration and differentiation of hematopoietic lineages [23, 39, 44, 45]. However,
recent studies indicate that hematopoiesis support is associated with a nestin+ BMSC
2 Adipocytes, Lipid Metabolism, and Hematopoiesis 33
with multilineage differentiation potential (adipogenic, chondrogenic, osteogenic),

consistent with the conclusions of earlier studies [31, 45, 46].
Historically, investigators viewed marrow fat solely as a space filler [46, 47]. It is
now appreciated as a dynamic contributor to the hematopoietic microenvironment or
“stem cell niche” [48–51]. Hematopoiesis is an energy-dependent process that
depends on and is regulated by the adipose reserves of the body. Adipose tissue is a
source of cytokines and growth factors that modulate the proliferation and differentia-
tion of HSC [46, 48, 52–54]. Conditions requiring increased erythropoiesis deplete
the stores of “yellow” or fatty marrow [41, 55–57]. This is accomplished experimen-
tally in vivo by hypoxic exposure, surgical evacuation of the marrow cavity or treatment
of animals with phenylhydrazine, an erythroid lytic agent [27, 55, 56, 58, 59]. In vitro,
exogenous pro-inflammatory and other cytokines (IL-1b, IL-6, TGFb, TNFa) can
inhibit or reverse adipogenesis in BMSC lines, suggesting that these factors play a
role in vivo [60–63]. In contrast, hypertransfusion of erythrocytes in vivo, by reduc-
ing demand for on-going hematopoiesis, drives marrow to an adipose-rich state [64].
In extreme circumstances, such as aplastic anemia (AA), the “acellular” marrow is
filled almost entirely with adipocytes that exhibit reduced hematopoietic support func-
tion [38, 65, 66]. Nevertheless, confocal microarchitectural analyses of human AA mar-
row demonstrate that the majority of CD34+ putative HSC are in close proximity to
one or more adipocytes [67]. This supports the hypothesis that BMSC adipocytes
produce hematopoietic inhibitory factors [66, 68] (see Sect. 2.3). The character of
the marrow adipose tissue remains in question. The lipolytic and lipid-storing activ-
ity of marrow adipose tissue differs from subcutaneous or visceral WAT in some
studies [40, 69]. Indeed, the fact that marrow adiposity relates to body temperature
has led to the hypothesis that it bears resemblance to BAT [15, 16, 20, 70]. Consistent
with this is the rare report of a bone marrow fatty tumor with hibernoma or BAT
characteristics; however, no evidence has been published documenting the presence
in marrow of uncoupling protein 1 (UCP1), the quintessential BAT marker [71].
Adipose-derived Stromal/Stem Cells: Peripheral subcutaneous and visceral adipose
depots contain adipose-derived stromal/stem cells (ASC) comparable to BMSC [72–
75]. The ASC can be isolated by collagenase digestion of intact adipose tissue and
are found in the stromal vascular fraction (SVF) [74]. The ASC secrete a range of
hematopoietic regulatory cytokines, including CCL20, GM-CSF, IL6, IL7, IL8,
IL11, M-CFS, SDF, and TGFb, [72, 76, 77]. The ASC surface immunophenotype
includes markers associated with BMSC such as CD29 (b1 integrin), CD44
(hyaluronate receptor), CD73 (5¢ ecto nucleotidase), CD90 (Thy1), and CD105
(endoglin) [73, 78–80]. Nevertheless, the two populations are not identical as they
differ in expression of the stem cell-associated marker, CD34, as well as CD36,
CD106, and CD146 [73, 81]. While these may be inherent differences, they may
reflect alternatively the distinct isolation and culture conditions between ASCs and
BMSCs. Additionally, ASC are capable of supporting HSC differentiation in vitro
[72, 82–84]. Likewise, ASC display immunomodulatory function and can suppress
mixed lymphocyte reactions in vitro through the release of prostaglandin E2 in a
manner similar to BMSC [84–89]. While it remains unproven, ASC may be the cell
lineage responsible for the pathological changes observed in POH [7–10]. In vitro
34 J.M. Gimble
and in vivo studies show that, like BMSC, ASC are capable of adipogenic, chondrogenic,
endothelial, and osteogenic differentiation (reviewed in [74, 75, 90]). Some evidence
indicates that BMSC osteogenesis is superior to that of ASC while ASC adipogen-
esis is superior to BMSC [91]; this may reflect cellular epigenetic programming
from the tissue of origin. Thus, while ASC are located outside the traditional
hematopoietic network, they may have contributory function.
Thymic stromal cells: The thymus is an extramedullary hematopoietic site that
contains epithelial-derived stromal cells. With advancing age, the thymus under-
goes involution characterized by stromal adipogenesis in both the cortex and
medulla [92]. It is hypothesized that the thymic stromal cells undergo an epithelial
to mesenchymal transition [93]. Recent studies show that a combination of factors
(glucocoriticoids, insulin, isobutylmethylxanthine, and thiazolidinediones), similar
to those used in ASC and BMSC studies, can induce primary thymic stromal cell
adipogenesis in vitro [93]. In vivo murine and human models show that diet-induced
obesity is associated with increased thymic adipose stores and decreased numbers
of T-lymphocytes [94]. Thus, as in the bone marrow microenvironment, thymic
hematopoietic function is closely linked to its stromal adipogenic status.
2.2 Transcriptional Regulators: Common Themes Between

Adipogenesis and Hematopoiesis
Adipogenesis is positively regulated directly by the helix–loop–helix family members,

CAAT/Enhancer Binding Proteins (C/EBPs a, -b, -d) and Adipose Determination
and Differentiation1/Sterol Response Element Binding Protein (ADD1/SREBP),
the nuclear hormone receptor family members, Glucocorticoid Receptor (GR),
Peroxisome Proliferator Activated Receptor g (PPARg), and Retinoid X Receptor
(RXR) and negatively regulated by the GATA family [95, 96]. These and other
transcription factor families control myelopoiesis and have been implicated in
hematological malignancies [97]. For example, treatment with the PPARg inhibitor,
BADGE, enhanced bone marrow engraftment in irradiated mice while reducing
marrow adipogenesis [66]. Consistent with this, the hypomorphic mutant PPARghyp/
hyp
mice are lipodystrophic, display increased bone mass with reduced marrow vol-
ume, and exhibit extramedullary (splenic) hematopoiesis [98]. Likewise, analyses
of BMSC from patients with AA exhibit reduced GATA-2 and elevated PPARg2
expression levels [96]. THOC5 is a leucine zipper and splicesome protein that con-
tributes to the M-CSF and PDGF receptor signal transduction pathways and potenti-
ates the adipogenic actions of C/EBPs by shuttling the transcription factor between
the cytosol and nucleus [99, 100]. Furthermore, THOC5 null mice are embryonic
lethal secondary to hematopoietic deficiencies [101]. The PU.1 transcription factor
is required for myeloid and B-lymphoid development and interacts with the C/EBP,
GATA, and c-Jun regulatory proteins [102]. Additionally, PU.1 inhibits adipogenesis
via interactions with these same protein families [102]. Thus, a shared set of tran-
scription factors control lineage determination in BMSC and HSC.
2.3 Adipogenic-Related Hematopoietic Regulatory Factors
Pre-adipocytes express the EGF-like molecule known as Pref-1 or Delta like (dlk)
which inhibits BMSC adipogenesis and osteogenesis [103–106]. With down-regu-
lation of dlk in BMSC/hematopoietic cell co-cultures, IL-7 is no longer necessary
for pre-B lymphopoiesis [103]. Consistent with this, dlk−/− mice display increased
numbers of early lineage B cells in their bone marrow [106]. With adipogenesis, dlk
expression levels decrease significantly [105].
Likewise, adipogenic-induced cytokines, which include adiponectin, leptin, pre-B
cell enhancing factor, gp130 receptor cytokines, and resistin, have been implicated in
hematopoietic events. Adiponectin acts as a paracrine factor within bone marrow and
inhibits BMSC adipogenesis [70]. Additionally, it inhibits B lymphopoiesis indirectly
via activation of the BMSC cyclooxygenase pathway and production of prostaglandin
E2 (PGE2) [107]. At the level of the HSC, adiponectin acts directly via its receptors
to increase proliferation and maintain the cells in the undifferentiated state [108].
Bone marrow adipocytes produce leptin which acts via its receptors on HSC and
progenitor cells to regulate erythropoiesis and lymphopoiesis [53, 109, 110]. Pre-B
cell enhancing factor, also known as nicotinamide phosphoribosyltransferase
(NAMPT) and visfatin, is found within the proteome of differentiated adipocytes and
contributes to G-CSF-mediated myelopoiesis through the actions of sirtuin [111, 112].
Adipocytes are a source of IL-6 and related cytokines (Cardiotrophin, IL-11, Leukemia
Inhibitory Factor, Oncostatin) employing the gp130 protein in their receptor complex
[113]. IL-6 not only contributes to insulin resistance and metabolism [114] but also it
is well established as a hematopoietic regulator [115]. IL-11 stimulates erythropoiesis
and myelopoiesis while inhibiting BMSC adipogenesis [116, 117], as do other gp130
receptor ligands [61]. Resistin promotes differentiation of myeloid lineage osteoclasts
in vitro, suggesting a potential role in bone remodeling and modulation of the stem
cell niche [118].
2.4 Lipid Ligands
Adipose cells are also a source of lipid factors with autocrine and paracrine regula-
tory function. Lipid derivatives such as prostaglandin J2 and nitrolinoleic acid act as
PPARg ligands promoting BMSC adipogenesis [119, 120]. In addition to synthesis
of endogenous lipids, adipose tissue can store environmental-derived chemicals that
act as PPARg ligands modulating both adipogenesis and hematopoiesis [121].
Arachidonic acid metabolism in the BMSC yields leukotrienes and prostaglandins
that modify marrow function [122]. A subset of mice with deficiency in 12/15 lipox-
ygenase, the enzyme responsible for arachidonic and linoleic acid oxidation, display
a myeloproliferative defect, indicating that its downstream metabolites are required
to maintain HSC quiescence [123] The production of PGE2 regulates BMSC
secretion of Macrophage-Colony Stimulating Factor (M-CSF) with subsequent
myelopoietic effects [124]. In addition to regulating hematopoietic differentiation,
36 J.M. Gimble
lipid mediators such as lysophosphatidic acid act as lymphoid chemotactic factors,

modifying migration of hematopoietic cells within the marrow [125–127]. The
BMSC synthesize the phospholipid metabolites, 2-arachidonylglycerol and anand-
amide, which are endogenous ligands for the cannabinoid receptors 1 and 2 expressed
on the surface of HSCs [128, 129]. Endocannabionids contribute to the mobilization
and migration effects of Granulocyte-CSF (G-CSF) on hematopoietic progenitor
cells in vivo [128, 129]. Thus, lipid metabolism by BMSC pre-adipocytes and
adipocytes regulates HSC hematopoiesis and inflammatory responses.
3 Aging and Nutrition: Impact on Adipocytes and

Hematopoietic Organs
3.1 Bone Marrow Microenvironment
Adipose tissue accumulates in the bone marrow microenvironment with advancing

age, with pronounced changes occurring at or near puberty [18, 46, 47, 130–133].
This may reflect the changing ratio between the circulatory and marrow cavity volume
with body growth. As individuals grow, they may no longer need the full hematopoietic
capacity of the marrow except under exceptional conditions, such as hypoxic expo-
sure, traumatic blood loss, orthopedic trauma, or other stressors. Consequently, adipo-
cytes may replace the hematopoietically dormant marrow cavity. Increased marrow
adipogenesis is associated with reduced bone mass and correlates with osteoporosis
[134]. The inverse relationship between adipogenic and osteogenic BMSC differen-
tiation reflects the transcriptional activity of PPARg2, Runx2, and the circadian-
associated leucine zipper factors glucocorticoid-induced leucine zipper (GILZ) and
nocturnin [135–140]. Historically, quantitative studies of marrow adipogenesis relied
on autopsy measures [18, 130–133]. Now, noninvasive nuclear MRI and dual energy
X-ray absorptiometry (DXA) methods have led to further advances [21, 141, 142].
Marrow adiposity, as determined by MRI, is inversely related to bone mineral density,
as assessed by DXA, in female subjects with osteoporosis [21]. Likewise, marrow
adiposity increased from 24% in subjects of age 11–20 to 54% in subjects age >60
based on MRI [142]. With myelodysplastic disorders, MRI has determined that
marrow adiposity decreases as a function of disease progression [141].
Nutritional status substantially alters marrow adiposity. In patients with advanced
anorexia nervosa, the marrow adipose tissue is replaced with a gelatinous mucopoly-
saccharide matrix [143–146]. The acellular marrow is associated with leucopenia
which can be reversed with adequate nutrition [147–149]. Relative to age-matched
controls, anorectic patients exhibit a twofold elevation in circulating adiponectin
levels after normalization for subject body mass index (BMI) [150]. This is consis-
tent with the hypothesis that adiponectin inhibits BMSC adipogenesis and maintains
HSC in their undifferentiated state [70, 108]. Additionally, adiponectin levels have
been found to increase significantly with weight loss in obese subjects and are
inversely related to adipose mass [151]. Thus, altered adipokine levels may account
for hematological disorders in anorexia nervosa; however, recent murine studies

present paradoxical findings [152]. When immature mice are placed on a calorically
restricted diet, their marrow displays increased adiposity while extramedullary adi-
pose stores are depleted [152]. This correlates with reduced bone mineral density
(BMD) and bone strength and differs from the effects of caloric restriction in older
mice [152, 153]. When exposed to diet-induced obesity, mice exhibit a similar reduc-
tion in BMD and increased marrow adiposity [154, 155]. Further studies evaluating
the impact of nutrition on marrow adipogenesis and hematopoiesis are warranted.
3.2 Thymic Microenvironment
Like the bone marrow, the thymic adiposity increases with age. Recent murine stud-
ies indicate that caloric restriction to levels associated with increased longevity
(~76% of ad libitum pair fed controls) maintains the epithelial status of the thymic
stroma and delays involution or adipogenesis [93]. Unlike the anorexia studies,
caloric restriction was initiated when mice had reached 14–16 weeks of age [93].
The altered adiposity correlated directly with reduced expression of PPARg2 [93].
Furthermore, it led to the maintenance of thymopoiesis and prevention of age-
dependent loss of the T-cell receptor repertoire [93]. In contrast, when mice were
fed a high-fat diet beginning at 6 weeks of age, they displayed accelerated thymic
adiposity or involution by 13 months of age relative to chow fed controls as well as
increased obesity [94]. This was accompanied by reduced thymocyte numbers [94].
Furthermore, at the level of the marrow, obesity was associated with a reduced lym-
phoid and an increased myeloid population [94]. Thus, dietary status can significantly
alter hematopoiesis within the marrow and thymus.
4 Peripheral Adipose Tissue and Hematopoiesis
Accumulating evidence suggests that extramedullary or peripheral adipose tissues

may provide a reservoir for hematopoietic progenitors and HSCs. Using a lethally
irradiated murine model, pioneering experiments showed that the SVF cells from
subcutaneous adipose depots contained sufficient numbers of HSC to repopulate
the bone marrow and rescue 40% of the recipient animals; in contrast, 100% of the
untreated controls died [156]. The murine SVF cells included a CD34+ population and
this has since been confirmed in human specimens [81, 85, 156]. Consistent with
these findings, independent laboratories have determined that ASC, like BMSC adi-
pocytes, support the differentiation of hematopoietic progenitors in vitro, but not the
renewal of HSC themselves [72, 82, 83, 157]. In vivo murine studies indicate that co-
transplantation of ASC with CD34+ HSC accelerates engraftment relative to BMSCs
[157]. Additionally, mast cell progenitors have been localized to adipose depots, from
which they can home to other tissues where they fully differentiate [158]. Thus, just
38 J.M. Gimble
as it was necessary to reconsider extramedullary adipose tissue as an endocrine organ,

we may also need to re-evaluate its hematpoietic role in the adult.
5 Conclusions and Future Directions
With its critical role in energy balance, adipose tissue modulates hematopoiesis in
health and disease. Autocrine, endocrine, and paracrine interactions mediate the
close relationship between adipose tissue and hematopoiesis. Lipid and protein
factors provide the signaling interactions between the adipogenic stromal cells and
the hematopoietic progenitors. This chapter has reviewed the substantial body of
evidence from multiple disciplines that represents our current understanding of this
important physiology. Nevertheless, there are multiple avenues for future study and
several are listed below:
(a) The role of central mechanisms integrating adipogenesis, hematopoiesis, and
osteogenesis. Feedback loops involving the sympathetic nervous system (SNS)
and peripherally derived proteins (leptin, osteocalcin) exist between the brain,
adipose tissue, and bone [159–161]. In light of the inverse relationship between
marrow adipogenesis and osteogenesis on HSC proliferation and differentiation,
it would be fruitful also to explore the impact of the SNS on hematopoiesis.
(b) The role of circadian mechanisms in hematopoiesis and synchronization with
adipogenesis and osteogenesis. Circadian oscillating genes play a role in deter-
mining ASC and BMSC differentiation as well as HSC migration and function
[162, 163]. The interface between stem cell differentiation and circadian mecha-
nisms is an emerging area of potential importance.
In conclusion, the interface between adiposity and hematopoiesis remains an
important field of study. Research in this field will have increased importance as the
world’s population deals with the increased incidence and physiological conse-
quences of overnutrition.
Acknowledgments Lori Steib and Marilyn Hammond for research and library support; Laura
Dallam for administrative support; the many authors who graciously provided pdfs of their publi-
cations in response to my email requests; Youn-Hee Youm PhD and Fareena Bilwani MD for
comments on the manuscript; my colleagues in the Stem Cell Laboratory for their suggestions and
thoughts; and the Pennington Biomedical Research Foundation for support.
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Chapter 3
Mechanisms Linking Obesity
and Leukemia Prognosis
Steven D. Mittelman and Anna Butturini
Abstract Obesity increases the risk of developing all four common subtypes of leu-
kemia. In addition, children and adults who are obese when they are diagnosed with
acute lymphoblastic leukemia (ALL), have a higher risk of relapse. While a number
of potential mechanisms linking obesity and cancer have been postulated, none can
convincingly explain the links between obesity and leukemia incidence or relapse. In
the present chapter, we review the evidence that obesity increases leukemia relapse,
and explore some mechanisms that might contribute to this observation.
1 Introduction
Epidemiological studies have enlightened us to the fact that obesity is responsible

for increasing cancer incidence and mortality. Identifying the mechanisms linking
these two diseases has been difficult, due to the fact that obesity is a very complex
condition. While obesity causes a large number of physical and physiological
changes, it is also associated with numerous behavioral, environmental, and genetic
alterations which could impact cancer (Table 3.1). These various factors could inde-
pendently affect cancer incidence, treatment efficacy, treatment complications, and
overall survival. This large variety of differences makes teasing apart mechanisms
responsible for obesity-induced increased cancer mortality difficult. Furthermore, it
is possible that multiple mechanisms are relevant and could differentially impact
S.D. Mittelman (*)

Center for Endocrinology, Diabetes & Metabolism, Children’s Hospital Los Angeles,
4650 Sunset Blvd, MS #93, Los Angeles, CA 90027, USA
e-mail: smittelman@chla.usc.edu
A. Butturini
Agensys Inc, Santa Monica, CA, USA
48 S.D. Mittelman and A. Butturini
Table 3.1 Some potential mechanisms linking obesity to cancer

Genetic Physical Physiological Life style
Shared genetic Increased fat mass Insulin resistance Increased fat intake
predisposition Increased lean mass Dyslipidemia Increased sugar intake
Ectopic fat in other High free IGF-1 Increased carcinogen
organs (e.g., liver, Altered adipokine exposure
pancreas, muscle) profile Decreased exercise
Increased body surface Inflammation Poorer health care
area Impaired immunity surveillance
More adipocytes Low vitamin D Decreased fiber intake
Larger adipocytes
different types of cancer. Thus, this conundrum highlights the importance of a

transdisciplinary approach to understanding the impacts of obesity and cancer.
Hematological malignancies are common in both children and adults. Their
prognosis after conventional chemotherapy ranges from extremely poor for most
adult leukemias to an ~90% cure for children with low-risk acute lymphoblastic
leukemia (ALL). And yet it appears that obesity may affect the response to therapy
in some of these malignancies.
In the present chapter, we will focus on potential mechanisms whereby adipocytes
can increase leukemia mortality. Like a fractal, focusing in on this specific potential
relationship illuminates a wide variety of mechanisms and unanswered questions.
2 Obesity Affects Leukemia Outcome
The first information linking obesity and cancer are from the early 1980s, when a
number of case reports, including a few of leukemia patients [1–3], suggested
that obese patients tolerated chemotherapy poorly. This prompted the practice of
empirically decreasing the doses of cytotoxic drugs in patients whose weight was
perceived as excessive. These modifications were off-protocol, and their exact
frequency is unknown [4], though they likely affected the treatment of 10–50%
of obese patients. Similar practices were recently associated with an increased risk of
breast cancer recurrence [5].
More systematic data on the effects of obesity on the outcome of patients with
hematopoietic malignancies were generated more than 15 years later and derive
from retrospective analyses of patient registry and clinical trials. These analyses by
necessity defined obesity on the base of the patient weight [even if often corrected
for height in the body mass index (BMI)] at the time of diagnosis. This introduced
two biases: first, weight may poorly reflect body fat in many patients with leukemia
or lymphoma because of muscle loss due to asthenia and reduced physical activity,
and because of the presence of organomegaly, edema, and effusions. Second, the
measurement at diagnosis will reflect cancer-induced weight loss, which has
prognostic significance in lymphoma, as discussed later.
3 Mechanisms Linking Obesity and Leukemia Prognosis 49
Table 3.2 Reported effects of obesity on outcome of hematologic malignancies

Age group Disease subtype Therapy TRM Relapse References
AML Children Any Chemo Increased No effects [6]
Adults Any Chemo No effects No effects [7]
Adults APL Chemo Increased Increased [8]
Adults Any auHSCT Increased No effects [9]
ALL Children High risk Chemo No effects Increased [10, 11]
Adults BCR/ABL neg Chemo No effects Increased [12]
HL Adults Any Chemo No effects Decreased [13]
NHL Adults DLCL Chemo No effects Decreased [14]
MM Adults Any auHSCT No effects No effect or [15]
decreased
TRM treatment-related mortality, auHSCT autologous hematopoietic stem cell transplant, AML
acute myelogenous leukemia, ALL acute lymphoblastic leukemia, APL acute promyelocytic leuke-
mia, HL Hodgkin lymphoma, NHL non-Hodgkin lymphoma, DLCL diffuse large cell lymphoma,
MM multiple myeloma
Results of these studies are complex (Table 3.2). Increased chemotherapy

failures were reported in obese children [6] (but possibly not in adults [7]) with acute
myelogenous leukemia (AML), who have an excess in treatment-related deaths, and
in obese patients with acute lymphoblastic leukemia (ALL) [10–12] or acute promy-
elocytic leukemia (APL, [8]), who are instead at increased risk of leukemia recur-
rence. Obese recipients of autologous or allogeneic hematopoietic transplant are
more likely to have accelerated engraftment [16], but may be at increased risk of
death from graft versus host disease (GVHD), toxicity, or recurrence ([9, 17, 18],
see also Chap. 6). On the contrary, obesity is associated with a better outcome in
patients with lymphoma [13, 14] and possibly multiple myeloma [15].
Part of these discrepancies may result from biases of study design. Several data,
however, suggest that obesity may in fact affect chemotherapy pharmacokinetics
and the individual tolerance to chemotherapy (Table 3.3). Also, as we will discuss
in this chapter, obesity-related factors may alter the characteristics of the bone
marrow microenvironment. These factors may act differently in various hematopoietic
cancers or in relation to various therapies (Table 3.4 summarizes the general schemes
of the treatment of the different hematopoietic malignancies). Understanding the
different outcomes in obese patients with different hematopoietic malignancies may
clarify the complex relationship between obesity, cytotoxic therapy, and cancer.
Obesity and chemotherapy toxicity. In individuals without cancer, obesity and
the obesity-related metabolic syndrome affect the integrity of several organs and
systems, including insulin and glucose regulation, immunity, microcirculation, and
recovery from tissue damage. These alterations can all cause damage to organs like
the liver and the heart [24] and increase the probability of developing infection [25].
On the contrary, obesity is not associated with decreased bone marrow function;
despite functional defects mostly related to dyslipidemia and/or inflammation, the
number of neutrophils, red blood cells, and platelets in obese persons are as high as
or higher than in normal individuals [39, 40].
Table 3.3 Possible mechanisms underlying the reported effect of obesity on leukemia outcome
Possible
Target Related mechanisms consequence References
Chemotherapy Doses empirically decreased on base Higher risk [4]
doses and intensity of obesity of relapse
Doses adjusted and intervals between Higher risk [10]
cycles prolonged on the base of relapse?
of actual toxicity
Decreased doses per kg when chemo- Higher risk [10]
therapy dosed on the base of body of relapse?
surface or capped (i.e., Vincristine)
Drug pharmacokinet- Increased AUC and/or reduced Higher risk [19–21]
ics/pharmacody- clearance (cyclophosphamide, of toxicity
namics doxorubicin, methylprednisolone)
Decreased AUC and/or increased Higher risk [22]
clearance (6 mercaptopurine) of relapse
Decreased compliance with fasting or Higher risk [23]
avoidance of food interfering with of relapse
drug absorption (i.e., milk and
6-mercaptopurine)
Organ function Pro-inflammatory status, oxidative Higher risk [24]
stress, microangiopathy of toxicity
Infections Pro-inflammatory status, microangiopa- Higher risk of [25]
thy, increased incidence of dental infection
caries, higher risk of hyperglycemia
AUC Area under the curve—for circulating drug levels
Table 3.4 General treatment paradigms for hematologic malignancies

Expected TRM/
Cancer Standard chemotherapy design early death (%) References
ALL 3–6 cycles of moderately intense chemotherapy 2–10 [26, 27]
including steroids, vincristine, asparaginase,
anthracyclines, 6MP, MTX, followed by
2–3 years of continuous therapy with 6MP, MTX
± vincristine and steroids (maintenance therapy)
AML 2–5 cycles of very intensive chemotherapy including 7–25 [28, 29]
anthracyclines, 6TG, AraC, etoposide
PML 2–5 cycles of intensive therapy including ATRA and 5–25 [30, 31]
anthracyclines, followed by 1–2 year mainte-
nance with ATRA ± 6MP, MTX
NHL 2 to >8 cycles of moderately intense chemotherapy 3–10 [32, 33]
including anthracyclines, vincristine, steroids,
cyclophosphamide, etoposide ± anti-CD20 moAb
HL 2–8 cycles of moderately intense chemotherapy 1–5 [34, 35]
including alkylators, anthracyclines, tubulin
inhibitors ± steroids
MM Biotherapy ± steroids ± myeloablative chemotherapy 5–10 [36–38]
including high-dose alkylators and auHSCT
6MP 6mercaptopurine, MTX methotrexate, 6TG 6thioguanine, AraC cytarabine, ATRA all-
trans-retinoic acid, TRM treatment-related mortality
These characteristics parallel the findings in obese patients treated with chemo-
therapy for their hematopoietic malignancies. Obesity increases the risk of acute
toxicity, including pancreatic, liver, and lung toxicity in ALL [10, 12]; liver toxicity
and infection in AML [41]; and infections in diffuse large cell lymphoma [13].
Obesity does not appear to increase hematopoietic toxicity or interval between
chemotherapy cycles [6, 10, 12]. In fact, there are occasional reports of more rapid
hematopoietic recovery after transplant in obese patients, possibly due to the fact that
they receive more cells in the graft, as the number of cells in the graft is typically
calculated on the basis of patient weight [42].
Several studies, especially in patients undergoing transplant, however, fail to
report any increased risk of toxicity or toxic death in obese patients [42]. This may
be related to the retrospective analysis design and from the prognosis of the disease
analyzed. Regarding the study design, for example, the characteristics of the study
and control groups can be pivotal for determining the ability of detecting an obesity-
related effect. Underweight individuals typically have high risk of therapy-related
complications: their inclusion in the control group lead to an underestimation of
the effect of obesity. Also, the obese and control group may be unbalanced for other
prognostic factors. This may be particularly true in the context of allogeneic transplant,
where multiple variables predict GVHD and transplant-related morbidity and mortality.
Finally, reduction in chemotherapy doses in obese patients could be unrecorded.
The discrepancies in the effect of obesity on toxicity may also depend on the different
incidence of treatment-related morbidity and mortality among diseases. For example,
the chemotherapy of AML is inherently associated with a high risk of toxic deaths,
while the treatment of lymphoid malignancies is relatively less toxic. Therefore, studies
in ALL for example may not have the statistical power of detecting an increase in
toxic death among obese patients.
Obesity and Leukemia Relapse. Obesity is associated with increased risk of
relapse in ALL. In more than 6,000 patients treated in five Children’s Cancer Group
studies [10] and two studies of the Italian Group for the Adult Hematologic Diseases
(GIMEMA, [12]), we found that obesity was an independent predictor of relapse
in those who had BCR/ABL negative disease and were older than 10 years
at diagnosis. The increased risk of recurrence did not depend on differences in
chemotherapy doses or intensity during the initial aggressive phases of therapy,
while we could not evaluate possible late variations in the doses and/or timing
of chemotherapy. Interestingly, the effect of obesity was detectable only after the
third month of therapy.
Similar analyses in smaller populations of children with ALL were performed by
other investigators [11, 43, 44]. Obese patients with high risk ALL, either for age or for
leukemia characteristics, consistently had an increased (about 1.5–2 times higher) risk
of recurrence than controls, albeit with different degree of significance (Table 3.5).
Several clinical investigations, including pharmacokinetics studies, have been
conducted or are in progress to understand the effect of obesity on ALL outcome. So
far, no data clarify its underlying mechanisms. For example, glucocorticoids are an
important part of therapy for ALL; glucocorticoid receptor polymorphism is associated
with obesity, but not with steroid resistance in ALL cells [45]. Similarly, although
Table 3.5 Reported event free survival (EFS) and/or adjusted hazard ratio (HR) for events in
obese and nonobese ALL patients
Obese Nonobese Adjusted
Population n 3yEFS n 3yEFS p HR p References
Age 10–20 95 63% 908 74% 0.01 1.5 <0.01 [10]
167 70% 993 80% <0.01 1.4 0.03 [10]
22 nr 59 nr 0.15 1.84 NS [43]
Age < 20 55 72.7%a 400 78.7%a 0.7 nr nr [44]
Age < 20, HR nr 50%a nr 73%a 0.03 1.9 0.03 [11]
Age > 20 BCR/ 45 22.9% 426 39.5% <0.01 1.5 0.02 [12]
ABL neg 50 26.6% 385 49.4% 0.06 1.5 0.1 [12]
a
EFS at 5 years
serum levels of adipokines in ALL patients correlate with both obesity and leukemia
burden, there are no data indicating that they may affect response to therapy
[ 46, 47]. A general limitation of such studies is that the size of the population
studied and the observation time are insufficient to detect differences because of the
high cure rate of pediatric ALL.
The second leukemia where obesity may increase the likelihood of recurrence is
APL, a type of AML characterized by a novel gene resulting from the fusion of the
alpha retinoic acid receptor gene, RAR, to the PML gene. In addition to increasing
APL incidence [48, 49], one recent study [8] suggests that obesity is associated with
both failure to achieve remission and with relapses, differently from what was
reported earlier [50]. Also, obese patients may be prone to develop the leukocytosis
and cytokine storm defined as “differentiation syndrome” after therapy with retinoic
acid [51, 52]. Thus, for both ALL and APL, obesity can negatively impact incidence
and treatment.
Obesity has no reported effect on relapse in children with other types of AML
[6, 7], and may actually decrease relapse in lymphoma. In one study, obese patients
with Hodgkin lymphoma have disease with better prognostic features and less
probability of dying of their cancer than normal weight patients [14]. Notably,
weight loss (along with fever and night sweat) is part of the B symptoms caused by
the lymphoma and associated with negative prognosis, therefore it may appear
tautological that the presence of obesity at diagnosis predicts better outcome. In one
study on more than one thousand patients with a type of non-Hodgkin lymphoma,
intermediate diffuse large cell lymphoma [13], however, overweight and obese
patients had a lower risk (statistically significant in case of the overweight patients)
of progression and death, independently from B symptoms. Obesity was also asso-
ciated with a better outcome in another malignancy of mature lymphocytes, multiple
myeloma, after high-dose melphalan, and autotransplant [15] (See chapter 4).
Overall, obesity is consistently associated with increased risk of recurrences in
ALL and APL, but not in most AML or lymphomas. ALL originates from early
lymphoid precursors, expands primitively in the bone marrow and its treatment
includes 2 years of continuous maintenance therapy with 6-mercaptopurine and
methotrexate. Notably a maintenance therapy was recently incorporated into APL
therapy [30]. Thus, two not mutually exclusive hypotheses are possible: Obesity
may directly or indirectly affect the activity of the drugs used in maintenance ther-
apy, or, obesity-related factors may alter the biology of malignant early lymphoid
cells (and maybe malignant promyelocytes) in the bone marrow.
3 Adipocytes in the Leukemia Microenvironment
Like normal hematopoietic cells, leukemia cell development may need the bone
marrow microenvironment. There is evidence that bone marrow stroma confers leu-
kemia chemoresistance in vitro [53–57]. This has led to the evaluation of drugs
which block leukemia cell homing in the bone marrow as an adjunctive therapy to
traditional chemotherapy regimens [58–60].
As described in detail in Chap. 2, the bone marrow microenvironment is a
complex three-dimensional structure involving a wide variety of cell types that
support hematopoiesis. An understudied component of this environment is the
adipocyte. Once thought to be merely an energy-storage cell, the adipocyte has
recently been shown to be a complex endocrine cell with important interactions
with many tissues, including the brain, pancreas, and immune system [61, 62].
Numbers of bone marrow adipocytes increase gradually with age, as marrow converts
from “red” to “yellow” [63–65]. Diet-induced obesity causes an increase in marrow
adipocytes in rodents [66], though the association between marrow adiposity and
obesity in humans is less consistent [67, 68].
Although the link between bone marrow adipogenesis and obesity is not clear, it
is likely that bone marrow adipocytes have a pivotal importance in the response of
ALL to therapy. In patients with ALL, we observed a dramatic and rapid increase in
bone marrow adipocytes during the course of induction chemotherapy (Fig. 3.1a).
How this process may be affected by obesity is unknown, but it is clear that bone
marrow adipocytes can be in close proximity to leukemia cells during this important
therapeutic window. In mouse models of ALL, we documented a physical rela-
tionship between adipocytes and leukemia cells, even after treatment (Fig. 3.1b).
A similar process has also been demonstrated in human cutaneous B- and T-cell
lymphoma, where malignant cells are found to form a rim around adipocytes in the
subcutaneous space (Fig. 3.1c, [70]). Below we will present data suggesting that the
proximity of adipocytes to leukemia and lymphoma cells may facilitate a two-way
interaction leading to drug resistance and potentially treatment failure.
4 Evidence That Adipocytes Protect Leukemia Cells
Although obesity is associated with an increased incidence of all major types of

leukemia [71] and impaired ALL treatment outcomes [10–12], this does not prove
that obesity per se causes these effects. We therefore tested whether diet-induced
Fig. 3.1 Adipocytes in the microenvironment of hematologic malignancies. (a) Bone marrow
biopsy specimen from an adolescent with ALL, at time of diagnosis (left), and at day 29, after
induction chemotherapy (right). Adipocytes appear as white ovals. Stained with Wright-Giemsa.
Magnification 200×. (b) GFP + 8093 ALL cells in the perirenal fat pad of a transplanted obese
mouse that developed progressive leukemia during vincristine treatment. Lipid is stained with Nile
Red, and the image is counterstained with 4¢,6-diamidino-2-phenylindole (DAPI). Image was
taken on a Leica DM RXA2 (32× final magnification). Adapted from Behan et al. [69]. (c) Rimming
of adipocytes by NK/T-cell lymphoma, nasal-type (top) and lymphoplasmacytic lymphoma (bot-
tom). Reprinted with permission from Wolters Kluwer Health, Lozzi et al., American Journal of
Dermatopathology, The Rimming of Adipocytes by Neoplastic Lymphocytes: A Histopathologic
Feature Not Restricted to Subcutaneous T-Cell Lymphoma, reference [70]
obesity would increase the progression of spontaneous leukemia in two mouse

ALL models—the BCR/ABL transgenic and the AKR mouse. Indeed, both of these
mouse models developed leukemia earlier when made obese by a high-fat diet [72].
Conversely, others have shown that caloric restriction decreases the incidence of
spontaneous T-cell leukemia [73] and radiation-induced myeloid leukemia [74],
and slows the progression of transplanted leukemia cells [75]. We also demonstrated
that obese C57Bl6/J mice transplanted with syngeneic leukemia and treated with
either vincristine or l-asparaginase monotherapy had poorer survival than nonobese
mice [69, 76]. Thus, the effects of obesity on leukemia incidence and prognosis
observed in humans are recapitulated with obesity in mice, supporting the hypothesis
that obesity is directly responsible for these effects.
After vincristine treatment, we noted leukemia cells in adipose tissue of mice
with progressive leukemia. These cells were viable and capable of proliferating ex
vivo, implying that adipose tissue could be a sanctuary site for leukemia during
treatment. Indeed, this could represent a similar phenomenon as discussed above,
where leukemia cells are more likely to survive chemotherapy when in coculture
with a stromal layer of cells [54–56]. Like stem cells, primary ALL cells do not
proliferate well in culture in the absence of some feeder layer that mimics part of
the bone marrow niche, such as OP-9 cells, murine embryonic fibroblasts, or human
bone marrow-derived mesenchymal stem cells. Since both murine 3T3-L1 and OP9
cells can be differentiated into adipocytes, we compared the effects of undifferentiated
and adipocyte-differentiated cells on ALL cell growth and response to chemotherapy.
We found that adipocytes protect leukemia cells to a greater degree than their
undifferentiated stromal precursors. In our hands, 3T3-L1 adipocytes protect murine
BCR/ABL leukemia cells (8093 cells, [170]) from five different chemotherapies (vin-
cristine, l-asparaginase, dexamethasone, daunorubicin, and Nilotinib) significantly
more than undifferentiated 3T3-L1 cells ([69] and unpublished data). Protection
was also seen using OP-9 murine adipocytes, and ChubS7 immortalized human
adipocytes [171]. The adipocyte protection also does not require cell–cell contact,
implying that secretion of soluble factors is responsible for this protective effect.
Others have shown an effect of adipocytes on leukemia cells: adipocytes protect
APL cells from ATRA and doxorubicin, via cell contact [50], and support prolifera-
tion and prevent apoptosis in multiple myeloma cells, though to a similar degree as
bone marrow stromal cells [77].
4.1 Adipocyte-Derived Factors
4.1.1 Leptin
Leptin is a 16-kDa protein secreted by adipocytes in direct proportion to body

adiposity [78–81]. Its primary role is believed to be the long-term regulation of
body weight, as it signals through POMC neurons to the arcuate nucleus of the
hypothalamus, causing satiety [82]. However, leptin also plays a role in the immune
system, as deficient individuals have immune impairment [83], and leptin receptors
are expressed on most immune cells [84]. Leptin receptors have been identified in a
variety of different cancer types, and have been shown to stimulate their growth (see
review by Lang and Ratke, [85]). Leptin signals primarily via activation of the JAK/
STAT pathway, though it also may stimulate PI3K and AKT activity. Thus, leptin is
an attractive candidate to link obesity to increased cancer incidence and mortality,
as it signals through multiple pathways which have been shown to promote cell
survival and proliferation in cancer cells.
Leptin receptors are expressed on normal CD34+ hematopoietic precursors, and
leptin stimulates their proliferation [86]. In addition, several groups have reported
that leptin receptors are expressed on various leukemia cells, including AML [87–90],
APL[50, 87] and chronic myeloid leukemia (CML) [88, 91]. Interestingly, expression
of the functional (long) isoform of the leptin receptor (OB-Rb) appears to be rare
or absent on B-lineage leukemia cell lines and primary samples [87, 88, 90].
In AML, leptin increases the proliferation rate, possibly dependent on STAT3/MAPK
signaling [89]. This hormone also reduces apoptosis of AML cells induced by cytokine
withdrawal [87], and increases AML secretion of IL-6 [90]. Tabe et al. showed that
MSC-derived adipocytes protect APL cells from ATRA and doxorubicin, and sug-
gested that this protection was mediated at least partially by leptin [50].
Several groups have measured leptin levels in patients with leukemia, with quite
variable results. Leptin levels in patients with AML have been reported to be higher
[92], lower [93, 94], and similar [95, 96] to controls. Likewise, in childhood ALL,
leptin levels at diagnosis have been reported as either elevated [46, 47] or low [93],
and these levels either increase [97, 98] or decrease [47] after therapy. A single
study has reported leptin concentrations in bone marrow of children at diagnosis of
ALL and found them to be significantly lower than that of controls [99]. The bone
marrow leptin levels then increased by the time of complete hematological remis-
sion, such that they were no different than peripheral blood plasma leptin concen-
trations in controls. The reason for the decreased bone marrow plasma leptin levels
at the time of ALL diagnosis is unclear, but may be due to the replacement of the
normal bone marrow by leukemia cells at the time of diagnosis, while the end of
induction is associated with a large increase in bone marrow adipocytes
(Fig. 3.1a).
Thus, there is mechanistic data in vitro that leptin might contribute to treatment
resistance in leukemia, particularly AML and APL, but a paucity of in vivo data
addressing whether leptin exerts a significant effect on leukemia treatment/survival.
4.1.2 Adiponectin
Adiponectin is the most abundant adipokine in plasma, circulating at levels between

~2 and 17 mg/ml in healthy humans. Unlike most adipokines, adiponectin levels
decrease with increasing adiposity. Adiponectin infusion and overexpression [100]
improve insulin sensitivity, and low adiponectin levels have been suggested to
contribute to the insulin resistance associated with obesity.
There is scant evidence linking adiponectin to leukemia prognosis or pathogenesis.
Adiponectin inhibits in vitro growth of normal myeloid precursors [101], and in
some conditions, of B-cell precursors [102], and may contribute to the bone
marrow suppression in patients with AML [103]. The adiponectin receptor Adipo1
was found to be highly expressed on malignant B-cells from patients with chronic
lymphocytic leukemia (CLL, [104]), though their function in these cells has not
been evaluated.
There is a high degree of variability in studies measuring plasma adiponectin
levels in patients with hematological malignancies. Circulating adiponectin levels
have been reported to be low in children at diagnosis of ALL [47], high in adults
diagnosed with NHL [105], and normal in individuals with CLL compared to
controls [106]. Serum adiponectin is also lower in children with AML than in
either controls or children with ALL [107]. Overall, there is scant evidence linking
adiponectin with the pathogenesis of hematological malignancies, though more
work is likely forthcoming.
4.1.3 VEGF
Vascular endothelial growth factor (VEGF) is a glycoprotein with numerous isoforms.

The most well-studied member, VEGFa, has been found to play a role in cancer
progression, primarily via induction of angiogenesis. For example, VEGF expression
is increased in a number of cancers [108], and VEGF inhibition, by drugs such as
bevacizumab (Avastin, Genentech), is being used in solid tumor therapy. Although
angiogenesis was originally thought not to be important in leukemia, it was later
shown that leukemia is associated with increased bone marrow vascularity, with
approximately two to sevenfold more microvessels in marrow from leukemia
patients compared to controls [109, 110].
VEGF has also been shown to affect cancer cells directly. The VEGF receptors
are tyrosine kinases, which can stimulate a number of signaling pathways involved
in cancer proliferation and treatment resistance, including PI3K/AKT [111], PKC
[112], MEK/ERK [113], and p38 MAPK [114] pathways (see review by Podar
and Anderson [108] for a more detailed discussion). Leukemia cells express both
VEGF and the VEGF receptor [115, 116], and VEGF can increase leukemia
cell proliferation and induce chemotherapy resistance in vitro [117–120]. This
resistance has been linked to signaling through Bcl-2 family proteins, with increase
in Bcl-2 [118] and Mcl-1 [120] expression, and increased BCL2 phosphorylation
[117]. A number of clinical studies are currently evaluating VEGF inhibition for the
treatment of hematological malignancies [108].
VEGF could represent a link between obesity and cancer, as it is secreted by
adipocytes within omental and subcutaneous adipose tissue [121, 122]. This secretion
increases with stimulation by cytokines such as IL-6 and oncostatin M [123], and
may contribute to the reported correlation, albeit mild, between plasma VEGF concen-
tration and BMI in adults [124]. However, since plasma VEGF measures were recently
shown to be confounded by release from platelets if samples are not procured correctly
[125], careful studies of VEGF levels in obese subjects are warranted.
4.1.4 Visfatin
Visfatin is now known to be an obesity-related adipokine, but was first described as

a stimulator of lymphocyte proliferation and maturation; hence, it was originally
named pre-B-cell colony-enhancing factor [126]. Visfatin is secreted by visceral
adipose tissue, and may contribute to inflammation and insulin resistance in obese
individuals [127]. The visfatin gene encodes for the enzyme nicotinamide phospho-
ribosyltransferase (NAMPT), which regulates NAD + biosynthesis [128]. Most of
the work relating visfatin to hematological malignancies has been on its role in
cancer cell metabolism: lymphoma cells express high levels of visfatin [129], and
selective inhibition of this enzyme can cause apoptosis [130]. However, exogenous
visfatin stimulates the MAPK and PI3K/Akt pathways, and increases VEGF and
MMP 2/9 production in human umbilical vascular endothelial cells (HUVECs,
[131]), opening the possibility that adipocyte-derived visfatin could play an
endocrine or paracrine role in leukemia/lymphoma proliferation or therapy resis-

tance. However, this has not yet been explored in the literature.
4.1.5 SDF-1a
SDF-1a (stromal-derived factor 1a, also known as CXCL-12) is a chemokine which

contributes to the bone marrow homing of both normal hematopoietic precursors
[132] and leukemia cells [59, 133–135]. Leukemia cells are believed to be relatively
protected from chemotherapy by the bone marrow stroma, and therefore SDF-1a
may increase leukemia resistance to treatment [53]. Blockers of the SDF-1a receptor,
CXCR4, are being investigated to mobilize leukemia cells from the bone marrow to
enhance chemotherapy efficacy [58–60].
Adipocytes are known to secrete SDF-1a, which mediates T-cell infiltration into
adipose tissue [136]. Interestingly, this secretion appears to increase with diet-induced
obesity. As previously described, we found ALL cells in adipose tissue depots in mice
after vincristine chemotherapy [69], and adipocytes have been identified in close asso-
ciation with lymphoma cells in humans [70]. In vitro, we found that ALL cells migrate
toward adipocytes (and adipocyte-conditioned media); this effect appears to be medi-
ated by adipocyte secretion of SDF-1a [137]. The CXCR4 antagonist, AMD3100,
effectively blocked leukemia cell migration toward adipocytes. Multiple myeloma
cells also migrate toward adipocytes [77], and modestly toward SDF1a [138].
Therefore, the adipocyte secretion of SDF-1a (along with other factors, see below)
may contribute to leukemia cell migration into the bone marrow as well as adipose
tissue depots, where they may be relatively resistant to chemotherapy treatment.
4.1.6 MCP-1
Monocyte chemotactic protein 1 [MCP-1, also known as CCL-2 (see [139] for review)]
is a chemokine secreted predominantly by monocytes and macrophages [140].
MCP-1 stimulates recruitment of other monocytes/macrophages, T lymphocytes,
and NK cells to sites of inflammation. There is little evidence to suggest that MCP-1
plays a major role in migration of leukemia cells, but rather appears to stimulate
migration of monocytes/macrophages toward leukemia cells [141]. Since tumor-
associated macrophages are known to be poor prognostic markers in solid tumors
[142], MCP-1 may promote environmentally mediated drug resistance by recruiting
macrophages to the leukemia/lymphoma microenvironment. Indeed, “bystander”
macrophages, or “nurse-like cells” have been shown to protect CLL cells from
chemotherapy [143].
MCP-1 is also secreted by a number of stromal cells, including adipocytes.
Adipocytes secretion of MCP-1 increases approximately sixfold in obese patients
[144], which likely contributes to the drastic increase in adipose tissue macrophage
infiltration [145]. Adipose tissue expression and plasma levels of MCP-1 are higher
in obese subjects [146], and decrease with weight loss [147]. While leukemia cells
have been shown to stimulate expression of MCP-1 in bone marrow mesenchymal

stem cells [148], their effect on adipocytes has not been reported. However, patients
with leukemia have higher bone marrow concentrations of MCP-1 [148, 149],
reflecting a likely induction by leukemia cells.
4.1.7 Insulin-Like Growth Factor-1
There is substantial evidence linking insulin-like growth factor-1 (IGF-1) to risk of

developing a variety of cancers [150]. Higher levels of bioactive IGF-1 have been
associated with increased incidence of breast, colorectal, and prostate cancers [151].
Conversely, patients with congenital IGF-1 deficiency (e.g., Laron dwarfs) are
relatively protected from cancer [152, 153]. While the mechanisms linking IGF-1
and cancer incidence have not been established, it is believed that IGF-1 stimulation
of signals such as mTOR, s6k, PI3K, ERK, and AKT may increase cell prolifera-
tion, leading to increased risk of mutation, as well as impair apoptosis, which would
impair the suicide signals that protect mutated cells from malignant transformation.
Since obese individuals have higher bioavailable IGF-1 levels, it is reasonable to
consider that IGF-1 may contribute to their increased cancer risk.
With respect to hematological malignancies, higher IGF-1 levels may explain the
strong association between increased birth weight and incidence of childhood
leukemia [154, 155]. The IGF-1R is highly expressed in ALL [156], AML [157],
and CML [158] cell lines and isolates. Receptor expression correlates with extent of
disease, increasing with the percentage of bone marrow blasts in AML [159], and
as CML progresses from chronic phase to blast phase [158, 160]. Furthermore,
IGF-1R expression in CLL may correlate with resistance to apoptosis in vitro [161].
AML cells are sensitive to IGF-1 stimulation, which increases PI3K/Akt and Erk
pathway signaling [162] and proliferation [163]. Conversely, inhibition of the
IGF-1R with small molecule inhibitors or neutralizing antibodies inhibits proliferation
and/or clonogenicity in AML [157, 159, 163] and CML [158] cells. Caloric restriction
slowed the progression of transplanted mononuclear cell leukemia in rats via decrease
in IGF-1 levels [75].
Although the majority of circulating IGF-1 is produced by the liver, local production
is known to act in a paracrine manner at the growth plate [164]. In addition, adipocytes
are known to secrete IGF-1 [165, 166], though how this secretion is physiologically
regulated and how it contributes to local IGF-1 levels is not known. Thus, further
studies are needed to investigate the IGF-1 concentration in the leukemia/lymphoma
microenvironment, and how this is affected by obesity.
4.2 Other Factors
In addition to those listed above, there are a number of additional mechanisms

which could potentially link obesity and leukemia. Insulin circulates at higher levels
in obese animals and patients, primarily as a compensatory mechanism for

obesity-induced insulin resistance. There is some cross-talk between IGF-1
and insulin signaling, implying that insulin could promote leukemia proliferation or
survival via insulin or IGF-1 receptor signaling [167]. Type VI collagen is released
by adipocytes and enhances breast cancer invasion into the surrounding adipose
tissue [168, 169], though an effect on leukemia/lymphoma cells has yet to be reported.
Adipose tissue releases a number of metabolic fuels, including glycerol, free fatty
acids, and amino acids, any of which could enhance survival of cancer cells.
5 Future Directions
It is clear that obesity causes innumerable changes in mammals, many of which

could influence cancer incidence, progression, and treatment. Given the breadth of
studies investigating the relationships between obesity and cancer, it is unlikely that
one adipokine or a simple pharmacokinetic alteration is wholly responsible for the
effect of obesity on any given cancer. Therefore, the search for the links between
obesity and malignancy should be done in a holistic context. Collaborative teams,
including oncologists, cell biologists, pharmacologists, and physiologists, would
be well-suited to investigate these mechanistic links in the context of the whole
organism and disease process.
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Chapter 4
Obesity and Multiple Myeloma
Tracey Beason and Graham Colditz
Abstract Multiple myeloma (MM) is a plasma B-cell malignancy that is characterized

by the presence of clonal proliferation of malignant plasma cells in the bone marrow,
monoclonal protein in blood or urine, and organ dysfunction. It accounts for 10% of
hematological malignancies and approximately 1% of all cancers in the USA.
Several etiologic agents are associated with its development. Notably, obesity is
consistently associated with increased risk and drives mechanistic pathways important
in its development. In addition to age, black or African American heritage is a
consistent risk factor as is male gender. Epidemiologic evidence on causes and biologic
pathways supporting the obesity relation are presented. Diagnosis and treatment of
MM patients are considered in the context of obesity as a cause with potential
impact on treatment and outcomes among those with disease.
1 Obesity and Cancer Risk
The association between cancer and obesity is well established in the literature.
Bergstrom et al. [1], in a meta-analysis, concluded that increased body weight
expressed as body mass index (kg/m2) is associated with an increased risk of developing
a range of cancers including breast, colorectal, endometrial, prostate, kidney, and
gallbladder cancer. Their findings suggested that it is possible to prevent a large
T. Beason, Ph.D., M.S.P.H (*)

Division of Public Health Sciences, Department of Surgery,
Washington University School of Medicine, St. Louis, MO 63110, USA
e-mail: beasont@wudosis.wustl.edu
G. Colditz, M.D., Dr. P.H
Chief Division of Public Health Sciences, Department of Surgery, Alvin J. Siteman Cancer
Center, Washington University School of Medicine, St. Louis, MO 63110, USA
e-mail: colditzg@wustl.edu
72 T. Beason and G. Colditz
proportion of cancers by simply avoiding adult weight gain (through modification

of nutritional habits and physical activity), and hence maintaining a healthy normal
weight. Another study adding further support to the obesity–cancer relationship
is the Million Women Study, which is a large cohort of >1.2 million women in
the UK between the ages of 50–64 years at entry who were followed for 5 years.
This study showed strong empirical evidence of a significant positive association
between BMI and risk of certain cancers, namely, endometrial cancer (relative risk
per 10 units increase in BMI = 2.89), adenocarcinoma of the esophagus (2.38), kidney
cancer (1.53), leukemia (1.50), multiple myeloma (1.31), pancreatic cancer (1.24),
non-Hodgkin’s lymphoma (1.17), ovarian cancer (1.14), postmenopausal breast
cancer (1.40), and premenopausal colorectal cancer (1.61). As in other studies, asso-
ciations for several of the cancer sites were greater in never smokers, removing the
confounding of body weight and disease risk by smoking. In addition, with increasing
BMI, the risk of cancer appeared to be modulated by menopausal status in women.
This study also found an association between BMI and hematopoietic cancers [2].
The classic paper by Calle [3] from the American Cancer Society Cancer Prevention
Study II cohort documenting excess mortality among overweight and obese adults
complements these data on cancer incidence. Renehan et al. [4] in a meta-analysis
of prospective cohort studies provide a landmark summary of evidence on BMI and
cancer incidence, showing through rigorous analysis that risk of hematopoetic
malignancies, including multiple myeloma, increases with increasing BMI in both
men and women. Based on the follow-up of ten cohorts for a mean of 14.6 years
(5.1 million men and women), the analysis is based on 4,273 cases of multiple
myeloma in men and 3,664 cases in women. For each 5 kg/m2 increase in BMI, the
relative risk of multiple myeloma was 1.11 (95% CI 1.05, 1.18) for men and 1.11
(1.07, 1.15) for women. In sum, there is strong empirical evidence supporting an
association between increased obesity (adiposity) and an increased risk for cancers.
Based on Calle et al., overweight and obesity are the underlying cause of 14–20% of
all cancer mortality. These data largely relate to adult measures of BMI. Additional
insights to the potential for prevention will be informed by understanding the timing
of weight gain and obesity in relation to risk and the potential reduction in risk after
successful and sustained weight loss. Even though there have been few studies
asserting weight loss is associated with a reduced risk of cancer [5], two large
studies of bariatric surgery show that weight loss following bariatric surgery is asso-
ciated with reduced cancer deaths [6, 7], but this observation was not present for
hematological malignancies [8].
1.1 Physical Activity, Energy Balance, and Cancer Risk
There is a large body of supporting evidence showing an inverse association between

physical activity, cancer, and mortality as reviewed by the IARC committee in 2002
[9]. Physical activity is most strongly and consistently related to reduced risk of
4 Obesity and Multiple Myeloma 73
breast and colon cancer [9–11]. Excess body weight is associated with increased
mortality from all cancers [3, 9, 12]. Overweight and obesity are characterized by
the accumulation of fat due to excess nutritional intake relative to energy expenditure
or physical activity. Little or no physical activity is one of the leading causes of
increased body mass [12]. In the American Cancer Society CPSII cohort, overweight
and obesity were related to cancer mortality including non-Hodgkin’s lymphoma
and myeloma [3]. As noted above, Renehan et al. show a direct positive relation
between BMI and risk of multiple myeloma [4]. Of note, physical activity has been
shown to reduce the systemic inflammation, whether by itself or in combination
with a reduction in weight/BMI [13].
Two studies have evaluated physical activity and the risk of multiple myeloma.
Drawing on prospective data, Birmann et al. [14] analyzed the Nurses’ Health
Study and the Health Professionals Follow-up Study. In this analysis, relating
updated cumulative average level of physical activity (assessed with a validated
questionnaire) [15, 16] no significant trend between hours of physical activity and
the risk of MM was observed, and the test for trend was not significant. In a
Japanese study, individuals who walked less than 30 minutes a day had a greater
risk of dying from MM (RR 1.99; 95% CI 1.16–3.39) compared to those who
walked more than 1 h per day [17], suggesting a possible protection from higher
levels of activity. As both cohort studies controlled for BMI, confounding by BMI
may be assumed to be controlled; however, the time frame for the BMI and activ-
ity levels may not be temporally correct. While clear benefits of greater physical
activity lowering risk of breast and colon cancer are convincing and well estab-
lished [9], findings for hematologic malignancies are sparse. For the hematologic
malignancies, growing strong evidence supports excess energy balance as mea-
sured by BMI, while energy expenditure is not related to risk. Several important
pathways that link adiposity with the immune function and growth factors are
therefore worth more detailed consideration. These biologic systems will be
described after a more detailed review of the epidemiologic evidence on the causes
of multiple myeloma.
2 Multiple Myeloma
Multiple myeloma is a hematological cancer otherwise known as Kahlers diseases,

myelomatosis, and plasma cell myeloma characterized by malignant proliferation
of a single clone of plasma cells that are involved in the production of immuno-
globulins/antibodies [18]. These plasma cells reside in the bone marrow of individuals
[19]. The malignancy associated with plasma B-cells causes an overproduction of
antibodies (immunoglobulins). Immunoglobulins are composed of two heavy chains
and two light chains. The immunoglobulin that is secreted by the malignant plasma
B-cell is the M protein, which can be found in the serum and urine of individuals
with multiple myeloma [20].
Myeloma is the second most common hematological malignancy in the USA

[21]. It has its clinical onset late in life, with a typical survival of 5 years. While MM
outcome has improved recently with the development of more effective therapies
[22], 5-year survival is barely 40% for patients diagnosed between 1999 and 2006
[23]. There are two premalignant stages to the disease, monoclonal gammopathy of
undetermined significance (MGUS) and smoldering multiple myeloma (SMM).
Differentiation of the stages of disease progression is important in distinguishing
active multiple myeloma from these premalignant stages [24, 25]. Other diseases
related to this aberrant plasma cell disorder include Amyloidosis, and Waldentröm’s
Macroglobulinemia.
2.1 Amyloidosis
Amyloidosis is a disease in which proteins change their shape or conformation,

aggregate, and then form fibrils that infiltrate tissues, potentially leading to organ
failure or death. Amyloid can be deposited throughout the body or it can be locally
deposited in certain organs. The main systemic amyloid diseases are amyloid A
(AA) amyloidosis. This type of amyloidosis is associated with chronic infections
and inflammatory diseases. On the other hand, Amyloid light chain (AL) amyloidosis
is associated with plasma cell dyscrasias and hereditary amyloidoses. Hereditary
amyloidosis has an autosomal-dominant mode of inheritance. The incidence of AL
amyloidosis is 8 per million per year. Approximately 15% of patients with AL amyloidosis
disease also satisfy the clinical criteria for multiple myeloma and vice versa.
Progression of this disease is dependent on the concentration of amyloidogenic
precursor protein. Median survival after diagnosis of AL amyloidosis is 1–2 years
with <5% of patients surviving 10 years after diagnosis [26].
2.1.1 Waldentröm’s Macroglobulinemia
Waldentröm’s macroglobulinemia (WM) is named after Jan Gosta Waldentröm who

first identified the condition in two of his patients suffering from nose bleeds. WM is
defined as a mature B-cell lymphoma characterized by serum monoclonal immuno-
globulin M (IgM). WM is a rare disorder and represents 2% of nodal lymphomas [27].
It is incurable, of unknown etiology, and most patients die of the disease, with a
median survival of 5 years. Prognosis is dependent on age, hemoglobin concentration,
serum albumin level, and b2-microglobulin levels [28]. WM usually presents late in
life, and can also contribute to mortality of coexisting diseases unrelated to WM [28].
Clinical features of the disease are: anemia, organomegaly, lymphadenopathy, and
hyperviscosity. WM seems to appear in families, suggesting the influence of a single
genetic defect [29]. Median age of onset is 63 years of age and this disease is more
common in males than females [29, 30] and has a higher incidence in whites, with
blacks accounting for only 5% of patients [28]. The predominant risk factor for
WM is pre-existing IgM MGUS [28].
3 Overview of Pathogenesis
The pathogenesis of multiple myeloma is still unclear, but there are emerging
insights into potential causes of multiple myeloma. Exposure to pesticides, radiation,
insecticides, organic solvents, hair dyes and coloring products, and other occupational
and environmental factors have been associated in some studies with the risk of
MM [18, 20]. Increased incidence of multiple myeloma has also been observed
among persons diagnosed with rheumatoid arthritis [31]. Increasing age is the single
most important risk factor for multiple myeloma and other established risk factors
include gender, family history of lymphatohematopoietic cancer (LHC), and MGUS
[19]. Family history encompasses studies of clustering of myeloma in families,
pedigree-based studies, and self-report through epidemiologic population based
studies. Together these studies support family history conveying risk through shared
genetic factors [32, 33]. Multiple myeloma appears to aggregate in families with
MM, chronic lymphocytic leukemia, and non-Hodgkin lymphoma (NHL) [33] and
may follow an autosomal-dominant mode of inheritance [34, 35].
3.1 Incidence in the USA
Multiple myeloma affects people primarily between the ages of 40–84 years and is
rarely diagnosed before the age of 40 years. After the age of 84, MM incidence
steadily tapers off [20]. Blacks have a younger age at onset (<50) compared to white
Americans (p = 0.002) in numerous studies [36]. MGUS has a higher prevalence in
African Americans consistent with the increased risk of multiple myeloma in blacks
compared to Caucasians [37]. Historically, Kyle et al. [38] developed studies based
on the population of Olmstead County, MN, and reported on data from 1985 to 1998
showing a median age of 66 at the diagnosis of multiple myeloma [38]. Incidence
rates for multiple myeloma are higher among males than females approximately 1.5
times and highest among African Americans [20] . African Americans have
twice the incidence of multiple myeloma compared to whites [38, 39]. In the
Connecticut Tumor Registry, the annual incidence of multiple myeloma increased
during the period of 1935–1939 from 0.4 per 100,000 in men and 0.5 per 100,000
in women to 4.7 per 100, 000 in men and 2.8 per 100, 000 in women from 1990 to
1991 [40]. Furthermore, the annual incidence of MM among males in Connecticut,
Atlanta, Georgia, San Francisco-Oakland, and Detroit areas was 1.5 per 100,000 in
men and 1.1 per 100,000 in women during the years of 1947–1950 and rose to
3.8 per 100, 000 in men and 2.7 per 100,000 in women during 1969–1971. Incidence
rates did not change appreciably between the years 1969–1971 and 1983–1984 [41].
The Surveillance Epidemiology and End Results (SEER) Registry data from 1975
on incidence are summarized by race–ethnicity in Fig. 4.1. The SEER data indicate
the age-adjusted overall incidence rate from 1975 to 2007 was 5.56 per 100, 000 for
all races and 6.94 per 100,000 for males and 4.59 per 100, 000 for females [42].
Fig. 4.1 SEER Incidence and US Death Ratesa Myeloma, Both Sexes -Joint Analyses for Whites
and Blacks from 1975-2007 and for Asian/Pacific Islanders, American Indians/Alaska Natives and
Hispanics from 1992-2007. Source: Incidence data for whites and blacks are from the SEER 9
areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta).
Incidence data for Asian/Pacific Islanders, American Indians/Alaska Natives, and Hispanics are
from the SEER 13 Areas (SEER 9 Areas, San Jose-Monterey, Los Angeles, Alaska Native Registry,
and Rural Georgia). Mortality data are from US Mortality Files, National Center for Health
Statistics, CDC. a Rates are age-adjusted to the 2000 US Standard Population (19 age groups—
Census P25-1103). Regression lines are calculated using the Joinpoint Regression Program Version
3.4.3, April 2010, National Cancer Institute. Joinpoint analyses for whites and blacks during the
1975–2007 period allow a maximum of four joinpoints. Analyses for other ethnic groups during
the period 1992–2007 allow a maximum of two joinpoints. bAPI = Asian/Pacific Islander. cAI/
AN = American Indian/Alaska Native. Rates for American Indian/Alaska Native are based on the
CHSDA (Contract Health Service Delivery Area) counties. dHispanic is not mutually exclusive
from whites, blacks, Asian/Pacific Islanders, and American Indians/Alaska Natives. Incidence data
for Hispanics are based on NHIA and exclude cases from the Alaska Native Registry. Mortality
data for Hispanics exclude cases from Connecticut, the District of Columbia, Maine, Maryland,
Minnesota, New Hampshire, New York, North Dakota, Oklahoma, and Vermont. Reproduced with
permission from SEER [42]
3.2 Obesity and the Risk of Multiple Myeloma
Empirical evidence linking obesity and multiple myeloma has emerged over the
past 20 years. Friedman et al. [43] in an early prospective study at Kaiser Permanente
Medical Care Program in Northern California followed 143,574 individuals of
the health maintenance organization and observed a positive association between
obesity and subsequent diagnosis of multiple myeloma. Based on 33 observed
cases, the standardized morbidity ratio (SMR) was 1.55 (95% CI 1.06–2.17). This
association was examined further in an additional Multiphasic–Health Check-up
Cohort (MHCs) of 163,561 who were followed for 24 years. Participants of this
cohort received multiphasic health checkups between 1964 and 1972 at the Kaiser
Permanente Medical Centers in Oakland and San Francisco. BMI assessed at base-
line was associated with multiple myeloma in white men among whom 66 cases
were diagnosed (RR 1.07; 95% CI 1.01–1.15 per unit increase in BMI); but not in
white women (49 cases), RR = 0.97 (0.90, 1.04). Smaller numbers of cases among
black men and women showed increasing risk with increasing BMI though the
estimates were not significant [43].
Additional early prospective data come from Japanese men and women ages
40–79 years in the Japan Collaborative Cohort Study, who were followed to assess
the association of BMI and multiple myeloma. After adjusting for age, the relative
risk was higher for men than women (HR 1.5; 95% CI 1.0–2.2). Men and women
who were obese (BMI ³ 30 kg/m2) had a significantly increased risk of multiple
myeloma compared to normal weight individuals (HR 2.8; 95% CI 1.0–7.7) [17].
In a multisite case–control study building on SEER registry sites, Brown et al. [44]
evaluated the association of BMI and multiple myeloma among men and women
30–79 years of age diagnosed between the years of 1986 and 1989. In this study,
weight and height were reported by participants as their usual adult values. Obese
(³30 kg/m2) compared to normal weight (18.5–24.9 kg/m2) individuals were at
increased risk of multiple myeloma; odds ratios were elevated both in whites
(OR 1.9; 95% CI 1.2–3.1) and in blacks (OR 1.5; 95% CI 0.9–2.4). A significant
trend in risk with increasing BMI was observed in white men and women (p for trend
<0.001), and for black women (p for trend = 0.042) but not in the subset of black men
for whom risk of myeloma among the overweight and obese was not elevated.
Additional prospective studies reporting on the association between obesity
and multiple myeloma include the Iowa Women’s Health Study. This prospective
study of 37,083 postmenopausal women followed from 1986 through 2001
evaluated self-reported height, weight, and waist circumference in relation to 95
cases of incident multiple myeloma. In age-adjusted models, women in the highest
category of anthropometric measurements compared to the lowest category were at
increased risk of developing multiple myeloma. For BMI, the rate ratio was 1.5
(95% CI 0.92–2.6); weight 1.9 (95% CI 1.1–3.4); waist circumference 2.0 (95% CI
1.1–3.5); and hip circumference 1.8 (95% CI 1.0–3.0) [45].
Data from the Nurses’ Health Study and the Health Professionals Follow-up
Study include 136,623 participants (>2.1 million person-years at risk) and 215
incident cases of multiple myeloma. In this study, BMI was positively and significantly
associated with the incidence of multiple myeloma. The association was strongest
in men with a BMI ³30 kg/m2 compared to participants with BMI <22 kg/m2 (RR
2.4; 95% CI 1.0–6.0). After adjusting for gender, the trend in risk with increasing
BMI was significant [14]. A listing of all prospective studies of BMI and incidence
of multiple myeloma is presented in Table 4.1.
Renehan combined prospective cohort data separately for men (seven studies)
and women (six studies) and observed a relative risk of 1.11 for a 5 kg/m2 increase
Table 4.1 Cohort studies of obesity and incidence of multiple myeloma
Cases Assessment BMI (kg/m2) categories Relative risk
(cohort of weight and (95% CI) obesity
Study Sex and age size) height Reference Overweight Obesity vs. normal weight
Friedman et al. [43] Men and women 167 (150,296) Measured £23.1;£21.0 25.2–27.3; ³27.3; ³25.8a 1.92(0.92–4.01)m;
aged 13–92 22.9–25.8a 0.75 (0.37–1.53)w
Blair et al. [45] Women aged 55–69 years 95 (37,083) Self-reported 18.5–22.9 25.0–29.9 ³30.0 1.50 (0.92–2.60)w
MacInnis et al. [46] Men and women aged 27–75 years 55 (40,909) Measured <25.0 25.0–29.9 ³30.0 1.00 (0.50–2.10)m,w
Oh et al. [47] Men aged ³20 years 103 (781,283) Measured 18.5–22.9 25.0–26.9;
27.0–29.9
Birmann et al. [14] Men aged 40–75 years and women 215 (136,623) Self-reported <22.0 25.0–29.9 ³30.0 2.40 (1.00–6.00)m;
aged 30–55 years 1.20 (0.70–2.20)w
Engeland et al. [48] Men and women 6,115b Measured 18.5–24.9 25.0–29.9 ³30.0; 30.0–34.9; 1.28 (1.10–1.47)m;
aged 20–74 years (2,000,424) 35.0–39.9; ³40.0a 1.31 (1.16–1.48)w
Fernberg et al. [49] Men aged 14–72 years 520 (336,381) Self-reported 18.5–25.0 25.1–30.0 ³30.0 0.70 (0.46–1.06)m
Reeves et al. [2] Women aged 50–64 years 491 (1,222,630) Self-reported 22.5–24.9 25.0–27.4; ³30.0 1.16 (0.95–1.42)w
27.5–29.5
Britton et al. [50] Men and women aged 25–70 years 268 (371,983) Measured <25.0 25.0–29.9 ³30.0 1.17 (0.80–1.72)m;
1.06 (0.72–1.58)w
Pylypchuk et al. [51] Mena and women 279 (120,852) Self-reported <24.9 25.0–29.9 ³30.0 1.13 (0.68–1.88)m,w
aged 55–69 years
Söderberg et al. [52] Men and women aged 18–96 years 140 (70,067) Self-reported 18.5–24.9 25.0–29.9 ³30.0 2.10 (1.10–3.70)m,w
De Roos et al. [53] Women aged 50–79 years 92 (81,219) Measured <25.0 25.0–29.9 30.0–34.9; ³35.0 0.73 (0.43–1.23)w
Kanda et al. [54] Men and women aged 40–69 years 88 (94,547) Self-reported 23.0–24.9 25.0–29.9 ³30.0 0.76 (0.18–3.20)m,w
Lu et al. [55] Women aged 22–84 years 111 (121,216) Self-reported 20.0–24.9 25.0–29.9 ³30.0 0.86 (0.48–1.55)w
Troy et al. [56] Men and women aged 55–74 years 243b(142,982) Self-reported 18.5–24.9 25.0–29.9 ³30.0 1.68(1.02–2.77)m;
1.71 (1.02–2.87)w
a
BMI categories for men and women, respectively
b
Plasma cell neoplasms
m
Men
w
Women
in BMI for each gender [4]. This meta-analysis also reported no meaningful heterogeneity
among the studies evaluating BMI and multiple myeloma. A subsequent updated
analysis reported by Wallin et al. [57] also summarizes the prospective evidence of
an association of body mass index and the risk of multiple myeloma. For this study,
they searched PubMed and EMBASE through January 26, 2011. Prospective cohort
studies, relative risks, and 95% confidence intervals were included in evaluating the
association. A random effects model was used to combine the study specific data.
A total of 20 studies (15 on incidence of multiple myeloma and 5 on mortality) were
included. Compared to individuals in the normal weight category, the risk of multiple
myeloma was statistically significant for the overweight (RR 1.12; 95% CI 1.07–1.18)
and obese (RR 1.21; 95% CI 1.08–1.35) categories. Corresponding relative risk
estimates for multiple myeloma mortality were overweight (RR 1.15; 95% CI 1.04–1.27)
and obese (RR 1.54; 95% CI 1.35–1.76).
To address the question of timing of obesity and risk of multiple myeloma,
Birmann et al. evaluated data from pictograms and self-reported weight at age 18 in
the Nurses’ Health Study. A validated somatogram-depicted body shape (current
and at ages 5, 10, 20, 30, and 40 years) [58] was queried in 1988. An analysis of life
course weight and weight change included women who completed the 1988
(somatogram) questionnaire and had no cancer history at that time. Women were
followed through June 2008. As in previous analyses of somatogram data [59], we
classified body shapes as relatively lean, medium, and heavier at the specified ages
and for the average shape at ages 5 and 10 (“childhood”) and ages 10 and 20 years
(“adolescent”). We confirmed 126 cases of multiple myeloma over 1,049,600 person-
years for the somatogram analyses and observed suggestive increases in MM risk
among women who reported heavier average body shapes in childhood versus those
with a relatively lean childhood shape (HR 1.8; 95% CI 0.8–4.2) and adolescence
(HR 1.6; 95% CI 0.6–4.1) after controlling for subsequent weight gain. These data
are consistent with existing evidence that obesity is positively associated with the
risk of MM and suggest that obesity over the life course (or area under the curve of
life) may drive risk of multiple myeloma. Similar data for weight at age 20 and
increased risk of NHL in the prospective PLCO trial add support to the role of lifetime
adiposity in hematologic malignancies [56]. Confirmation of this finding for multiple
myeloma in men and in other large populations may help inform our understanding
of the role of adiposity in etiology of this disease. Questions of timing of adiposity
and disease development may also be informed by data on intermediate markers.
The clearest such marker is MGUS, which we discuss next.
3.3 Obesity and MGUS
MGUS develops years before diagnosis of multiple myeloma. Cross-sectional data

support a relation between BMI and the prevalence of MGUS. Given the lack of
surveillance for this abnormality, incidence per se is not readily studied. It may
however be informative. Screening 1,000 black and 996 Caucasian women between
the ages 40–70 years of similar socioeconomic status, MGUS was detected in 39 or
3.9% of blacks and 21 or 2.1% of Caucasians. In multivariate analysis, obesity (OR
1.8; 95% CI 1.03–3.1; p = 0.04) and black race (OR 1.8; 95% CI 1.04–3.1; p = 0.04)
were independently associated with an increased risk of MGUS [60]. Thus, obesity
and race are related to MGUS in a similar pattern as they are to multiple myeloma,
suggesting they operate at an earlier stage in disease etiology. On the other hand,
obesity and race may also operate to change the rate of transformation from MGUS
to multiple myeloma, though this has not been rigorously studied. How obesity
relates to patterns of gammopathy and risk of progression from MGUS to disease
may help inform strategies to interrupt this progression.
4 Biologic Mechanisms Linking Obesity to Multiple Myeloma
We next consider plausible pathways that may relate risk factors to etiology and
provide insights for further study or potential for points to interrupt pathogenesis.
4.1 Insulin-Like Growth Factor Receptors
There is evidence that implicate IGF-I and its receptor in tumor progression [61].
Insulin-like growth factors (IGFs) are multifunctional peptides that are involved in
cell proliferation, differentiation, and apoptosis. The IGF system is a complex
molecular system that is composed of two ligands (IGF-I and IGF-II), two receptors
(IGF-IR and IGF-IIR), and approximately six high-affinity binding proteins
(IGFBP-1 to-6). The biological accessibility and activity of IGF-I are modulated by
the binding proteins (IGFBPs) in several ways. IGFBPs transport IGFs from circu-
lation to the peripheral tissues, maintain a reservoir of IGFs in circulation, inhibit
IGF action, and also mediate IGF-independent biological effects [62]. The IGF-I
receptor is an important regulator of cell cycle [62, 63]. Studies have consistently shown
that an increase in circulating insulin levels is associated with an incremental
increase in body mass index. In the insulin-cancer hypothesis, prolonged hyperinsu-
linemia causes a decrease in the production of IGF binding protein specifically
IGFBP-1 and IGFBP-2 which typically bind to IGF-I inhibiting its action. Increased
amounts of free IGF-I cause changes in the cellular environment enhancing tumor
growth or proliferation. The activation of the insulin receptor by insulin triggers a
signaling cascade in the extracellular-signal-regulated kinase (ERK) and phospho-
rylated-3 kinase (PI-3k) pathways suggesting that insulin signaling has the capability
to be both mitogenic and antiapoptotic.
Studies have documented greater expression of IGF-I and IGF-IR in many human
malignancies such as lung, breast, thyroid, gastrointestinal tract, prostate, glioblas-
tomas, neuroblastomas, rhabdomyosarcomas, and leukemia [61]. In addition, high
plasma IGF-I levels are considered a potential risk factor for premenopausal breast,
prostate, and colon cancer [64–68]. Circulating IGF-1 mainly binds to IGF binding
protein, IGFBP-3, and both peptides are dependent on growth hormones but are
affected by other factors such as age, sex, and nutritional status. However, to date,
no data relate IGF plasma measures to risk of multiple myeloma. SNPs from the
IGF pathway have been evaluated in a small set of cases from the Harvard cohorts.
Though limited by small sample size, SNPs in genes encoding insulin receptor
substrate 1 (IRS-1), IGF-1, IGF binding protein 2, IRS-2, and gp130 showed sug-
gestive associations with multiple myeloma risk [69].
IGFs have also been delineated to be important regulators of bone remodeling.
Bone formation or bone resorption would then be dependent on the type of IGF
binding protein present. Moreover, studies have shown that myeloma cells produce
IGFBP-4, which may be important for IGF induction of osteoblast activation conse-
quently causing less bone formation [70].
4.2 Adipokines
It has become increasingly clear that adipose tissue is not just involved in long-term
energy storage but is a large source of endocrine and metabolic activity. White adipose
is now considered an active endocrine organ that communicates with the brain and
peripheral tissues through a variety of polypeptide hormones called adipokines
[63, 71]. There are approximately 100 different adipokines in humans as well as
rodents and these adipokines influence many biologic systems such as inflamma-
tion, immunity, hemostasis, fluid balance, cell proliferation, angiogenesis, glucose
homeostasis, hematopoiesis, and neurotropic functions [71]. Typically adipose tissue
deposits in the subcutaneous and visceral areas. When obesity occurs adipose
tissue expands in these areas and also to other areas [72].
Adipokines are important as most stimulate inflammatory responses and are
upregulated in obesity and promote obesity-induced metabolic and cardiovascular
diseases. These findings have led to the belief that metabolic dysfunction is due in
part to an imbalance in pro- and anti-inflammatory adipokines contributing to
obesity-related complications. During states of obesity, adipokines are upregulated
and proinflammatory proteins promote obesity-related disorders. Proinflammatory
proteins include leptin, tumor necrosis factor (TNF), IL-6, resistin, retinol-binding
protein 4 (RBP4), lipocalin 2, IL-8, angiopoietin-like protein 2 (ANGPTL2),
CC-chemokine ligand 2 (CCL2), CXC-chemokine ligand 5 (CXCL5), and nicotin-
amide phosphoribosyltransferase (NAMPT). It is the upregulation of the above
listed proteins that contribute to metabolic dysfunction in many individuals [72].
4.3 Leptin
Leptin is an adipocyte-derived hormone that acts on the brain to regulate food con-
sumption. Leptin is postulated to act as a signal, alerting someone of when they
have reached satiety and when they are starving, therefore leptin is considered an
anorectic hormone. Leptin is a multifunctional hormone and a product of the obese

(ob) gene. Circulating leptin levels are associated with total body fat and to a smaller
extent body mass index. Hence the secretion of leptin is strongly correlated with fat
cell volume in addition to acting as an antiobesity hormone.
One current hypothesis states that elevated leptin bioactivity which is directly
related to obesity and high fat consumption is a major factor in the development
process of cancer [73–75]. Leptin plays a key role as an angiogenic factor enhanc-
ing vascular endothelial cell proliferation in vitro [76]. Moreover, leptin is believed
to play an important role in the growth of hematopoietic malignancies [77]. In one
study, plasma concentration of leptin was increased in male and female myeloma
patients at the time of diagnosis compared to healthy controls and leptin was found
to induce changes in genes that played a key role in cellular growth, viability, and
intracellular signaling in two myeloma cell lines [78]. Other studies have also noted
elevated leptin levels in MM compared to controls [79]. However, in contrast to the
previous reported findings, in a case–control study, leptin was not associated with
risk of MM [80]. To date, no epidemiologic studies have evaluated this pathway for
risk of multiple myeloma.
4.4 Adiponectin
Adiponectin is an adipocyte secreted endogenous insulin sensitizer. Circulating

levels are inversely associated with insulin resistance, insulinemia, and sex steroids.
Adiponectin, also denoted gelatin-binding protein-28 (GBP28), adipoQ, ACRP30, or
apM1, is considered a key link between obesity, insulin resistance, and also diabetes.
Unlike other adipose tissue derived proteins, adiponectin levels are found to be lower
in obese compared to lean individuals. Accumulating evidence suggests that circu-
lating adiponectin levels are negatively correlated with obesity, or more specifically
central obesity, insulin resistance, type 2 diabetes, and circulating adiponectin levels.
Plasma concentrations of adiponectin appear to increase with weight loss [81].
Studies have reported that circulating levels of adiponectin in vivo is inversely asso-
ciated with obesity, insulin resistance [82], and cancers such as endometrial cancer
[83], leukemia [84], postmenopausal breast cancer [85], and colon cancer [86].
Dalamaga et al. [80] observed that lower levels of adiponectin were associated with
higher risk of MM after adjusting for age, gender, BMI, and serum levels of leptin. It
is hypothesized that adiponectin may play a protective role in MM.
No mechanistic data have been reported relating adiponectin to multiple myeloma.
This pathway requires further study as a means to identify risk of disease.
4.5 IL-6
One potential mechanism whereby excess body weight may contribute to the
increased risk for multiple myeloma is through the cytokine interleukin-6 (IL-6).
IL-6 is synthesized by adipocytes, and concentrations of IL-6 are directly associated
with obesity. IL-6 plays a key role in the immune response, inflammation, and
hematopoiesis [87, 88]. In the blood, approximately 15–35% of total IL-6 is produced
by adipose tissue, and cumulating evidence suggest that obesity is characterized by
a state of chronic low-grade inflammation.
Moreover, IL-6 is considered a key growth factor in the development of multiple
myeloma. Bone marrow plasma cells are derived from plasmablastic cells. IL-6 was
first identified as an inducer of Ig in the Epstein–Barr virus-infected CESS lympho-
blastoid cell line [89]. IL-6 has been shown to be involved in the proliferation of
normal plasmablastic cells and has an effect on the development of plasmablastic
cells into mature plasma cells. IL-6 is an important growth factor for multiple
myeloma in vivo and plays a key role in the promotion and survival of malignant
plasma cells. In addition, the importance of IL-6 is supported by the finding
that concentrations of IL-6 may be correlated to tumor size (mass), disease stage,
and prognosis of MM patients [90]. Treatment of individuals with IL-6 monoclonal
antibody resulted in a decrease in serum M protein levels, inhibition of multiple
myeloma cell proliferation, decrease in tumor mass, and a reduction in toxicities
associated with the tumor. IL-6 acts as an antiapoptotic factor by protecting myeloma
cells from apoptosis [90]. Some epidemiologic data bear on this issue. Cozen
assessed IL-6 promoter SNPs and risk of multiple myeloma in a case–control study
in Los Angeles County, observing significant associations with several SNPs [91].
Evaluating SNPs, Birmann et al. noted that three IL-6 receptor SNPs were significantly
associated with the risk of multiple myeloma. Again small numbers preclude strong
conclusion based on these preliminary data. The ongoing collaborative analysis of
over 500 cases and matched controls from nine cohorts should add insights to the
potential for these or other SNPs to help identify high-risk populations [69].
It has also been suggested that IL-6 plays a key role in myeloma bone disease.
This cytokine has been shown to inhibit bone formation in vitro and has been found
to enhance and leads to osteoclast formation. This is further supported by the use of
monoclonal anti-IL-6 antibodies in myeloma patients to reduce hypercalcemia
and bone disease [70]. Consequently, it is clear that the IL-6 does play an important
role in the pathogenesis of MM, both as a growth factor, a survival factor in MM,
and the inhibition of apoptosis in multiple myeloma cells. Together these data
support a role of IL-6 and suggest a potential for this pathway to mediate some of the
effect of obesity on risk.
4.6 TNF-a
Tumor necrosis factor (TNF-a) is a cytokine that is involved in inflammatory and

immune responses [70]. It is expressed in and secreted by adipose tissue. The level of
TNF-a is correlated with the level of obesity/adiposity in the body and is also asso-
ciated with insulin resistance [92]. It is involved in hematologic malignancies, such
as multiple myeloma, and can be found in high concentrations in the plasma of MM
individuals. This protein is produced in malignant and nonmalignant plasma cells in
bone marrow (BM) [70]. Circulating levels of TNF-a are mediated by activation of
NF-кB (nuclear factor кB). TNF-a concentration is higher in patients with bone
disease possibly because it is a potent stimulator of IL-6 [93] which is involved in
bone resorption [94].
4.7 Nuclear Factor-kB
Obesity is considered a state of low-grade inflammation and nuclear factor kappa B

is important in mounting an inflammatory response [95]. Nuclear factor кB promotes
immunity from diseases by controlling the expression of certain genes that are crucial
in inflammation. NF-кB is a group of dimeric transcription factors that regulate vari-
ous genes that mediate cell growth, angiogenesis, cell adhesion, and protect from
apoptosis [96]. Activation of NF-кB is induced by cytokines, chemokines, growth
factors, adhesion molecules, antigen receptors, environmental stress, and pathogen-
associated molecular patterns. It also regulates the expression of many of the same
factors delineated above. As a transcription factor involved in the regulation of many
genes, NF-кB has been shown to contribute to the pathogenesis of multiple myeloma
in numerous ways. It regulates many proteins that are involved in the pathogenesis
of multiple myeloma. IL-6 is considered an important growth and antiapoptotic
cytokine for multiple myeloma that is regulated by NF-кB. NF-кB also regulates
GM-CSF another cytokine that contributes to multiple myeloma cell growth. NF-кB
regulates BAFF (B-cell-specific growth factor), which modulates multiple myeloma
cell proliferation and survival possibly through the activation of NF-кB AKT and
mitogen-activated protein kinase (MAPK) signaling pathways that regulate other
growth and survival factors such as Bcl-2 and Mcl-1 [97].
The regulation of cytokines and chemokines by NF-кB in addition to prompting
tumor cell proliferation is also involved in the clinical presentation of multiple
myeloma. MIP-1a is an osteoclast stimulator in multiple myeloma that contributes
to the development of osteolytic bone lesions, but MIP-1a is also a growth and
survival factor in the pathogenesis of multiple myeloma [98, 99].
In addition, NF-кB also regulates cell cycle regulators, namely, c-Myc, cyclin
Ds, cyclin E, and E2F3a that cause cells to become insensitive to cell cycle arrests.
Moreover, the dysregulation of cyclin D1 occurs in approximately 40% of MM
patients and cyclin D1 overexpression occurs in MGUS, indicating that cyclin D1
dysregulation is involved in the early stages of multiple myeloma pathogenesis
[100, 101]. Nuclear factor-кB has been shown to play an antiapoptotic role as well.
It regulates the expression of antiapoptotic molecules in multiple myeloma such as
Bcl-2, Bcl-xL, A1, cellular inhibitor of apoptosis protein (cIAP), X-linked IAP
(XIAP), and c-FLICE-inhibitory protein (FLIP) [97].
NF-кB signaling in numerous cell types contributes to the pathogenesis of mul-
tiple myeloma. It is clearly demonstrated that nuclear factor-кB plays an important
role in the pathogenesis and survival of tumorous cells based on a multiplicity of
evidence presented above.
4.7.1 Aspirin Use and Risk of MM
As above, the low-grade inflammatory state associated with obesity suggests that
aspirin may have a potential role in prevention. In this section, aspirin use and MM
risk will be reviewed.
Returning to epidemiologic evidence on etiology and prevention of multiple
myeloma, provocative data from the Nurses’ Health Study and Health Professionals
Follow-up Study suggest that long-term use of aspirin may significantly reduce
the risk of disease. Aspirin inhibits several pathways mediated by nuclear factor
(NF)-kB, cyclooxygenase (COX)-2, or their targets that are important in MM pathogene-
sis. Of particular interest, aspirin suppresses nuclear factor (NF)-kB, a family of
transcription factors that mediate normal B-cell development and are upregulated in
MM cell lines [102, 103], and cyclooxygenase (COX)-2, which metabolizes aracha-
donic acid to numerous proinflammatory and potentially tumorigenic molecules
[104]. COX-2 is highly expressed in MM cells, predicts poor outcome in MM patients
[105], and is a molecular target of NF-kB. Aspirin may also suppress other targets
of NF-kB or COX-2 involved in MM pathogenesis, including interleukin (IL)-6, a
pleiotropic proinflammatory cytokine and an important growth factor for MM [106],
and cyclin D1, which influences normal and malignant cell proliferation and is
dysregulated in MM [107, 108].
Regular aspirin users may have a reduced risk of Hodgkin lymphoma (HL)
[109, 110], NHL [111, 112], and several solid tumors [113], as well as a reduced risk
of mortality from hematologic malignancies with 5 or more years of regular use
[114]. In a population-based case–control study of women in Connecticut (179 MM
cases, 691 controls), regular aspirin use at least 1 year prior to diagnosis or interview
was not associated with MM risk; duration of aspirin use was not evaluated [115].
The null findings in the Connecticut study may be explained in part by the relatively
stringent definition of regular aspirin use: daily use for 6 months or more during the
reference period. Only 9 MM patients and 35 controls reported regular use by that
definition [115]. To examine whether regular aspirin use influences MM risk, we
conducted prospective analyses in the Health Professionals Follow-up Study and
Nurses’ Health Study cohorts. We used biennially updated data to characterize
aspirin use from baseline through a cancer diagnosis, death, or 2006. We applied a
4-year lag in exposure classification to diminish the influence of preclinical MM on
aspirin use habits. We obtained hazard ratios (HR) and 95% confidence intervals
(CIs) from multivariable proportional hazard models to assess the association of
aspirin use with MM risk. We tested for trend across increasing dose and duration
of aspirin use. During 2,179,486 person-years, we confirmed 273 incident MM
diagnoses, 222 of which had prospective information on typical aspirin dose.
Compared to never-users, participants with a cumulative average of ³5 adult strength
(325-mg) tablets per week had a 48% lower MM risk (HR 0.52; 95% CI 0.31–0.86;
tablets per week, p-trend = 0.03). MM risk was also reduced in persons with
³11 years of continuous regular aspirin use (HR 0.62; 95% CI 0.39–1.00; duration,
p-trend = 0.27). The associations appeared stronger in men than in women, possibly
reflecting gender differences in use patterns. These data from the first prospective
study of aspirin use and MM support an etiologic role for NF-kB- or COX-2-mediated
pathways. Further study will be needed before moving to a clinical role for aspirin
or COX-2 inhibitors for chemoprevention, including refined understanding of the
temporal impact of exposure on progression.
5 Impact of Obesity on Multiple Myeloma Diagnosis
Obesity is related to increased incidence of multiple myeloma, increased mortality

due to myeloma, and is associated with MGUS a precursor lesion and risk marker.
In addition, the pathways summarized above offer important underlying biology to
support the inflammatory state of obesity as an etiologic or causal pathway for this
disease. Questions remain. Langren et al. found that MGUS was twice as common
in obese women compared to nonobese adults, independent of race [60]. Whether
higher BMI modifies the rate of progression from MGUS to MM remains to be
fully elucidated. Does BMI modify the clinical likelihood of detecting MGUS or of
diagnosing multiple myeloma? Data to support these possibilities has not been
reported. Whether obesity modifies the stage or subtype of myeloma and the aggres-
siveness of disease also remains to be quantified.
6 Diagnosis of Multiple Myeloma
It is extremely difficult to diagnose multiple myeloma during its early stages because
there may be no symptoms until the disease has reached advanced stages. The
most common symptoms at presentation are fatigue, bone pain, recurrent
infections [19, 116] weakness, and weight loss [19]. The tests that are involved in
the diagnosis of multiple myeloma include a detailed medical history report, physical
examination, bone marrow biopsy, and laboratory testing (which include complete
blood count, chemical analysis, serum and urine protein electrophoresis with
immunofixation, and quantification of monoclonal protein). To determine bone-
related lesions, radiography of the spine, skull, chest, pelvis, humeri, and femora is
considered the standard of care. For patients with normal results from conventional
radiography and in patients with the possible presence of plasmacytoma of bone,
magnetic resonance imaging is recommended. Computed tomography and MRI are
also recommended in persons with possible cord compression and this should be
performed on a rather urgent time frame. Staging is according to the international
staging system which defines three risk groups according to b2-microglobulin and
albumin levels [117].
The International Myeloma Working Group has established a precise diagnostic
criterion for multiple myeloma (see Table 4.2). Some patients will present with no
detectable monoclonal protein but will satisfy the other diagnostic criteria and
are classified as having nonsecretory multiple myeloma. A useful tool to monitor
oligosecretory and nonsecretory myeloma is the serum-free light chain [116].
With the advent of technology, new prognostic markers have been identified for the
Table 4.2 Diagnostic criteria for multiple myeloma

1. Monoclonal plasma cells in the bone marrow ³10% and/or presence of a biopsy-proven
plasmacytoma
2. Monoclonal protein present in the serum and/or urine
3. Myeloma-related organ dysfunction (one or more)
C-calcium elevation in the blood (serum calcium >10.5 mg/l or upper limit of normal)
R-Renal insufficiency (serum creatinine >2 mg/dl)
A-Anemia (hemoglobin <10 g/dl or 2 g < normal)
B-Lytic bone lesions or osteoporosis
Adapted from: Durie, B. G.; Kyle, R. A.; Belch, A.; Bensinger, W.; Blade, J.; Boccadoro, M.;
Child, J. A.; Comenzo, R.; Djulbegovic, B.; Fantl, D.; Gahrton, G.; Harousseau, J. L.; Hungria, V.;
Joshua, D.; Ludwig, H.; Mehta, J.; Morales, A. R.; Morgan, G.; Nouel, A.; Oken, M.; Powles, R.;
Roodman, D.; San Miguel, J.; Shimizu, K.; Singhal, S.; Sirohi, B.; Sonneveld, P.; Tricot, G.; Van
Ness, B., Myeloma management guidelines: a consensus report from the Scientific Advisors of the
International Myeloma Foundation. Hematol J 2003, 4 (6), 379–98 [118]
identification of chromosomal abnormalities in MM cells such as array-based comparative

genomic hybridization (CGH), spectral karyotyping, and interphase fluorescence in
situ hybridization (FISH) [119]. These techniques are used to detect cytogenetic and
genetic abnormalities present in multiple myeloma clonal plasma cells. In the early
years, conventional karyotyping was the method used to identify cytogenetic
abnormalities in patients. However, because of the low proliferative capacity of MM
cells, karyotyping is only able to successfully identify approximately 40% of abnormal
metaphases in MM patients [120, 121] Therefore, newer conventional methods are
considered more informative about a patient’s disease status. FISH and CGH have
increased the detection of genetic abnormalities in MM patients. No data relate any
of these abnormalities to risk factors for multiple myeloma.
Chromosomal abnormalities were initially believed to occur in a highly irregular
and nonspecific pattern; however, they seem to follow a particular logic. These
abnormalities have gained acceptance as biomarkers and may be used in clinical
decision making [119]. Chromosomal abnormalities can be found in approximately
20–60% of new cases and 60–70% of patients with progressive disease suggesting
an increase in chromosomal abnormalities with a disease in progression [122]. No
relation to risk factors or variation in rates of disease progression has been reported
for chromosomal abnormalities. Rather, chromosomal abnormalities are important
independent predictors of survival in MM patients, predictors of response to treat-
ment, event-free survival, and overall survival. The detection of these abnormalities
typically indicates a proliferative and aggressive tumor and consequently a poor
prognosis for many MM patients [120].
6.1 Common Chromosomal Abnormalities
Chromosomal gains, losses, translocations, and mutations can all be found in

multiple myeloma and almost all of these aberrations can also be found in MGUS
[121, 122]. In multiple myeloma, there are four types of aneu ploidy. The categories
are hypodiploid 44–45 chromosomes, pseudodiploid 44/45–46/47 chromosomes,
hyperdiploid > 46/47 chromosomes, and hypotetraploid has greater than 75 chromo-
somes [119, 120]. These genetic changes noted above may impair or prevent
apoptosis of myeloma cells which continue to grow in the bone marrow [122].
One particular mutation associated with a poor outcome is chromosome 13
abnormalities, otherwise referred to as D 13, which has a wide range of reported
prevalence among various studies [119, 123]. D 13 has been found to be associated
with poorer survival and a poorer response to treatment [119]. There also appears to
be a strong association between D 13 and other genetic changes such as t(4;14) and
t(14;16) [123].
Mutations of the tumor suppressor gene (TP53) have a frequency of 2–20% in
MM patients. The TP53 mutations have been found in MGUS but at low rates and
appear to gradually increase with the progression of disease, reaching 80% in MM
cell lines. TP53 has also been found to be associated with poor overall prognosis
[123]. Other important mutations include genes of the Ras family. Two genes that
belong to the Ras family, N-ras and K-ras mutations, are associated with a higher
proliferation rate in MM patients than in MGUS patients and are associated with
poorer survival in persons with MM [122, 123]. Despite this breadth of knowledge,
no risk factor studies have been conducted relating environmental or lifestyle factors
to risk through these potential pathways.
7 Effect of Obesity on Treatment
Obesity can affect treatment through a variety of means. Obesity can cause variation
in treatment outcomes through alterations in chemotherapy dosing and also pharma-
cokinetics (see Chap. 5). The factors that affect the distribution of drugs in tissues
and the volume of distribution (Vd) are body composition, regional blood flow,
and binding to plasma protein. In addition, the liver of obese individuals often
has fatty infiltration which can significantly inhibit the metabolic activity of the
liver. Finally, renal function of obese individuals is frequently altered resulting in
decreased drug clearance [124]. All these hemodynamic changes may affect drug
distribution and clearance.
While the selection of the correct dose in anticancer treatment can be particularly
challenging because of its cytotoxic effects, this process is made even more
difficult by the lack of information concerning dosing in obese individuals. According
to the current data, obesity can change the pharmacokinetics of some anticancer
agents. As a result, dosing of obese patients should be individualized according
to each drug [125]. However, there are no uniform clinical dosing guidelines
for obese individuals [126]. Moreover, there is sparse evidence supporting dose cap-
ping in obese patients, particularly since this practice may cause suboptimal treatment
outcomes [125, 127].
A recent article that evaluated the effect of obesity on outcomes of autologous

hematopoietic stem cell transplantation (AutoHCT) in myeloma patients found
that obesity did not appear to influence outcomes from AutoHCT treatment with
melphan alone or with melphan in combination with total body irradiation (TBI).
This study further asserted that variation in dose in obese individuals did not affect
the outcome. Obesity did not appear to negatively affect outcomes from stem cell
transplantation in MM patients. The authors concluded that obese multiple myeloma
patients should not be excluded from AutoHCT because of excesses in weight [128].
Similar findings were also noted in a study that evaluated the effect of BMI on allo-
genic transplant outcomes in hematological malignancies. This study found that
high BMI did not affect overall survival and progression-free survival in patients
who underwent allogenic transplantation for hematological malignancies but it did
affect infection rates and hospitalization in this group [129].
8 Treatment Options for Multiple Myeloma
Multiple myeloma that is active or symptomatic should be treated immediately,

whereas smoldering or asymptomatic myeloma (SMM) is typically treated with obser-
vation as clinical studies have shown no benefit from early intervention with
conventional chemotherapy. Immunomodulatory drugs are currently being investi-
gated to delay the progression of asymptomatic to symptomatic multiple myeloma
and this treatment strategy is age related. In patients below the age of 65 years who
do not suffer from heart, lung, renal, and liver complications, initiation of induction
therapy using thalidomide, lenalidomide, or bortezomib in addition to hematopoietic
stem cell transplantation is recommended. Patients above the age of 65 years or
those with coexisting conditions should receive conventional therapy combined
with thalidomide, lenalidomide, or bortezomib; if autologous stem cell transplanta-
tion is considered, conditioning with a reduced intensity regimen is recommended.
For patients over the age of 75 years or in patients who are younger with coexisting
conditions, a less intensive approach that limits toxic effects is appropriate [117].
9 Summary
Excess body weight is a risk factor for MGUS, multiple myeloma, and mortality
from multiple myeloma. The empirical evidence presented suggests that multiple
myeloma and mortality from the disease may at least in part be prevented by main-
taining a healthy body weight. Other major risk factors are not modifiable, including
age, race (black or African American), gender (male), and family history. Biologic
pathways and prospective data support a potential role for aspirin in prevention.
Like obesity, increased understanding of the time course of disease etiology is
needed to refine strategies for prevention.
Even though there has been extensive research delineating the deleterious effects
of excess weight on cancer risk including multiple myeloma, there are sparse
data on weight loss and subsequent risk of multiple myeloma. One study by
De Roos et al. [53] sheds some light on intentional weight loss and the risk of
lymphohematopoietic cancers in the Women Health Initiative Observational Study.
For multiple myeloma, they observed nonsignificant findings. Clarifying the
temporal relation is essential for malignancies which overall, or in aggressive
subsets, leads to weight loss often over months or years prior to diagnosis, potentially
leading to biased associations.
Refinement of our understanding of risk factors that may operate across the life
course could help focus prevention perhaps in high-risk groups such as those with
family history, etc. In the mean time, avoiding weight gain has many benefits that
are far more common than the potential few avoided cases of multiple myeloma.
Acknowledgments Supported by U54CA155496, U54CA153460, and RO1CA127435.
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Chapter 5
The Impact of Obesity on Pharmacokinetics
and Dosing of Leukemia Chemotherapy
Jennifer Kendrick, Dawn Warkentin, and Mary H.H. Ensom
Abstract Recommendations for dosing chemotherapy in obese patients are limited

and there is inconsistent use of various body weight estimates for the calculation of
chemotherapy doses in obese patients. Multiple cohort studies of cancer chemo-
therapy have examined efficacy and safety outcomes in obese as compared to
normal-weight patients. There are a limited number of pharmacokinetic studies and
case reports for chemotherapy drugs in obese patients. Neither the cohort studies
nor the pharmacokinetic studies support the routine use of dosing strategies that use
a capped body surface area (BSA) or calculating BSA based on ideal body weight
(IBW). Anthracyclines, carboplatin, and corticosteroids have special dosing consid-
erations in obese patients. There are limitations to the available information that
preclude clear dosing guidelines for obese children and adults.
J. Kendrick, B.Sc. Pharm, ACPR, Pharm.D.

Clinical Pharmacist–Pediatrics, Children’s and Women’s Health Centre of British Columbia,
D. Warkentin, B.Sc. Pharm, ACPR, Pharm.D.
Leukemia/Bone Marrow Transplantation, CSU Pharmaceutical Sciences, Vancouver Coastal
Health Authority, 12th and Oak Site, Vancouver, BC, Canada
Faculty of Pharmaceutical Sciences, The University of British Columbia
M.H.H. Ensom, B.S. (Pharm), Pharm.D., FASHP, FCCP, FCSHP, FCAHS (*)
Clinical Pharmacy Specialist, Children’s and Women’s Health Centre of British Columbia,
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
e-mail: ensom@mail.ubc.ca
98 J. Kendrick et al.
1 Introduction
Drug development and clinical trials in oncology do not uniformly report body size
or obesity. Recommendations for dosing chemotherapy in obese patients are lim-
ited, although a handful of review articles address the issue [1–3]. As a result, there
is inconsistent use of various body weight estimates for the calculation of chemo-
therapy doses in obese patients. Limited data exist to describe the pharmacokinetic
parameters (drug disposition) and pharmacodynamic parameters (drug action) of
chemotherapy drugs in obese patients. Cohort studies describing outcomes in obese
patients receiving leukemia chemotherapy should therefore also be considered in
determining initial chemotherapy doses in this population. This chapter provides a
review of general pharmacokinetic parameters in obesity, leukemia-specific phar-
macokinetic parameters in obesity, and descriptions of chemotherapy dosing and
outcomes in obese patients with leukemia.
2 General Pharmacokinetic Differences in Obesity
The pharmacokinetic parameters that are reported in the literature for any given drug
may include clearance (CL), half-life (t1/2), and volume of distribution (Vd). The rela-
tionship between these parameters is described by the following equation (5.1):
0.693 × Vd
t1/ 2 = . (5.1)
CL
Half-life is the pharmacokinetic parameter that determines the time to steady-
state drug concentration and is used to determine the dosing interval. Half-life is
dependent on CL and Vd, which are discussed below [4].
2.1 Absorption
The effect of obesity on drug absorption appears to be minimal in adults [4]. To our
knowledge, no information on drug absorption in obese children is available [5].
2.2 Distribution
Volume of distribution represents the extent that a drug distributes into body tissues
and is the pharmacokinetic parameter that is important in the calculation of loading
doses of drugs. In pharmacokinetic studies, it is expressed as absolute Vd (uncor-
rected for body weight) or weight-normalized Vd [6]. Drugs that distribute exten-
sively generally have a large Vd. Factors that affect a drug’s Vd include lipophilicity,
5 The Impact of Obesity on Pharmacokinetics and Dosing of Leukemia Chemotherapy 99
polarity, ionization at physiologic pH, tissue blood flow, and plasma and tissue pro-
tein binding [6].
Lipophilic drugs have a larger Vd in obese patients. This would result in a pro-
longed t1/2 in obese patients compared to normal-weight patients if CL is similar
(5.1). However, because the increased fat mass in obese patients is poorly perfused,
the increase in Vd is not proportional to the increase in fat mass [6]. Hydrophilic
drugs may have a similar Vd in obese as compared to normal-weight patients.
However, because the water content of adipose tissue is almost completely extracel-
lular, if hydrophilic drugs distribute extensively into the extracellular fluid, their Vd
is higher in obese patients.
Vd does not appear to be altered in obese adults and children for drugs that are
bound to albumin [6, 7]. There is conflicting information on the effect of obesity Vd
for drugs that are bound to alpha1-acid glycoprotein [6].
2.3 Metabolism
The main metabolic pathways for drug elimination include the Phase 1 cytochrome
P450 (CYP) enzymes and the Phase 2 conjugation and acetylation pathways [4, 6].
Metabolism is also affected by liver blood flow, which is not significantly altered in
obesity.
The effect of obesity on Phase 1 enzymes is unknown for CYP1A2, CYP2C9,
CYP2C19, and CYP2D6. In obese adults, there is an increase in CYP2E1 activity
which is responsible for the metabolism of acetaminophen and ethanol [6]. There is
a decrease in CYP3A4 and CYP2B6 activity in obese adults [4]. CYP3A4 is
responsible for the metabolism of many drugs, including cortisol, cyclosporine,
midazolam, paclitaxel, tacrolimus, and vincristine. To our knowledge, the effect of
obesity on Phase 1 enzymes in children has not been studied.
Glucuronidation and sulfation (responsible for the metabolism of lorazepam and
acetaminophen, respectively) appear to be increased in obese adults [4]. Acetylation
appears to be unaffected by obesity [4]. To our knowledge, the effect of obesity on
Phase 2 enzymes in children has not been studied.
2.4 Excretion
Clearance is a measure of the volume of drug cleared per unit time and is important
for the calculation of maintenance doses of drugs. Increased CL would result in
shorter t1/2 if Vd is not different. Conversely, decreased CL would result in longer t1/2
if Vd is not different (5.1). Clearance is determined by blood flow to the organ and
the organ’s ability to remove the drug [6]. For drugs that are eliminated renally,
glomerular filtration, tubular secretion, and tubular reabsorption are important.
Glomerular filtration is increased in obese adults and children [4–6]. Tubular secretion
is increased and reabsorption is decreased in obese adults [4, 6]. Together, these
Table 5.1 Alternate weight descriptors used for the calculation of BSA [1, 7, 9, 10]
Body weight estimate Equation in adults Equation in children
Ideal body weight Metropolitan life insurance tables McLaren: 50th percentile
(IBW) (kg) Devine: (%) of weight for height
[50 kg (male) or 45.5 kg (female)] + Moore: corresponding
2.3 kg for each inch over 5 ft weight % for height
Robinson: BMI method: BMI 50th %
[52 kg (male) or 49 kg (female)] + for age × [height (m)]2
1.9 kg (male) or 1.7 kg (female)
for each inch over 5 ft
Lean body weight Male: (9,270 × TBW)/ None
(LBW) (kg) (6,680 + 216 × BMI)
Female: (9,270 × TBW)/
(8,780 + 244 × BMI)
Adjusted body weight AdjBW25=IBW+0.25(ABW-IBW) IBW + 0.4(ABW – IBW)
(AdjBW) (kg) AdjBW40 = IBW + 0.4(ABW – IBW)
Predicted normal weight Male: 1.57 × ABW – 0.0183 × None
(PNW) (kg) BMI × ABW – 10.5
Female: 1.75 × ABW – 0.0242 ×
BMI × ABW – 12.6
differences lead to increased clearance of drugs such as vancomycin, aminoglyco-

sides, cimetidine, and lithium in obese individuals.
Most equations that have been developed to predict creatinine clearance have not
been validated in obese patients. The Cockcroft–Gault equation using fat-free mass
(FFM) or lean body weight (LBW) was found to be the best estimate of creatinine
clearance in morbidly obese adults, compared with actual body weight (ABW) or
adjusted body weight (AdjBW) [8]. The Schwartz equation, which is used exten-
sively to estimate creatinine clearance in pediatric patients with and without renal
impairment, has not been validated in obese children.
3 Size Descriptors in Obesity and Leukemia Chemotherapy
Chemotherapy is traditionally dosed based on a patient’s body surface area (BSA),

commonly calculated using the Mosteller equation [1]. There is concern that using
the obese patient’s ABW to calculate BSA could result in excessive toxicity. Often,
the BSA is capped at 2 m2 or an alternate weight descriptor is used to calculate BSA
in obese patients. Alternate weight descriptors include ideal body weight (IBW),
LBW, AdjBW, predicted normal weight (PNW), and FFM (Table 5.1). IBW is most
commonly calculated using the Devine estimation in adults and the McLaren method
in children [9, 11]. AdjBW has been validated for dosing aminoglycosides in obese
adults, but it has only been used to estimate tobramycin Vd in a small group of chil-
dren [7]. Concern has also arisen that using an alternate weight descriptor to calcu-
late BSA or capping BSA in obese patients could lead to reduced chemotherapy
efficacy and poorer outcomes [1, 12].
Standard dosing practice does not appear to exist for dosing chemotherapy in
obese patients. Thompson et al. [13] conducted a survey of 174 oncology pharmacists
and medical oncologists in the USA, and found that 19.7% of respondents reported
an institutional standard of practice regarding empiric dose adjustment in obese
patients. Factors considered include degree of obesity, comorbidity, performance
status, age, curative intent, type of medication, and pharmacokinetic properties.
The method of empiric dose adjustment was most commonly based on BSA using
AdjBW (52%). Capped BSA (22%) and IBW (10%) were also used. A retrospective
cohort study of children with leukemia found that 7% of obese patients (11% of
obese patients aged 10–18 years) received less than the protocol-specified dose
of chemotherapy that should have been based on actual BSA [14].
Multiple retrospective cohort studies of cancer chemotherapy have attempted to
examine efficacy and safety outcomes in obese patients as compared to their normal-
weight counterparts. Studies in obese patients with gynecologic, breast, colon,
rectal cancers, and lymphoma suggest that overall survival may be lower than in
normal-weight counterparts when obese patients are not dosed according to ABW;
they also suggest that obese patients experience less Grade 3 or 4 toxicities when
not dosed according to ABW [15–19]. Similar studies where obese patients were dosed
according to ABW failed to show excess toxicity [20–26].
Five retrospective cohort studies examined obese patients, all children, with leu-
kemia. In a study of 322 children (15.2% obese) by Baillargeon et al. [27] which did
not report dosing of chemotherapy, obesity was not associated with overall survival
(OS) or event-free survival (EFS). In a study of 181 children (35.9% overweight or
obese) by Gelelete et al. [28], which also did not report dosing of chemotherapy,
overweight/obesity was an independent prognostic factor for lower 5-year EFS after
adjusting for age, white blood cell count (WBC) at diagnosis, and response to pred-
nisone. In the three other studies, obese children received chemotherapy doses based
on ABW or actual BSA (Table 5.2). Both the study by Butturini et al. [29] and
Lange et al. [31] excluded patients with Down syndrome. In the study by Butturini
et al. [29], the vincristine dose was capped at 2 mg. In all three of the studies, OS
and EFS were either lower or no different for the obese children as compared to the
normal-weight children. Toxicity was reported in the three studies. The large study
by Butturini et al. [29] showed that obesity had no effect on length of interval
between diagnosis and completion of the fourth phase of chemotherapy, the risk of
hospitalization, or the risk of death during induction or death secondary to toxicity.
This study adjusted for the confounders age, sex, WBC at diagnosis, and bone mar-
row response to chemotherapy at day 7 in the efficacy but not toxicity analysis. The
study by Hijiya et al. [30] found no significant association between the frequency of
Grade 3 or 4 toxicity and BMI. This study adjusted for the confounders age, sex,
WBC at diagnosis, immunophenotype, and deoxyribonucleic acid (DNA) index in
the efficacy but not toxicity analysis. In contrast to these two studies, the study by
Lange et al. [31] found that more Grade 3 or 4 abdominal pain, hypertension, pul-
monary function abnormalities, coagulopathy, and treatment-related mortality
occurred in obese children. This study adjusted for the confounders age, race, WBC
at diagnosis, cytogenetics, and stem cell transplant (SCT) in both the efficacy and
toxicity analyses.
Table 5.2 Effect of obesity on cancer outcomes in studies that describe chemotherapy dosing
102
Study/design Patients Chemotherapy Efficacy Safety

Leukemias
Butturini et al. [29] − 4,620 children with − All patients: vincristine, − Obese patients had lower − Toxicity not reported
Retrospective ALL treated with prednisone, l-asparaginase, 5-year EFS (72% vs. uniformly
cohort CCG-1881, 1922, methotrexate, mercaptopurine 77%, p = 0.02) − Obesity had no effect on length
1891, 1882, 1901 − Most patients: dexamethasone, − Obese patients had higher of interval between diagnosis
− 38% obese daunorubicin, doxorubicin, risk of relapse (26% vs. and completion of the fourth
(BMI ³ 95th %) cyclophosphamide, cytarabine, 20%, p = 0.02) phase, hospitalization, death
thioguanine during induction, death
− Drug doses based on BSA secondary to toxicity
calculated with ABW in 98.5%
obese patients
− Vincristine dose capped at
2 mg
Hijiya et al. [30] − 621 children (>1 year) − High-dose methotrexate − No significant difference − No significant difference in the
Retrospective with ALL 1,500–5,000 mg/m2 in CR, OS according to frequency of Grade 3 or 4
cohort; PK study − 8.9% obese − Etoposide 300 mg/m2 BMI toxicity according to BMI
(BMI ³ 95% for age) − Cytarabine 300 mg/m2
− Tenoposide 200–375 mg/m2
− 6-MP oral 75 mg/m2
− Dosing based on actual BSA;
dosing adjusted based on CL
Lange et al. [31] − 768 children with AML − Idarubicin, daunorubicin, − More dose reductions in − Treatment-related mortality
Retrospective cohort treated with CCG 2961 cytarabine, dexamethasone, overweight vs. normal higher in overweight vs.
− 10.9% overweight, etoposide, thioguanine weight (4.8 vs. 0.7%; normal weight: HR 3.49 (95%
defined as BMI ³95% − SCT or high-dose cytarabine, p = 0.006) CI 1.99–6.1) when adjusted for
for age l-asparaginase − OS lower in overweight prognostic factors
− 15.1% received SCT − Dose based on ABW if vs. normal weight: HR − More Grade 3 or 4 abdominal
<3 years and BSA calculated 1.88 (95% CI 1.25–2.83) pain, hypertension, pulmonary
using ABW if ³3 years when adjusted for function abnormalities, and
prognostic factors coagulopathy in overweight vs.
J. Kendrick et al.
normal weight
5
SCT
Deeg et al. [32] − 2,238 children and − Cyclophosphamide − Higher body weight not − Not reported
Retrospective cohort adults who underwent − GVHD prophylaxis with statistically associated
allogeneic SCT for combinations of methotrexate, with reduced survival
aplastic anemia, cyclosporine, corticosteroids,
myelodysplastic antithymocyte globulin
syndrome, leukemia, − Doses “generally” based on
lymphoma ABW
− Body weight groups:
<85% IBW, 85–95%
IBW, >95–145% IBW,
>145% IBW
Coughlin-Dickson − 473 patients undergo- − Carmustine, busulfan, − BMI associated with − Not reported
et al. [33] ing autologous SCT for lomustine, cyclophosphamide, nonrelapse mortality
Retrospective cohort hematologic etoposide (NRM)
malignancies − Dose based on BSA calculated − HR for NRM in BMI
with ABW or BSA calculated 120–139% and 140–
with AdjBW if ABW >15% 199% of age-adjusted
above IBW BMI: 2.9 (95% CI
1.4–6.0) and 2.7
(1.0–6.9)
− No effect of BMI on
EFS or relapse
Meloni et al. [34] − 54 adults who − Busulfan 4 mg/kg/day PO × − Obese vs. normal weight − More infections in obese vs.
Retrospective cohort underwent autologous 4 days and cyclophosphamide associated with lower normal weight (78 vs. 44%;
SCT for AML 60 mg/kg × 2 days probability of OS (0.22 p = 0.04)
− 17% obese − Dose based on ABW vs. 0.63; p = 0.01) and − Obesity correlated with delay
(BMI ³ 27.8 kg/m2 for DFS (0.22 vs. 0.58; of granulocyte engraftment
men and p = 0.02) − No difference in mucositis,
BMI ³ 27.3 kg/m2 for hemorrhagic cystitis, platelet
The Impact of Obesity on Pharmacokinetics and Dosing of Leukemia Chemotherapy
women) engraftment
(continued)
103
Table 5.2 (continued)
104

Pine et al. [35] − 200 children − Cyclophosphamide and − No association between − Not reported
Retrospective cohort (2–18 years; median antithymocyte globulin or body weight and DFS or − No association between body
7.8 years) undergoing busulfan and melphalan OS weight and TRM
unrelated cord blood − Doses based on AjBW40 for
transplant for malignan- patients ³125% IBW
cies (28% AML, 57%
ALL, 16% other)
− 17.5% overweight
(BMI 85–95% for age);
19.5% obese
(BMI ³ 95th% for age)
Sriharsha et al. [36] − 262 patients undergo- − Cyclophosphamide, busulfan, − Weight not a predictor − Not reported relative to weight
Retrospective cohort ing allogeneic SCT for cytarabine for OS and relapse-free
hematologic − Dosing weight derived from survival
malignancies Met-Life weight–height tables
− BSA calculated with large-
frame weight if ABW > large-
frame weight
Tarella et al. [37] − 121 adults who − Cyclophosphamide 7 g/m2, − Independent association − No difference in toxicity
Retrospective cohort underwent autologous methotrexate 8 g/m2, etoposide between overweight and
SCT for non-Hodgkin’s 2 g/m2 OS and EFS, when
lymphoma − ABW; if BMI ³ 22 kg/m2, used adjusted for prognostic
− 23% overweight “pharmacologic weight” variables: HR 2.9 (95%
(BMI ³ 28 kg/m2); 7% − Vincristine 2 mg CI 1.3–6.2) and HR 2.8
BMI ³ 32 kg/m2 (95% CI 1.5–5.3)
a 2
Obesity defined as BMI ³ 30 kg/m unless otherwise specified
ABW actual body weight, AdjBW adjusted body weight, ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, AUC area under the curve, BMI body
mass index, BSA body surface area, CCG Children’s Cancer Group, CI confidence interval, CL clearance, EFS event-free survival, CR complete remission,
GVHD graft vs. host disease, HR hazard ratio, IBW ideal body weight, NRM nonrelapse mortality, OS overall survival, RR relative risk, SCT stem cell trans-
plant, t1/2 half-life, Vd volume of distribution, % percentile
J. Kendrick et al.
Multiple retrospective cohort studies, one case control study, and one prospective
cohort study examined obese patients undergoing SCT for leukemias and lymphomas,
which is described in more detail in Chap. 6 [32–43]. Many studies did not report
chemotherapeutic agents and dosing; studies that reported chemotherapy dosing are
described in Table 5.2. Of the studies that reported dosing, toxicity outcomes between
obese and normal-weight patients were not consistent. The studies by Meloni et al.
[34] and Tarella et al. [37] did not adjust for potential confounders. In the study
by Meloni et al. [34], doses were based on actual BSA. Obesity was associated with
more infections, yet other adverse effects were not different between obese and nor-
mal-weight patients. In the study by Tarella et al. [37], where obese patients received
doses based on “pharmacologic weight,” there was no difference in toxicity between
obese and normal-weight patients. Pharmacologic weight was not defined. In the
study by Pine et al. [35], doses were based on AdjBW40 (AdjBW40 = IBW + 0.4[ABW–
IBW]) for obese children. There was no association between body weight and treat-
ment-related mortality. This study controlled for risk factors (not specified).
Limitations in the nature of retrospective studies and the potential confounders
that may influence survival necessitate the examination of pharmacokinetic studies
for the determination of dosing chemotherapy in obese patients. The available phar-
macokinetic studies which include obese patients for leukemia chemotherapeutic
drugs are reviewed in Table 5.3.
4 Pharmacokinetics and Dosing of Leukemia

Chemotherapy in Obesity
4.1 Alkylating Agents
4.1.1 Busulfan
High-dose busulfan is used in preparation for SCT and is given intravenously or

orally. Busulfan is discussed further in Chap. 6. It is a hydrophilic drug, which
distributes well into cerebrospinal fluid and saliva. It exhibits minimal protein
binding, primarily to albumin. Busulfan is primarily metabolized in the liver; very
little intact drug is eliminated in the urine.
Four retrospective studies describe high-dose busulfan pharmacokinetics in
children and adults who received busulfan as part of conditioning for SCT. The
study by Gibbs et al. [44] reported that busulfan CL was higher in obese vs. normal-
weight patients; however, there was no difference in CL normalized to actual BSA
or AdjBW25 (AdjBW25 = IBW + 0.25[ABW–IBW]). The study by Nguyen et al.
[45] reported that busulfan CL expressed as a function of BSA or AdjBW25 was not
different between obese or morbidly obese vs. normal-weight patients. CL expressed
as a function of ABW was lower in obese and morbidly obese vs. normal-weight
patients. The authors of both studies suggest, therefore, that actual BSA and AdjBW25
are appropriate for calculating initial busulfan doses in adolescents and adults.
106
Table 5.3 Effect of obesity on pharmacokinetic parameters

Study/design Patients Methods Results Conclusion
Gibbs et al. [44] − 279 adolescent and − PK parameters derived − ABW, actual BSA, AdjBW25 − BSA and AdjBW25
Retrospective PK study adult patients from plasma concentra- associated with busulfan CL/F appropriate for calculating
(12–60 years) who tions at 6 time points (r2 0.26–0.30) busulfan dose
underwent SCT and − Busulfan 0.44–1.8 mg/kg − CL/F obese vs. normal weight:
had busulfan PO Q6H × 4 days 223 vs. 190 mL/min; p < 0.05
monitoring as part − CL/F/kg ABW obese vs. normal
of their protocol weight: 2.6 vs. 2.9 mL/min/kg;
− 21.5% AML, 26.2% p < 0.05
CML − CL/F/m2 not statistically
− 35.5% obese different in obese vs. normal
(BMI ³ 27 kg/m2) weight: 107 vs. 108 mL/min/m2;
p > 0.05
Nguyen [45] − 127 adolescents and − PK parameters derived − No difference in CL/BSA and − BSA and AdjBW25
Retrospective PK study adults (14–64 years) from plasma-concentration CL/AdjBW25 for obese or appropriate for calculating
who underwent SCT time profiles using noncom- morbidly obese vs. normal busulfan dose
− 30.7% obese partmental analysis weight
(BMI 27–35 kg/m2) − Busulfan 0.2 mg/kg IV − CL/ABW lower in obese and
− 8.7% morbidly Q6H × 16 doses morbidly obese vs. normal
obese (BMI > − Dosing based on IBW weight
35 kg/m2) (68%), ABW (23%), or
AdjBW25 (9%)
Dupuis et al. [46] − 38 children − Busulfan 40 mg/m2 − Final busulfan dose not different − Authors later report error
Retrospective PK study (0.2–17.5 years) PO Q6H × 16 doses in children with ABW > IBW in assay may have led to
who underwent SCT − Dose adjusted to target falsely high concentrations
and had busulfan AUC 900–1,400 mM/min and calculated AUC
monitoring as part of − Suggestion that initial
their protocol busulfan doses based on
J. Kendrick et al.
actual BSA appropriate

5
Browning et al. [47] − 68 children (0 to − Busulfan 0.8 mg/kg IV over − No association between obesity − Dosing should be based on
Retrospective PK study 21 years) who 3 h as test dose and being under- or over-target therapeutic drug monitor-
underwent SCT and − Test dose based on ABW for test dose AUC ing and patient-specific PK
had busulfan − Subsequent dose adjusted to − Test dose based on ABW and parameters
monitoring target AUC 1,000 mM/min then adjustment based on PK
− 32% obese monitoring achieved target AUC
(BMI ³ 85th%) more often than if used AdjBW25
for regimen dosing
− CL obese vs. normal weight: 3.1
vs. 3.8 mL/min/kg; p = 0.03
− Regimen dose obese vs. normal
weight: 2.9 vs. 4.0 mg/kg;
p = 0.001
De Jong et al. [48] − 53-year-old obese − PK parameters derived from − No toxicity noted; doses − Higher exposure to
Case report woman with breast plasma-concentration time adjusted on day 3: AUC case vs. cyclophosphamide
cancer profiles using noncompart- population metabolite, thiotepa, and
− ABW 130 kg, BMI mental analysis; compared − Thiotepa 560 vs. 258 mM h carboplatin in obese
47 kg/m2 to normal-weight population − Cyclophosphamide 4,960 vs. patient dosed based on
− Doses calculated values 4,552 mM h actual BSA
based on actual BSA − Cyclophosphamide − 4-Hydroxo-cyclophosphamide − Authors suggest dosing
2.34 m2 1,000 mg/m2 daily 209 vs. 108 mM h using AdjBW40 for
− Thiotepa 80 mg/m2 BID − Carboplatin 25.5 vs. cyclophosphamide and
− Carboplatin daily according 14.9 mg min/mL: CL case vs. thiotepa and using
to Calvert formula using population AdjBW40 in Cockcroft–
target AUC 3.25 mg min/ − Cyclophosphamide 6.0 vs. Gault for carboplatin
mL and CrCl based on 5.1 L/h
Cockcroft–Gault − Thiotepa 43.2 vs. 34.5 L/h: Vd
(185 mL/min) case vs. population
− Cyclophosphamide 0.38 vs.
0.55 L/kg
− Thiotepa 0.51 vs. 0.66 L/kg

− Carboplatin 0.13 vs. 0.20 L/kg
107
(continued)
108

Powis et al. [49] − 16 women with − PK parameters derived from − No correlation between ABW − Mean/median PK
PK study breast cancer plasma-concentration time and Vd or CL normalized to parameters not reported for
− 43.8% ABW profiles on day 1 using ABW; or total CL obese vs. normal weight
120–130% IBW noncompartmental analysis − Positive correlation between
− 31.2% ABW > 130% − Cyclophosphamide ABW and t1/2 (r2 =0.62; p = 0.01)
IBW 150–300 mg/m2 with either − Negative correlation between
5-fluorouracil or ABW and CL normalized to
doxorubicin BSA (r2 = 0.58; p = 0.02) and
IBW
Lind et al. [50] − 16 adults with − PK parameters derived from − CL (mL/min) 76 vs. 72 (p = NS) − Ifosfamide elimination t1/2
PK study advanced nonsmall plasma-concentration time − CL (mL/min/kg) 1.01 vs. 1.31 prolonged in obese
cell lung cancer profiles using two-compart- (p = NS) patients, likely due to an
− 25% obese mental analysis − Vd (L) 42.8 vs. 33.7 (p < 0.05) increased Vd and not
(ABW ³ 120% IBW) − Ifosfamide 1.5 g/m2 × − Vd (L/kg) 0.55 vs. 0.53 (p = NS) decreased CL
5 days − t1/2 6.4 vs. 5.0 (p < 0.05) − Dosing based on actual
BSA may be appropriate
Hijiya et al. [30] − 621 children − PK parameters derived from − No difference in CL (mL/min/ − Dosing based on actual
Retrospective PK study (>1 year) with ALL plasma-concentration time m2) in obese vs. normal-weight BSA supported
− 8.9% obese profiles using noncompart- children
(BMI ³ 95th % for mental analysis − No significant difference in CR,
age) − High-dose methotrexate OS according to BMI
1,500–5,000 mg/m2 − No significant difference in the
− Etoposide 300 mg/m2 frequency of Grade 3 or 4
− Cytarabine 300 mg/m2 toxicity according to BMI
− Tenoposide 200–375 mg/m2
− 6-Mercaptopurine PO
75 mg/m2
− Dosing based on actual
BSA; dosing adjusted based
J. Kendrick et al.
on CL
5
Zuccaro et al. [51] − 18 children − PK parameters derived from − Overweight vs. normal-weight − AUC inversely correlated
PK study (3–15 years) with serum-concentration time children: lower AUC, Cmax, with BMI
ALL profiles following a single and higher CL and Vd − Dosing based on actual
− 50% BMI > 75% oral dose of 6-mercaptopu- − AUC(PO) 357 vs. 867 mcg h/L BSA may be insufficient
for age rine 75 mg/m2 (p < 0.001)
− AUC calculated using − CL 207 vs. 93 L/h (p < 0.001)
trapezoidal rule − Vd 236 vs. 142 L/kg (p < 0.05)
− t1/2 0.9 vs. 1.1 h (p = NS)
Fleming et al. [52] − 24-year-old obese − Methotrexate PK param- − CL 0.096 L/h/kg − CL and Vd higher than
Case report woman with eters derived from − Vd 0.4 L/kg previously reported; t1/2
osteogenic sarcoma serum-concentration time − No mucositis or neutropenia similar to previous reports
− ABW 107 kg; BMI profiles
39.3 kg/m2 − AUC calculated using
− Doses based on BSA trapezoidal rule
calculated using − Vincristine 1 mg/m2,
IBW 58 kg doxorubicin 40 mg/m2,
actinomycin 450 mg/m2,
bleomycin 12 mg/m2,
cyclophosphamide
600 mg/m2
− Methotrexate dose initiated
at 8 g/m2 and increased to
10 g/m2
Sauer et al. [53] − 16-year-old obese − Methotrexate dose − SCr increased from 0.6 to − Unclear association
Case report boy with ALL escalation to 250 mg/m2 2.8 mg/dL and renogram between obesity and
− ABW 110 kg; BMI suggesting acute tubular toxicity
38.1 kg/m2 necrosis 3 days following
− Doses based on methotrexate dose of 250 mg/m2
actual BSA of 2.3 m2 − Methotrexate level 2.9 mmol/L 4
days after dose
(continued)
109
110

Sparreboon et al. [54] − 1,206 adult patients − PK parameters derived from − CL (L/h) increased in obese − Dose capping or fixed
Retrospective PK study with cancer plasma-concentration time patients; statistical significance dosing would result in
− 13.4% obese profiles using noncompart- achieved for cisplatin, pacli- lower drug exposure
mental analysis taxel, troxacitabine − Dose based on actual BSA
− Carboplatin, cisplatin, − CL normalized for BSA (L/h/ should be considered for
docetaxel, doxorubicin, m2) not statistically different for most drugs (possible
irinotecan, paclitaxel, all drugs for obese vs. normal exceptions for docetaxel
topotecan, and troxacitabine weight and doxorubicin)
− AUC calculated as dose − AUC obese best approximated
divided by CL compared AUC lean when ABW used for
using various size carboplatin, cisplatin, irinote-
descriptors can, paclitaxel, topotecan,
troxacitabine
− AUC obese better approximated
AUC lean when IBW used for
docetaxel and doxorubicin
Barpe et al. [55] − 10 women with − Cyclophosphamide − AUC overweight vs. normal − Doxorubicin exposure
Pilot PK study breast cancer − Doxorubicin 60 mg/m2 weight 2,533 vs. 3,358 ng h/mL lower in overweight
− 70% overweight − PK parameters for (p < 0.05) patient
(BMI 29.0 ± doxorubicin derived from − Vd overweight vs. normal − Dosing based on actual
4.1 kg/m2) plasma-concentration time weight 1,246 vs. 703 L BSA appropriate
profiles using compartmen- (p < 0.05)
tal and noncompartmental − CL similar between groups (299
analysis vs. 292 units not reported;
J. Kendrick et al.
p = NS)
5
Rodvold et al. [56] − 21 adults − PK parameters derived from − AUC obese vs. normal weight − Doxorubicin exposure
PK study − 33% obese plasma-concentration time 2,209 vs. 1,190 ng h/mL higher in obese patients
(ABW > 130% IBW) profiles using noncompart- (p < 0.05) − Obese patients may require
− 33% normal weight mental analysis − CL obese vs. normal weight 891 lower doses
(ABW < 115% IBW) − Doxorubicin 50–70 mg/m2 vs. 1,569 mL/min (p < 0.001)
and 485 vs. 886 mL/min/m2
(p < 0.05)
− No difference in Vd
− No difference in doxorubicinol
AUC
Thompson et al. [57] − 22 children − PK parameters derived from − No difference in doxorubicin or − Doxorubicin dosing based
PK study (1–21 years) plasma-concentration time doxorubicinol Vd (L/m2) or CL on actual BSA appears
− 27.3% had body fat profiles using noncompart- (L/h/m2) between overweight appropriate
>30% mental analysis and normal-weight patients
− % overweight not − Doxorubicin dosed based on − No difference in doxorubicin Vd
reported (BMI >85th actual BSA or CL between patients with
% for age) body fat <30% and >30%
− Doxorubicinol Vd and CL lower
in patients with body fat < 30%:
37.2 vs. 64.8 L/h/m2 (p = 0.03)
and 802 vs. 1,450 L/m2
(p = 0.02)
(continued)
111
112

Ritzmo et al. [58] − 14-year-old boy with − Etoposide 240 mg − Doxorubicin median plasma CL − Child could have received
Case report Hodgkins disease (125 mg/m2 AdjBSA and 476 mL/min/m2 similar to the doxorubicin and etoposide
− BMI 46.3 kg/m2 and 94 mg/m2 actual BSA) × published median of 493 mL/ doses based on actual BSA
BSA 2.56 m2 5 days min/m2 (range 197–869 mL/
− AdjBSA of 1.91 m2 − Doxorubicin 76 mg min/m2)
used to dose (40 mg/m2 AdjBSA and − Doxorubicinol concentrations
chemotherapy 30 mg/m2 actual BSA) × within the normal range of
(calculated using 15 days 5–10% of intact doxorubicin
upper limit of weight − Vincristine 2 mg Q 1 week − Etoposide CL 16.1 mL/min/m2
for height on growth × 3 weeks similar to the published median
chart = 76 kg) − Plasma concentrations of CL of 14.9 mL/min/m2 (range
doxorubicin doxorubicinol, 11.0–31.7 mL/min/m2)
and etoposide measured; − Etoposide t1/2 3.6 h, compared to
compared with previously the published median t1/2 of
reported concentrations in 4.1 h (range 2.0–7.8 h)
children − No toxicity observed; ECG and
echo normal 2 months and
2 years. after treatment
Ekhart et al. [59] − 240 patients who − Carboplatin doses 267– − AdjBW40 best descriptor of − Carboplatin dose = target
Retrospective PK study received carboplatin 400 mg/m2 or using Calvert carboplatin CL in overweight AUC × carboplatin CL
for solid tumors and formula with target AUC and obese patients (vs. LBM in (8.38 L/h or 140 mL/min)
had plasma 10–20 mg min/L underweight and normal-weight may be best empiric
carboplatin samples patients) using the Cockcroft– dosing in overweight and
drawn Gault equation obese patients with normal
− 30% overweight; 6% − Flat dose based on population renal function
obese carboplatin CL (8.38 L/h or
140 mL/min) resulted in the
lowest bias and imprecision
overall: Prior to surgery
J. Kendrick et al.
5
Liu and Artz [60] − 54-year-old woman − Steady-state trough − 400 mg PO daily → Cmin − Possible reduced imatinib
Case report with CML concentrations obtained on 965 ng/mL: Postsurgery absorption following
− ABW 122 kg; BMI various doses of imatinib − 400 mg PO daily → Cmin gastric bypass
50 kg/m2 PO prior to and following 166 ng/mL (ABW 91 kg)
bariatric surgery − 400 mg PO BID → Cmin
− %Philadelphia + cells in 734 ng/mL (ABW 84 kg);
bone marrow also 540 ng/mL (ABW 72 kg);
determined 2,124 ng/mL (ABW 65 kg):
Prior to surgery
Pavlovsky et al. [61] − 36-year-old − PK parameters derived from − Cmin 1,558 ng/mL; − Increased CL/F and
Case report morbidly obese plasma concentrations of AUC 56.1 mcg h/mL; decreased Vd following
woman with CML imatinib and its metabolite CL/F 6.6 L/h: Postsurgery gastric bypass
− ABW 130 kg measured at various time − Cmin 659 ng/mL; AUC 40.1 − Decreased imatinib
points prior to and mcg h/mL; CL/F 12.2 L/h absorption following
following bariatric surgery (ABW 110 kg) gastric bypass
− Imatinib PO dose of − Cmin 791 ng/mL; AUC
400 mg/day maintained 30.8 mcg h/mL; CL/F 11.2 L/h
(ABW 92.5 kg)
Desar et al. [62] − 42-year-old man − Cycling sunitinib 50 mg − AUC 0.26 mg h/L (30–50% − May require higher doses
Case report with gastrointestinal PO daily × 4 weeks, then lower than previously reported) of sunitinib in obese
stromal tumor 2 weeks off − Css trough 19.9 and 25.2 ng/mL patients
resistant to imatinib − Plasma sunitinib samples on day 8 and 15 (70% lower
400 mg/day collected (9 samples than previously reported)
− ABW 134 kg; BSA per 24 h) − Vd “normal” when corrected for
46.9 kg/m2 ABW
(continued)
113
114

Dunn et al. [63] − 6 obese men − Methylprednisolone 0.6 mg/ − AUC obese vs. control: 2,797 − Authors conclude that
PK study (23–32 years) with kg IV in obese (based on vs. 1,040 ng h/mL obese patients should
ABW > 135% IBW ABW) − CL obese vs. control: 0.91 vs. receive steroid doses based
− 6 controls (21– − Methylprednisolone 40 mg 1.53 L/h/kg ABW (p < 0.05) and on IBW
33 years) within IV in controls 21.3 vs. 34.8 L/h (p < 0.05) − Dosing based on BSA not
10% IBW − Vd obese vs. control: 0.91 vs. examined
1.53 L/kg ABW (p < 0.05) and
104.9 vs. 122.2 L (p = NS)
a
Doses provided IV unless otherwise specified
ABW actual body weight, AdjBW adjusted body weight, ALL acute lymphoblastic leukemia, AUC area under the curve, BMI body mass index, BSA body surface
area, CL clearance, CL/F apparent oral clearance, Cmax maximum concentration, Css steady-state concentration, CML chronic myelogenous leukemia, CR
complete remission, ECG electrocardiogram, IBW ideal body weight, IV intravenous, NS not significant, OS overall survival, PK pharmacokinetic, PO oral, t1/2
half-life, SCT stem cell transplant, Vd volume of distribution
J. Kendrick et al.
The study by Dupuis et al. [46, 64] found that busulfan dose, after adjustment
based on serum concentrations, was not different when expressed as mg per m2 of
actual BSA. Browning et al. [47] found that busulfan dose, after adjustment based
on serum concentrations, was lower in obese children than normal-weight children.
They tested AdjBW25 and determined that it would result in over- or under-target
area under the curve (AUC) more often than when using patient-specific phar-
macokinetics. These studies suggest that actual BSA or ABW is appropriate for
calculating initial busulfan doses in children, but that therapeutic drug monitoring
is required to determine subsequent doses.
Three of the retrospective cohort studies that reported using busulfan prior to SCT
reported variable efficacy outcomes [33, 34, 36]. In the study by Coughlin-Dickson
et al. [33], where obese patients received doses based on AdjBW, higher BMI was
associated with higher nonrelapse mortality. In the study by Meloni et al. [34], where
all patients received doses based on ABW, obesity was associated with more infections.
Other adverse effects were not different between obese and normal-weight patients.
While high busulfan AUC and steady-state concentration (Css) are associated
with an increased risk of sinusoidal obstruction syndrome, formerly hepatic venooc-
clusive disease, low levels are associated with higher relapse and graft rejection.
Based on the three pharmacokinetic studies, it would be prudent to provide initial
busulfan dosing based on actual BSA or ABW and consider adjusting dose based on
serum concentrations. In adolescents and adults, initial busulfan doses could also
be provided based on AdjBW25.
4.1.2 Cyclophosphamide
Cyclophosphamide is an alkylating agent used in the treatment of leukemias. Cyclo-

phosphamide is a prodrug, which is metabolized in the liver by CYP3A4, 2B6, and
2C9 to its active form, 4-hydroxycyclophosphamide. CYP3A4 is also involved in
the metabolism of 4-hydroxycyclophosphamide to inactive dechloroethylcyclophos-
phamide. Approximately 5–25% of the dose is eliminated unchanged in the urine.
De Jong et al. [48] report a morbidly obese woman who received cyclophosph-
amide based on actual BSA, as part of her chemotherapy for breast cancer. Calculated
pharmacokinetic parameters were compared to the median values reported in the
normal-weight population. Total CL (L/h) was higher and Vd expressed as a function
of ABW was lower in this morbidly obese patient. AUC was similar for cyclophos-
phamide, but higher for the active metabolite 4-hydroxycyclophosphamide in this
patient. No toxicity was noted and doses were subsequently reduced.
In a small study by Powis et al. [49] where 75% of patients’ ABW was >120%
of IBW, cyclophosphamide pharmacokinetic parameters were calculated. ABW
correlated positively with cyclophosphamide half-life and negatively with clearance
normalized to BSA. ABW was not, however, correlated with total CL or Vd
expressed as a function of ABW. This suggests that obese patients would have lower
cyclophosphamide CL (L/h/m2) and similar Vd compared to normal-weight patients;
however, absolute values were not reported in this study.
One retrospective study reported using cyclophosphamide as part of treatment

for ALL in pediatric patients [29]. Doses were based on actual BSA and there was
no difference in the length of interval between diagnosis and completion of the 4th
phase of chemotherapy, hospitalization, death during induction, and death second-
ary to toxicity between obese and normal-weight children. Two retrospective stud-
ies in adults undergoing SCT reported using cyclophosphamide as part of their
chemotherapy [34, 37]. In the study by Meloni et al. [34], where all patients received
doses based on ABW, obesity was associated with more infections. Other adverse
effects were not different between obese and normal-weight patients. In the study
by Tarella et al. [37], where obese patients received doses based on “pharmacologic
weight,” there was no difference in toxicity between obese and normal-weight
patients.
As the pharmacokinetic case report and the small pharmacokinetic study are
conflicting, it is not clear whether initial dosing of cyclophosphamide should be based
on actual BSA. In addition, no pediatric pharmacokinetic information is available
for obese patients, nor is there, to our knowledge, published pharmacokinetic infor-
mation on high-dose cyclophosphamide in obese patients. If providing obese patients
with initial doses based on actual BSA, careful monitoring for toxicity and subsequent
re-evaluation of doses would be prudent.
4.1.3 Ifosfamide
Ifosfamide is an alkylating agent used in the treatment of leukemias. Ifosfamide

exhibits minimal protein binding and is metabolized extensively in the liver by the
CYP3A enzymes to its active form 4-hydroxyifosfamide. Variable amounts (3–56%)
of intact ifosfamide are eliminated in the urine.
In the small study by Lind et al. [50], ifosfamide clearance (total and expressed
per kg of ABW) was not significantly different in obese vs. normal-weight patients
with lung cancer. Volume of distribution was increased in obese vs. normal-weight
patients; however, there was no significant difference when Vd was expressed per kg
ABW. This suggests that ifosfamide may be dosed based on actual BSA, as was
done in the study.
4.2 Antimetabolites
4.2.1 Cytarabine
Cytarabine is an alkylating agent used in the treatment of leukemias. It is a hydrophilic

drug, which distributes well into the CNS. It is metabolized extensively in the liver
to inactive metabolites, which are primarily excreted in the urine.
Hijiya et al. [30] reported efficacy and safety outcomes, as well as pharmacokinetic
parameters in a large cohort of children who underwent treatment for ALL. Cytarabine
CL expressed as a function of actual BSA was not significantly different between
obese and normal-weight children who received 300 mg/m2 (783 vs. 774 L/min/m2;
p = 0.56). There was no difference in Grade 3 or 4 toxicity according to BMI.
Two other retrospective cohort studies reported using cytarabine as part of treatment
of ALL in children [29, 31]. Dosing was based on actual BSA in both studies. In the
study by Butturini et al. [29], there was no difference in the length of interval between
diagnosis and completion of the fourth phase of chemotherapy, hospitalization,
death during induction, and death secondary to toxicity between obese and normal-
weight children. In the study by Lange et al. [31], treatment-related mortality was
higher in obese vs. normal-weight children.
To our knowledge, no pharmacokinetic information is published on standard dose
or high-dose cytarabine in obese patients. Consideration should be given to providing
obese pediatric patients cytarabine doses based on actual BSA, given that CL is the
pharmacokinetic parameter that determines maintenance dosing and there is conflict-
ing information on the association between obesity and toxicity in this population.
4.2.2 Mercaptopurine
Mercaptopurine is an antimetabolite used in the treatment of leukemias. Mercapto-

purine’s bioavailability varies from 5 to 37%. It is widely distributed into tissues
(Vd 0.9 L/kg) and exhibits minimal protein binding. Mercaptopurine is metabolized
in the liver by methylation and oxidation and excreted in the urine as metabolites
and unchanged drug.
In the pharmacokinetic study by Zuccaro et al. [51], 18 children with ALL received
mercaptopurine based on actual BSA. Overweight children had lower exposure, as
measured by AUC, to mercaptopurine as compared to their normal-weight counterparts.
They also had higher clearance (L/h) and weight-normalized volume of distribution
(L/kg). Of note, the cut-off for overweight was BMI >75% for age. In the study by
Hijiya et al. [30], children with ALL received mercaptopurine as part of their treatment.
CL was not reported for this drug; however, there was no difference in Grade 3 or 4
toxicity according to BMI.
In the retrospective cohort study by Butturini et al. [29], children with ALL
received mercaptopurine as part of their treatment and dosing was based on actual
BSA. There was no difference in the length of interval between diagnosis and com-
pletion of the fourth phase of chemotherapy, hospitalization, death during induc-
tion, and death secondary to toxicity between obese and normal-weight children.
Based on the small pharmacokinetics study, it would be prudent to provide obese
children with mercaptopurine doses based on actual BSA to optimize exposure. To
our knowledge, no pharmacokinetic information is available for obese adults.
4.2.3 Methotrexate
Methotrexate is an antimetabolite used in the treatment of leukemias. Methotrexate

may undergo some intracellular and liver metabolism; however, it undergoes exten-
sive renal clearance with approximately 90% unchanged in the urine following
high-dose therapy.
Fleming et al. [52] found an obese woman, who was undergoing treatment with
high-dose methotrexate for osteogenic sarcoma, to have increased CL and larger Vd
(both expressed as a function of ABW) than previous reports. The patient had
received chemotherapy doses based on BSA calculated using IBW. No toxicities
were noted.
Hijiya et al. [30] found no significant difference in CL between obese and normal-
weight children receiving high-dose methotrexate 1.5–5 g/m2 (114.9 vs. 114.1 mL/
min/m2; p = 0.47) as part of their treatment for ALL. There was no difference in
Grade 3 or 4 toxicity according to BMI in this study.
Sauer et al. [53] reported nephrotoxicity in an obese adolescent following
intermediate-dose methotrexate, as evidenced by increased serum creatinine and a
renogram suggesting acute tubular necrosis. The methotrexate level 4 days following
the dose was “supratherapeutic.” The child improved following leucovorin and
intravenous fluids containing sodium bicarbonate. The association between obesity
and nephrotoxicity was unclear, especially given that the authors reference a case
report of four normal-weight adults who developed nephrotoxicity following inter-
mediate-dose methotrexate at 200 mg/m2 (Stark et al. [67]).
In addition to the Hijiya et al. [30] study, high-dose methotrexate was reported
in two retrospective cohorts. Butturini et al. [29] reported using methotrexate in
children with ALL and dosing was based on actual BSA. There was no difference
in the length of interval between diagnosis and completion of the fourth phase of
chemotherapy, hospitalization, death during induction, and death secondary to toxicity
between obese and normal-weight children. Tarella et al. [37] reported using metho-
trexate in adults who received SCT. Dosing in obese patients was based on a “pharma-
cologic weight” and no difference in toxicity between obese and normal-weight
patients was found.
Based on the two pharmacokinetic studies, we recommend that methotrexate
dosing be based on actual BSA in obese patients. There is more information supporting
this recommendation in obese children than in obese adults. No clear association
between obesity and toxicity has been found for this drug.
4.3 Anthracyclines (Daunorubicin, Doxorubicin, and Idarubicin)
Anthracyclines, such as daunorubicin, doxorubicin, and idarubicin, are used in the

treatment of leukemias. Doxorubicin is a lipophilic drug, which is bound approximately
75% to proteins. It is metabolized extensively in the liver to the active metabolite
doxorubicinol and excreted primarily in the bile and feces. The other anthracyclines
have similar pharmacokinetic properties; however, idarubicin is more extensively
protein-bound.
Sparreboon et al. [54] reported on pharmacokinetics from previously published
studies in adults with cancer. They found that doxorubicin CL and Vd at steady state
in obese (n = 23) vs. normal-weight (n = 41) patients were 60.5 vs. 57.6 L/h (p = 0.65)
and 14.5 vs. 14.0 L (p = 0.85), respectively. CL expressed as a function of actual

BSA was also not different between obese and normal-weight patients. Lean body
mass, IBW, and AdjBW were all good predictors of drug exposure, as measured by
AUC, in obese patients. ABW would result in higher exposure in obese vs. normal-
weight patients; however, this was found to be a result of lower CL expressed as a
function of ABW in the subgroup of obese women compared to normal-weight women.
In the small study by Barpe et al. [55], doxorubicin CL was similar between
overweight and normal-weight women. AUC was lower and absolute Vd was higher
in the overweight group.
In the small study by Rodvold et al. [56], doxorubicin CL (absolute and expressed
as a function of actual BSA) was lower in obese vs. normal-weight patients. AUC
was higher and absolute Vd was not different in the obese group.
In the small study by Thompson et al. [57], there was no significant difference in
the CL or Vd of doxorubicin or its metabolite doxorucinol, expressed as a function
of BSA, between overweight and normal-weight children. Doxorubicinol Vd and
CL were, however, higher in children with body fat >30% as compared to children
with body fat <30%.
In the case report by Ritzmo et al. [58], doxorubicin CL normalized to actual
BSA (mL/min/m2) was similar in a morbidly obese child, as compared to previous
reports in children.
Two retrospective studies in children with acute leukemias reported using anthra-
cyclines as part of their treatment. Neither study reported whether a cardioprotectant
such as dexrazoxane was used. Dosing was based on actual BSA in both studies. In
the study by Butturini et al. [29], where children received doxorubicin, there was no
difference in the length of interval between diagnosis and completion of the fourth
phase of chemotherapy, hospitalization, death during induction, and death secondary
to toxicity between obese and normal-weight children. In the study by Lange et al.
[31], where children received idarubicin or daunorubicin, treatment-related mortality
was higher in obese vs. normal-weight children.
The information regarding doxorubicin dosing in obese adults is conflicting.
Dosing based on actual BSA may be appropriate; however, it may result in increased
exposure, necessitating dosing based on BSA calculated using IBW or AdjBW.
In children, doxorubicin should be dosed based on actual BSA. This information
likely holds for other anthracyclines. The risk of long-term complications of anthra-
cyclines, such as cardiomyopathy, has not been described in obese patients relative
to normal-weight patients.
4.4 Platinum Compounds
Platinum compounds are not commonly used in the treatment of leukemias, though
they have been included in some research protocols for T-cell ALL and high-risk
AML [65, 66].
Platinum compounds exhibit extensive plasma protein binding and undergo rapid
and extensive nonenzymatic biotransformation in the plasma. Approximately half
of the platinum compound is eliminated in the urine.
Carboplatin is eliminated renally, with approximately 65% of the dose excreted
unchanged in the urine within 24 h. CrCl is often used to estimate glomerular filtra-
tion rate (GFR) and is calculated using the Cockcroft–Gault equation. The Calvert
formula [dose = target AUC × (GFR + 25)] is most widely used to calculate dose or
carboplatin.
Ekhart et al. [59] reported carboplatin CL in patients with solid tumors who received
various dosing schemes. They found that AdjBW40 was the best size descriptor in
the Cockcroft–Gault equation (used in the Calvert equation) for obese patients.
They also found that a flat dose based on population carboplatin CL resulted in the
least bias and imprecision in all patients.
De Jong et al. [48] described a morbidly obese woman who received carboplatin,
dosed using the Calvert formula with a CrCl of 185 mL/min, as part of her chemo-
therapy for breast cancer. Calculated pharmacokinetic parameters were compared to
median values reported in the normal-weight population. Vd expressed as a function of
ABW was lower in this morbidly obese patient. CL was not reported. Carboplatin
exposure, as measured by AUC, was higher in this patient. No toxicity was noted
and doses were subsequently reduced.
Sparreboon et al. [54] reported on pharmacokinetics from previously published
studies in adults with cancer. They found that carboplatin and cisplatin exposure, as
measured by AUC, in obese patients correlated best with AUC of lean patients when
ABW was used. CL normalized for actual BSA was similar between obese and
normal-weight patients.
Although conflicting data exist, using AdjBW to estimate CrCl in the Calvert
formula for carboplatin would be appropriate. Actual BSA may also be appropriate
for platinum compounds.
4.5 Plant Alkaloids
4.5.1 Etoposide
Etoposide is a plant alkaloid used in the treatment of leukemias. It is a lipophilic

drug with a large volume of distribution and extensive protein binding to albumin.
It is metabolized extensively in the liver and eliminated in the urine and the bile.
In the case report by Ritzmo et al. [58], etoposide clearance (mL/min/m2) was
similar in a morbidly obese child, as compared to previous reports in children. In the
study by Hijiya et al. [30], CL was not significantly different in obese vs. normal-
weight children with ALL who received etoposide 300 mg/m2 (50.2 vs. 48.7 mL/
min/m2, respectively). There was no difference in Grade 3 or 4 toxicity according to
BMI in this study.
In addition to the Hijiya et al. [30] study, Lange et al. [31] reported using etoposide
as part of their treatment of AML in children. In this study with approximately 10%
obese patients, doses were calculated based on actual BSA. Treatment-related
mortality was higher in obese vs. normal-weight children. In their retrospective
cohort, Tarella et al. [37] reported using etoposide in patients who received SCT.
Doses were based on “pharmacologic weight” and no difference in toxicity between
obese and normal-weight patients was found.
Obese children should receive etoposide doses based on actual BSA, given that
CL is similar when expressed as a function of actual BSA. The risk of any additional
toxicity is not clear. Dosing in obese adults is not clear.
4.5.2 Teniposide
Teniposide is a plant alkaloid used in the treatment of leukemias. Teniposide is a

lipophilic drug and is extensively bound to proteins. It is metabolized in the liver
and eliminated in the urine and feces.
Hijiya et al. [30] found no significant difference in CL between obese and
normal-weight children receiving teniposide 200–375 mg/m2 (14.2 vs. 14.0 mL/
min/m2; p = 0.35) as part of their treatment for ALL. There was no difference in
Grade 3 or 4 toxicity according to BMI. Based on this study, it would be appropriate
to provide obese children with teniposide doses based on actual BSA. To our knowledge,
there is no information for adults.
4.6 Tyrosine Kinase Inhibitors (Dasatinib, Imatinib,

Nilotinib, and Sunitinib)
Tyrosine kinase inhibitors, such as dasatinib, imatinib, nilotinib, and sunitinib, are used
in the treatment of leukemias. Tyrosine kinase inhibitors have high oral bioavail-
ability. They are extensively bound to albumin and alpha1-acid glycoprotein (>95%).
They are metabolized extensively in the liver, primarily by CYP3A4, and eliminated
primarily in the feces.
Two case reports describe the plasma concentrations of imatinib in morbidly
obese women with CML prior to and following bariatric surgery. Both case reports
suggest reduced imatinib absorption following gastric bypass. In one case, the dose
of imatinib was increased from 400 to 800 mg/day following gastric bypass in
response to low plasma concentration [60]. In the other case, the dose of imatinib
was maintained at 400 mg/day; however, the authors questioned the need to increase
the dose to target plasma trough concentrations of 1,000 ng/mL [61].
One case report described low AUC and steady-state trough concentrations in a
morbidly obese patient receiving sunitinib, suggesting that doses may need to be
individualized in obese patients [62].
Tyrosine kinase inhibitors are usually given in fixed doses. In obese patients,
doses may need to be increased relative to normal-weight patients. Higher doses
may also be required following bariatric surgery.
4.7 Other Drugs
4.7.1 Corticosteroids
Corticosteroids, most commonly dexamethasone or prednisone, are used in the

treatment of leukemias. One small pharmacokinetic study by Dunn et al. [63]
showed that methylprednisolone total CL and CL expressed as a function of ABW
were lower in six obese vs. six normal-weight control men. Vd expressed as a function
of ABW was also lower in the obese men. This study showed no significant phar-
macodynamic differences (cortisol and T helper response) between groups and sug-
gests that obese patients may require corticosteroid doses based on IBW.
4.8 Drugs Not Studied in Obesity
There is an absence of pharmacokinetic studies and reports of obese patients receiving

drugs such as all-trans retinoic acid, arsenic, 5-azacytadine, decitabine, clofarabine,
hydroxyurea, l-asparaginase, mitoxantrone, and thioguanine, which are used in the
treatment of acute leukemias; and alemtuzumab, bendamustine, chlorambucil,
cladrabine, fludrabine, ofatumumab, pentostatin, and rituximab, all used in the treatment
of chronic leukemias. In all studies reporting the use of vincristine, the maximum
dose provided was 2 mg regardless of the presence of obesity. Therefore, no dosing
recommendations can be made for these drugs.
5 Conclusion
From cohort studies (which attempt to examine the efficacy and safety of chemo-
therapeutic regimens in obese patients with leukemia and in obese patients undergoing
SCT compared to normal-weight patients), limited pharmacokinetic studies and
case reports in obese patients, it appears that the use of actual BSA for initial dosing
of leukemia chemotherapy in obese patients is appropriate (Table 5.4). Monitoring
for excessive toxicity should occur such that re-evaluation of subsequent doses
can occur. Dosing strategies using a capped BSA or calculating BSA based on IBW
are not supported and should be discouraged. Some drugs, such as anthracyclines,
carboplatin and corticosteroids, have special considerations. There is a paucity of
pharmacokinetic information to support the best dosing strategy for high-dose
5
Table 5.4 Summary of pharmacokinetic parameters and recommended dosing for cancer chemotherapy in obesity
Drug AUC CL (L/h) Vd (L) Initial dosing
Busulfan [44–46, 64] Not reported ↑ Not reported Actual BSA (adults, children)
↔ (L/h/kg) AdjBW25 (adults)
Carboplatin [48, 54, 59] ↑ or ↔ ↔ (L/h/m2) ↓ (L/kg) AdjBW40 for Calvert formula or Actual
BSA (adults)
Corticosteroids (methylprednisolone) [63] Not reported ↓ ↓ (L/kg) Unclear
Cyclophosphamide [48, 49] ↔ ↑ ↔ Unclear: actual BSA (adults)
↓ (L/h/m2) ↓ (L/kg)
Cytarabine [30] Not reported ↔ (L/h/m2) Not reported Actual BSA (children)
Doxorubicin [54–58] ↑ or ↓ ↔ or ↓ ↔ or ↑ Actual BSA (children)
Unclear: actual BSA or IBW (adults)
Etoposide [58] Not reported ↔ (L/h/m2) Not reported Actual BSA (children)
Ifosfamide [50] Not reported ↔ (L/h/kg) ↔ (L/kg) Actual BSA (adults)
Mercaptopurine [51] ↓ ↑ ↑ (L/kg) Actual BSA (children)
Methotrexate [30, 52] Not reported ↑ (L/h/kg) ↑ (L/kg) Actual BSA (adults, children)
↔ (L/h/m2)
Teniposide [30] Not reported ↔ (L/h/m2) Not reported Actual BSA (children)
Tyrosine kinase inhibitors [60–62] ↓ Not reported Not reported Higher doses (adults)
AdjBW adjusted body weight, BSA body surface area
123
cyclophosphamide or high-dose cytarabine in obese patients. In addition, vincristine

doses have been capped at 2 mg in most studies.
In addition to pharmacokinetic parameters (absorption, distribution, metabolism,
and elimination) of a given drug, consideration should be given to the obese patient’s
performance status, the curative intent, and the presence of comorbidities such as
organ dysfunction. The degree of obesity may be important, as pharmacokinetic
studies are more limited in obese subpopulations.
Limitations in the available evidence include the retrospective nature and variable
adjustment for confounders in the cohort studies, the limited information for high-
dose chemotherapy (e.g., cytarabine and cyclophosphamide), and the lack of information
on cumulative dose toxicities in obese patients (e.g., cardiomyopathy with anthracy-
clines). In addition, pharmacokinetic, efficacy, and safety data for obese adults may
not apply to obese children and vice versa. Therefore, there is a clear need for pro-
spective pharmacokinetic studies in obese patients for new chemotherapeutic drugs
under development. There is also a need for inclusion of obese and morbidly obese
patients in large prospective clinical trials in oncology, with stratification and report-
ing of outcomes according to weight.
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Chapter 6
The Impact of Obesity on Stem Cell Transplant
Willis H. Navarro and Fausto R. Loberiza Jr.
Abstract Hematopoietic cell transplantation (HCT) is a high-risk procedure of cura-

tive potential for patients with various malignant and nonmalignant hematological
diseases. Because the procedure carries considerable risks of treatment-related
morbidity and mortality and has variable results in improving disease-free survival,
patient selection plays an important role in its success. One patient factor that has
received attention in the last 20 years has been the concern that obese patients may
not have outcomes similar to normal weight individuals because of (1) altered phar-
macokinetics of commonly used chemotherapeutic agents [1, 2], (2) presence of
other medical comorbidities with obesity [3], and (3) higher morbidity associated
with obesity itself [4], which may result in higher post-HCT morbidity/mortality.
Because obesity has become a pandemic affecting both children and adults in the
United States and worldwide [5–8], the body of literature evaluating the relationship
between obesity and clinical outcomes in the setting of HCT has grown as well. This
chapter explores the pharmacokinetics, pharmacodynamics, and clinical outcomes of
HCT in the setting of obesity.
W.H. Navarro (*)

National Marrow Donor Program, 3001 Broadway St NE,
Suite 325, Minneapolis, MN 55413, USA
e-mail: wnavarro@nmdp.org
F.R. Loberiza Jr., M.D., M.S.
Department of Internal Medicine, University of Nebraska Medical Center,
987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA
e-mail: floberiza@unmc.edu
130 W.H. Navarro and F.R. Loberiza
1 Overview
Hematopoietic cell transplantation (HCT) is a high-risk procedure of curative potential

for patients with various malignant and nonmalignant hematological diseases.
Because the procedure carries considerable risks of treatment-related morbidity
and mortality and has variable results in improving disease-free survival, patient
selection plays an important role in its success. One patient factor that has received
attention in the last 20 years has been the concern that obese patients may not have
outcomes similar to normal weight individuals because of (1) altered pharmacoki-
netics of commonly used chemotherapeutic agents [1, 2], (2) presence of other
medical comorbidities with obesity [3], and (3) higher morbidity associated with
obesity itself [4], which may result in higher post-HCT morbidity/mortality. Because
obesity has become a pandemic affecting both children and adults in the United
States and worldwide [5–8], the body of literature evaluating the relationship
between obesity and clinical outcomes in the setting of HCT has grown as well. This
chapter explores the pharmacokinetics, pharmacodynamics, and clinical outcomes of
HCT in the setting of obesity.
2 Conditioning Regimens for HCT
The purpose of conditioning regimens for HCT varies, depending on the type of
HCT being performed. In the setting of autologous HCT, the intent of the condi-
tioning regimen is the obliteration of any remaining malignant disease when
chemotherapeutic resistance can be overcome by dose intensity. The collateral
damage of such dose intensity is near or complete myeloablation. Autologous hematopoi-
etic cells are then administered intravenously as a rescue from such therapy to
mitigate marrow aplasia.
In the allogeneic HCT setting, however, the cytotoxicity of the conditioning regimen
ranges from minimal to myeloablative. In some cases, such as in the treatment of
some low-grade lymphomas or nonmalignant diseases for example, the primary
therapeutic effect of allogeneic HCT is immunologic via a graft-versus-disease effect,
and conditioning regimen cytotoxicity is of little or no benefit. Non-myeloablative
or reduced intensity conditioning regimens are aimed primarily at inducing profound
recipient immunosuppression to prevent rejection of donor cells that would other-
wise lead to graft failure. Myeloablative allogeneic HCTs employ a conditioning
regimen that features both profound immunosuppressive capability and intense
cytotoxicity, typically used to battle malignant diseases with substantial risk of rapid
disease relapse or progression.
Obesity presents challenges with conditioning regimen dosing in several respects.
When chemotherapy at myeloablative dosing is used, the therapeutic index is even
narrower than in standard dose therapy since the dosing of the employed agents
has been intentionally set beyond the tolerance limit of the marrow and near the
6 The Impact of Obesity on Stem Cell Transplant 131
tolerance limit of the next organ system affected, frequently the gastrointestinal
tract. Effective dosing below anticipated levels may not provide sufficient cytotoxicity
to keep the underlying disease in check, whereas dosing above target may result in
excessive organ damage, increasing the morbidity or mortality of the HCT procedure.
In the allogeneic setting, relative to immunosuppression, another concern is with
conditioning regimen underdosing, resulting in an increased risk of graft rejection.
Thus, achieving optimal plasma levels of agents used in the conditioning regimen is
critical to the success of HCT.
3 Pharmacokinetics of Chemotherapeutics
in the Setting of Obesity
The dosing of a drug is based on the volume of distribution (Vd) and the clearance
(CL), which determine the appropriate loading and maintenance doses, respectively.
The elimination half-life (t1/2) is dependent on the Vd and CL. As discussed in Chap.
5, obesity may alter drug metabolism in several ways relative to lean patients: the
Vd, especially for lipophilic drugs, may be increased; blood flow to liver and kidney
may be relatively reduced; hepatic clearance may be impaired by fatty liver infiltration;
and increased plasma protein volume may provide more substrate for drug binding
[1, 2]. Moreover, drug pharmacokinetics (PK) may be altered when given in high
doses as is often the case in myeloablative conditioning regimens. In particular,
elimination kinetics may become nonlinear as the metabolizing enzyme(s) becomes
saturated or there is depletion of conjugating substrate. For drugs with significant
lipophilicity or extensive protein binding, high doses may increase these effects.
Despite the relatively limited repertoire of chemotherapeutics used in the high-
dose setting, there is a paucity of information to guide their optimal use in obese
patients. PK studies with standard dose chemotherapy agents in obese patients
have typically shown a prolonged terminal elimination phase (t1/2b) when com-
pared to normal weight subjects; in the case of doxorubicin, this appeared to be due
to decreased clearance [9], whereas for ifosphamide, the increase in t1/2b appeared
to be related to an increased Vd rather than decreased clearance [10]. Thus, the
reason for a longer t1/2b varies by agent, in part based on the physicochemical
properties of the drug and in part a result of differences in drug metabolism.
Sparreboom et al. performed an analysis of PK data from patients receiving stan-
dard dose chemotherapy where patients received at least one of the following
drugs: doxorubicin, topotecan, irinotecan, carboplatin, cisplatin, paclitaxel, and
docetaxel [11]. The authors found that there were no differences between normal
weight and obese patients with respect to t1/2 when normalized by weight for any
of the drugs except docetaxel, where there was a prolongation of t1/2 (16.9 vs. 10 h)
for the obese patients due to an increase in Vd. Of course, high doses of chemo-
therapeutic agents may result in different elimination characteristics than those
seen in the standard dose setting.
4 Chemotherapy Dosing in the HCT Setting
Despite the high stakes involved in proper dosing of conditioning regimen drugs in
the myeloablative setting, there is no standard correction for obesity. However,
most transplant centers employ a dose-adjustment schema for obesity. Grigg and
colleagues surveyed international transplant centers in 1997 and found that there
was no schema employed by a majority [12]. About a quarter of centers used actual
weight, 15% used only Ideal Body Weight (IBW), and the rest used adjustments
with some proportion of the difference between Actual Body Weight (ABW) and
IBW added to IBW. Looking at extremes of dosing for a very obese patient, dosing
differences could exceed 100%.
The best studied agent with respect to pharmacokinetics used in HCT is busulfan,
a bifunctional alkylating agent metabolized primarily in the liver via a glutathione-
reductase-dependent mechanism with minimal renal clearance. Busulfan has
been shown to cause fewest side effects, including sinusoidal obstruction
syndrome (previously termed veno-occlusive disease), without excessive rates of
graft failure when the area-under-the-curve (AUC) of plasma concentration versus
time is 900–1,500 mmol min [13–16]. Gibbs and colleagues performed a retrospec-
tive analysis of 279 patients examining the oral clearance (CL/F) of busulfan [17].
All patients had busulfan dose adjustments based on initial measured busulfan
plasma levels. Compared to nonobese patients, obese patients were noted to have
increased busulfan clearance of 16.2%. Of note, with correction of CL/F using body
surface area (BSA) or adjusted ideal body (AIBW) weight (IBW plus 25% of the
difference between ABW and IBW), comparable CL/F values were seen across
weight groups, suggesting that optimal dosing for busulfan should be based on BSA
or AIBW. Nguyen and colleagues also examined busulfan using the intravenous
preparation in a retrospective PK study of 127 adult patients [18]. In their analysis,
they found that AIBW or BSA were the best covariates to explain interpatient
variability, resulting in 16% interpatient variability, which was very close to intra-
patient variability of 13%. As with the Gibbs study, the authors concluded that
busulfan dosing by BSA or AIBW were best to achieve similar plasma levels
between normal and overweight/obese groups.
For agents other than busulfan in the setting of obesity, the data in the literature
remain anecdotal. De Jonge and coworkers in 2002 reported a case of a woman
receiving high-dose carboplatin, cyclophosphamide, and thiotepa for metastatic
breast cancer [19]. Doses were calculated using the patient’s ABW (130 kg; BSA
2.34 m2). Pertinent drug or metabolite levels for the three agents were obtained
and drug exposure was calculated based on the AUC. Exposure to 4-hydroxycy-
clophosphamide, the active metabolite of cyclophosphamide, was 94% higher
than for a nonobese cohort. For thiotepa plus the active metabolite tepa, the expo-
sure was 117% higher, and for carboplatin calculated using the Calvert formula,
the AUC was 71% higher than nonobese controls. Therapeutic drug monitoring
was employed and the patient’s drug doses were reduced. The authors recommend
using adjusted body weight [in this case, IBW plus 0.4 × (ABW–IBW)] to calcu-
late BSA and for dosing by weight.
5 Pharmacodynamics of Conditioning
Regimen Chemotherapy in HCT
Disease relapse and toxicity are two of the most important pharmacodynamic out-
comes. In the autologous HCT setting, where the conditioning regimen drives the
efficacy of the procedure, there is assumed to be an inverse relationship between
relapse risk and toxicity, though that relationship is likely to be nonlinear. Meloni
and coworkers reported outcomes for obese patients treated with autologous HCT
for acute myeloid leukemia (AML) where conditioning regimen dosing was based
on ABW [20]. A total of 54 patients were treated, 9 of whom were obese as defined
by a body mass index of ³27.8 and ³27.3 for men and women, respectively. The
obese group suffered from a markedly increased rate of toxic death (33%: 3 of 9)
versus 8% in the nonobese group, as well as statistically significantly poorer dis-
ease-free and overall survival for the obese group. The authors conclude that dose
adjustment for obesity appears important in the autologous HCT setting.
Tarella et al. reported on outcomes for autologous HCT for non-Hodgkin lymphoma
in 121 patients, 28 of whom were obese as defined by a BMI ³28[21]. Chemotherapy
dosing was based on ABW up to a BMI of 32, after which an unspecified dose-
adjustment schema was used. Most patients received a melphalan/mitoxantrone-
based regimen; five received carmustine (BCNU)/etoposide/cytarabine/melphalan
(BEAM). The investigators reported no significant differences in toxicity between
the normal and obese groups, though there was a trend for lower incidence and
duration of fever and of decreased transfusion requirements for the obese group.
However, overall and event-free survival was poorer for the obese group (RR 2.8
and 2.9 for failure of event-free survival, and of death, respectively compared to the
nonobese group), accounted for primarily by relapse.
Dickson et al. reported outcomes in autologous HCT for 473 patients treated
for various hematologic malignancies by the Stanford group in 1999 [22]. The
conditioning regimen was based on ABW up to 15 kg greater than IBW, then dosing
was based on [40% × (ABW–IBW)] + IBW. Of note, about 43% of patients received
total body irradiation (TBI) as part of the conditioning regimen, introducing another
variable of dosing of TBI in the obese setting. Patients were categorized by BMI
groups expressed as a percentage of an age-adjusted BMI based on IBW. The reference
group was 100–119% of expected BMI. There were also underweight groups at
70–79% and 80–99% and obese groups at 120–139% and 140–199%. There was a
statistically significantly increased rate of 5 year estimated nonrelapse mortality
(NRM) among the 70–79% BMI group (NRM = 18%) and for the 120–139% group
(NRM = 24%) compared to 13% in the reference group. However, relapse rates were
similar across all groups. Toxicity was higher among the obese, but because of the
high proportion of patients receiving TBI in this group, it is not clear how much
toxicity was related to chemotherapy and how much was related to TBI.
In the allogeneic HCT setting, the pharmacodynamic picture becomes substantially
more complex because the immune effects of the graft can dramatically affect both
relapse and morbidity and mortality. However, in a study by Deeg and colleagues
examining outcomes for all HCT (both autologous and allogeneic) performed at the
Fred Hutchinson Cancer Research Center from 1985 to 1992, no differences in day
150 nonrelapse mortality were detected among normal weight and patients with
varying degrees of obesity [23].
6 Obesity and Outcomes in HCT
Complex study designs have been used to evaluate outcomes in HCT in early
and long-term time frames. To understand the influence of adiposity on the outcomes
of HCT, we present a conceptual framework that has been the basis of most of
the studies conducted in this area of research. Such a conceptual framework will
facilitate interpretation of conflicting studies in this area of study. The framework
can also serve as a guide to future investigators in this field so that relevant factors
can be considered in their research design.
Figure 6.1 shows the complex relationships between patient-, disease-, and trans-
plant-related factors, as they relate to clinical outcomes of importance in HCT. The
left-hand side of the figure shows the many representative prognostic factors that
have been shown to exert an effect on the more common clinical outcomes considered
Fig. 6.1 Conceptual framework in evaluating the relationship between obesity and outcomes
after HCT
in HCT, which are presented on the upper right-hand side. Prognostic factors are
generally grouped into (a) patient factors such as age, performance score, race/
ethnicity, and socioeconomic status; (b) disease factors such as type of disease,
disease stage and status at transplant, cytogenetics, tumor sensitivity to chemother-
apy; and (c) treatment or transplant factors such as donor source, cell source and
dose, conditioning regimen. These factors are otherwise referred to as tradi-
tional factors. Traditional factors have been well validated with robust influence,
either positive or negative, on HCT outcomes. Nontraditional factors , not
illustrated in this figure, may include the following: individual factors such as psy-
chological, behavioral, cultural, and spiritual factors; and organizational factors
such as center effect, healthcare system, and follow-up care provider. The evidence
for the impact of nontraditional factors affecting HCT outcomes are fewer than
traditional factors and therefore not very robust.
The major outcomes considered in HCT studies usually include overall and
disease-free survival, disease progression or relapse, treatment-related or nonrelapse
mortality, engraftment, and graft-versus-host disease (GVHD) rates. The increase
in the number of patients surviving after HCT have also broadened the scope of
outcomes to include major organ toxicities such as the development of a second
cancer, cardiovascular disease, pulmonary disease, and others. The figure presents
obesity as one of the many important prognostic factors that can affect outcomes.
It also presents obesity as an independent factor, thus outside the box from the other
traditional factors. The reason for its independence is that obesity has been shown
to be related to the development of multiple diseases in many organ systems, as
shown in the lower right-hand side. Conduit A connects important prognostic
factors to direct influence on HCT outcomes. Conduit B links obesity as an independent
factor also directly influencing HCT outcomes. Conduits C and D illustrate the indirect
effects of obesity on transplant outcomes through the myriad diseases for which
obesity is known to be a risk factor. The occurrence of multiple diseases (as a modifier)
with obesity produces the effects on clinical outcomes (Conduit E).
It is important to point out that while obesity can be a risk factor prior to transplant,
it is also a phenomenon that can occur after transplant and therefore can exert effect
on post-HCT clinical outcomes, especially among long-term survivors. Obesity is
also a modifiable factor. While most studies have evaluated its effect as a pre-transplant
factor, most analyses assume that the state of being obese is one that is static, when
in reality it is very much a dynamic and evolving risk factor. The impact of modification
of this risk factor in the post-transplant setting in terms of its effects on transplant
outcomes has not been studied.
7 Outcomes After Autologous HCT
In 2011, Vogl et al. evaluated 1,096 recipients of autologous HCT for multiple
myeloma from multiple centers who provided data to the Center for International
Blood and Marrow Research (CIBMTR) [24]. In this study, patients received high-dose
melphalan with or without TBI. Of the eligible cohort, only 9 (<1%) were under-
weight based on BMI, and thus excluded from the analysis. On the other hand, only
292 (27%) were considered to have normal weight, and the rest were overweight
(43%), obese (18%) and severely obese (11%). Adjusting for other prognostic factors,
the study found that progression, nonrelapse mortality, progression-free survival, and
overall survival did not differ according to categories of BMI. However, in the subset
of patients receiving TBI with melphalan, both obese and severely obese auto-HCT
recipients were 51% and 61% less likely to have treatment failure, respectively, when
compared to normal for weight auto-HCT recipients. In this subset of patients, severely
obese auto-HCT recipients were also 57% less likely to develop progression com-
pared to normal for weight auto-HCT recipients. The findings suggest that current
strategies used in clinical practice to adjust for melphalan doses in obese patients do
not result in increased treatment-related mortality or overall mortality.
The protective effect of obesity was also seen in a similar multicenter study
published in 2006 by Navarro et al. regarding autologous HCT recipients treated
for lymphoma [25]. In this report, 4,681 patients were included. Only 2% of the
population was underweight at the time of autologous HCT, while 41% had normal
weight, 36% were overweight and 20% were obese. Adjusting for other prognostic
factors, the study showed that overweight and obese lymphoma patients who
received autologous HCT were 13% and 24% less likely to die from any cause after
autologous HCT respectively when compared to normal weight recipients.
Conversely, underweight patients were 49% more likely to die from any cause after
autologous HCT when compared to normal weight recipients. The survival advantage
in the overweight and obese cohorts appeared to be most likely due to decreased
treatment-related mortality in these patient groups. Again, the study supports the
approach that consideration of lymphoma patients for autologous HCT should not
be adversely influenced by obesity alone, as they enjoy similar to better outcomes
than normal weight individuals. The study also lends support to the idea that inter-
ventions to improve the nutritional status of underweight patients before and after
HCT may be warranted.
Navarro and colleagues also published in 2010 a similar analysis on 362 autologous
HCT recipients with acute myelogenous leukemia [26]. In this report, 1% of patients
were underweight, 45% were normal weight, 31% were overweight, and 22% were
obese. The study excluded the underweight patients in some analyses because of
small numbers. After adjusting for other prognostic factors, the study found that
normal weight, overweight, and obese patients did not differ in overall survival,
treatment failure, relapse, and treatment-related mortality. Similar to the lymphoma
study, the authors demonstrated that obesity does not appear to represent a significant
barrier to successful HCT among autologous HCT recipients with AML.
While the large, retrospective, observational contemporary studies just discussed
have shown no disadvantage to obesity, some older, smaller studies have shown
poorer outcomes for obese patients. In the autologous setting, the Meloni study
described previously showed inferior, disease-free, and overall survival for obese
patients, with the caveat that the poorer results appeared at least in part to be driven
by higher treatment-related mortality related to dosing [20]. Likewise, in the Tarella
study, outcomes were also inferior, with the obese patients suffering worse, event-
free, and overall survival (38% and 23% projected at 5 years, respectively, for the
obese group; 65% and 55% for the normal weight group) as well as a relative risk
of death of 2.9 for the obese group [21]. Based on a higher relapse rate and a trend
toward lower toxicity, it appears reasonably likely that the obese group was under-
dosed despite the lack of a dose-adjustment schema.
8 Outcomes After Allogeneic HCT
In 2010, Navarro et al. evaluated the outcomes of patients with AML who received
HLA-identical sibling HCT or unrelated HCT [26]. The HLA-identical sibling
cohort consisted of 2,041 patients, with 2% underweight, 58% normal weight, 27%
overweight, and 14% obese/morbidly obese. Adjusting for other prognostic factors,
the study found that underweight recipients of HLA-identical sibling transplants
for AML were at increased risk of relapse, treatment-related mortality, treatment
failure, and death from any cause when compared to normal weight recipients.
On the other hand, both overweight and obese/morbidly obese recipients HLA-identical
sibling transplants for AML did not significantly differ in risk of relapse, treatment-
related mortality, treatment failure, and death from any cause when compared to
normal weight recipients. The unrelated cohort consisted of 1,801 patients, with 2%
underweight, 48% normal weight, 29% overweight, and 21% obese/morbidly
obese. After adjusting for other prognostic factors in the underweight group, the
previously seen increased risks in relapse, treatment-related mortality, treatment
failure, and death from any cause when compared to normal weight recipients were
not observed. However, these results may have been limited by the small number of
patients who are underweight. The outcomes of overweight and obese recipients of
unrelated HCT for AML were similar to those of normal weight recipients, except
for relapse. Overweight and obese recipients of unrelated HCT were 18% and 24%
less likely to experience relapse when compared to normal weight recipients respectively.
Again the studies show evidence that obesity does not appear to have deleterious
effects on clinical outcomes after related or unrelated HCT in patients with AML.
On the other hand, there is some evidence that caution should be exercised among
underweight candidates for related HCT.
Several smaller studies evaluating the relationship between body mass index and
clinical outcomes after allogeneic HCT with varying case mix and utilizing less
complex analytical approaches have generally shown similar outcomes on major HCT
clinical outcomes of overweight and obese patients with normal weight patients.
While some secondary outcomes such as engraftment and graft-versus-host disease
differ, these were not enough to produce significant difference in overall survival.
Most studies have analyzed outcomes in adults, but in 2010, Pine et al. evaluated
the association between body mass index and clinical outcomes of 200 children less
than or equal to 18 years of age with various malignant disease, who received
unrelated cord blood transplant as part of a multicenter clinical trial. In this cohort,
58% were normal weight, 18% were overweight and 24% obese [27]. There were
no differences in the major characteristics of the patients according to weight groups.
The study showed that engraftment, acute graft-versus-host disease, treatment-related
mortality, treatment failure and overall survival were similar across weight groups.
The obese group had a slight increased in the incidence of chronic graft-versus host
disease, but not enough to produce differences in overall survival. The study concluded
that among children with malignant disease, obesity does not appear to have deleterious
effects on the outcomes of unrelated cord blood transplant. However, a larger retro-
spective study using observational data analyzing outcomes for 1,251 children
undergoing HCT for severe aplastic anemia from 1990 to 2005 found poorer overall
survival in obese children with a relative risk of death at 1.71 (95% confidence interval:
1.24–2.35; p < 0.01) [28]. Obesity was defined as >95% percentile using the CDC
BMI-for-age growth charts. The groups were generally well matched except that the
143 obese children received unrelated donor HCT at a rate of 18% versus 8% overall,
there were more Hispanic and fewer Asian children in the obese group, the obese
group had fewer transfusions but more were greater than 6 months from diagnosis
to transplant. Absolute rates of Grade 3–4 acute GVHD (aGVHD) at day 100 were
greater for the obese children at 24% versus 11% for normal weight patients.
However, the authors point out that in multivariable analysis, taking into account in
particular the higher rate of unrelated donor transplants rather than siblings in the
overweight group, the risk of aGVHD becomes similar to normal weight children.
The study did not present data on toxicities nor on conditioning regimen dosing that
could shed light on what role conditioning regimen toxicity may have played in the
increased mortality among obese children.
Similar to the data for autologous HCT, there are also two older studies in allogeneic
HCT showing poorer outcomes. Fleming and colleagues reported results of a single-
institution case–control study including 76 obese adults, defined as at least 120% of
IBW, compared to 166 nonobese patients treated for a variety of hematologic malig-
nancies [29]. Overall survival (OS) for the nonobese group was 30% at a median
follow-up of 296 days, whereas for the obese group, OS was 16% at 120 days of
median follow-up. Relapse rates were similar between the two groups. Hansen
and coworkers reported on outcomes for chronic phase chronic myeloid leukemia
[30]. A high body weight index (ABW/IBW), modeled as a continuous variable
in increments of 25%, proved to be a mortality risk factor in multivariable analysis
with a relative risk of 1.6.
9 Conclusions
Obesity, in contemporary studies across a variety of diseases and transplant types

(autologous, related, and unrelated allogeneic HCT), does not appear to be associ-
ated with poorer outcomes in the short or intermediate time frame. It is not clear
what impact obesity has on long-term outcomes after HCT as these studies have not
been performed. Ascertainment of appropriate dose adjustment for conditioning
regimens remains an area of need for investigation. Such studies, however, are likely
to be challenging since each drug used in conditioning has its own physicochemical
properties, so each will need to be studied individually. To date, this has only hap-
pened to any degree with busulfan but not systematically with other commonly
employed agents such as melphalan, cyclophosphamide, thiotepa, or carmustine.
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Chapter 7
Obesity Following Childhood Cancer:
Mechanisms and Consequences
Emily S. Tonorezos and Kevin C. Oeffinger
Abstract Due to advances in the treatment of pediatric cancer, the population of

adult survivors has increased dramatically. Many survivors face a significant threat
of becoming overweight, obese, and insulin resistant. In this chapter, we present
four case vignettes to illustrate the risks of obesity in adult survivors of pediatric cancer,
known mechanisms, studied interventions, and future directions in research.
1 Introduction
As a result of the tremendous improvements in the treatment of childhood cancer,

survival has increased substantially. Between 1975 and 2002, mortality from
pediatric cancer decreased by over 45%; currently over 80% of pediatric cancer
patients become long-term survivors [1]. Today, there are over 325,000 survivors of
pediatric cancer living in the United States [2, 3].
While the number of survivors is growing, their medical care is becoming more
challenging. Many survivors face the burden of late-occurring treatment-related
toxicities, known as “late effects,” which may not emerge clinically until many
years following primary treatment. By the time many late effects develop, most
E.S. Tonorezos, M.D., M.P.H

Department of Medicine, Memorial Sloan-Kettering Cancer Center,
1275 York Avenue, New York, NY 10065, USA
K.C. Oeffinger, M.D. (*)
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center,
Department of Medicine, Memorial Sloan-Kettering Cancer Center,
e-mail: oeffingk@mskcc.org
142 E.S. Tonorezos and K.C. Oeffinger
cancer survivors have left their primary treatment facility or pediatric oncology team.
The details of their cancer diagnosis and care may be unknown to the survivor or the
health care team. Nonetheless, a study by Oeffinger and colleagues found that by
30 years from the initial cancer diagnosis, 73% of pediatric cancer survivors had
developed at least 1 chronic physical health condition, and in 42% the condition was
severe, life-threatening, disabling, or resulted in death [4]. In contrast, only 36.8%
of non-cancer siblings of survivors reported having 1 chronic health condition,
and in just 5.2% was it severe or life-threatening. The most common conditions
sited were cardiovascular disease, renal dysfunction, severe musculoskeletal problems,
second cancers, and endocrine abnormalities [4]. Moreover, the excess risk of
morbidity and mortality does not appear to plateau with aging [4, 5]. Clearly, awareness
of the risks for survivors and risk-reducing strategies are of increasing importance
to the health care system.
As described in prior chapters, obesity is a public health problem of increasing
prevalence and with many deleterious effects. Data from the National Health and
Nutrition Examination Survey reveal that the overall age-adjusted prevalence of obesity
(body mass index [BMI] ³30) was 33.8% in 2007–2008 and that the prevalence of
overweight and obesity combined (BMI ³25) was 68% [6].
Overweight and obesity can directly contribute to adverse health, as is the case
in obstructive sleep apnea or osteoarthritis [7]. The major impact of obesity for
many patients, however, comes in the form of insulin resistance, Type 2 Diabetes
Mellitus (DM), and an increased risk of cardiovascular disease. Several large
epidemiologic studies have found that increasing BMI is associated with an
increased risk of all-cause and cardiac-specific mortality. The Cancer Prevention
Study II, a prospective study of mortality in more than one million men and
women in the United States and initiated by the American Cancer Society in
1982, found an increased risk of cardiovascular death with increasing BMI in adults
who never smoked and who had no history of cardiovascular disease at enrollment;
the risk was highest among men (relative risk 2.90) but was also elevated among
women [8].
The problems of obesity and insulin resistance in survivors of pediatric cancer
are complex. When all survivors are considered together, it is apparent that pediatric
cancer survivors are a heterogeneous group [9, 10]. Indeed, some specific groups of
survivors, such as males treated for neuroblastoma as young children, are at lifelong
risk for poor growth and being underweight [11]. Nonetheless, obesity and insulin
resistance are both common and medically burdensome in several specific groups of
survivors, particularly survivors of acute lymphoblastic leukemia (ALL) [12–16].
Mechanistically, obesity and insulin resistance may represent the result of
interactions between treatment-related effects, such as endocrinologic changes or
inhibition of normal adipocyte expansion, and behavioral factors, such as physical
inactivity and dietary intake [17]. In this chapter, we present four case vignettes
to illustrate the spectrum of mechanisms and consequences of obesity among
survivors of childhood cancer.
7 Obesity Following Childhood Cancer: Mechanisms and Consequences 143
2 Cases
2.1 Acute Lymphoblastic Leukemia
HT is a 25-year-old survivor of acute lymphoblastic leukemia (ALL) who was treated

beginning at 3 years, 5 months old with a regimen including cyclophosphamide, daunorubicin
(585 mg/m2), vincristine, prednisone, cytosine arabinoside, 6-mercaptopurine, thioguanine,
and methotrexate (intravenous and intrathecal). She did not receive cranial radiotherapy.
She led a healthy adolescence and young adulthood, with menstruation starting at age 11.
On presentation to the adult long-term follow-up program, she describes a vigorous exercise
program 4–5 days a week. Nonetheless, she is a petite 151 cm and her weight is 71 kg; her
body mass index (BMI) is 31 kg/m2 and her waist circumference is 92 cm. Blood pressure
is 110/65 mmHg, while laboratory analysis reveals elevated fasting blood glucose of
107 mg/dL, and elevated triglycerides of 187 mg/dL.
Survivors of childhood ALL account for more than 25% of pediatric cancer
survivors, more than any other diagnosis group [1, 3]. Long-term survivors of ALL,
especially females, are at increased risk for overweight, obesity, insulin resistance,
and dyslipidemia [12, 14, 15, 18, 19]. While women with a history of receiving
cranial radiotherapy (CRT) for ALL are at highest risk, many survivors of ALL are
at risk, as illustrated in this case. Unfortunately, these treatment-related metabolic
risk factors likely contribute to the increased risk of cardiovascular disease in this
population. Although still a relatively young group, the standardized mortality ratio
for death from cardiac causes among 5-year survivors of ALL diagnosed and treated
in the 1970s and 1980s is 4.2 [20].
Insulin is secreted by the b-cells of the pancreas in response to increased serum
glucose. Normally, insulin prompts the uptake of glucose and the normalization of
peripheral glucose levels. At times, high serum insulin is seen in the setting of
normal glucose levels; this clinical picture is termed insulin resistance (when serum
glucose is also abnormally high, DM is diagnosed). Insulin resistance is often seen
in the setting of obesity, particularly abdominal obesity, and is the central physiologic
abnormality in the metabolic syndrome. The prevalence of insulin resistance is
increasing rapidly, worldwide [21, 22]. At the same time, recent evidence implicates
insulin resistance in a wide range of negative health effects, including coronary
artery disease, hypertension, and systemic inflammation [23, 24].
Oeffinger and colleagues recently reported results from the ALLIFE Study, an
evaluation of cardiovascular risk factors in 118 adult survivors of pediatric
ALL (age range, 18–37 years). In a sex-specific cross-sectional comparison of ALL
survivors and 782 non-cancer subjects from the Dallas Heart Study (DHS), ALL
survivors were found to have significantly worse insulin resistance as measured
by the homeostasis model for assessment of insulin resistance (HOMA-IR)
when compared to subjects in DHS. Female survivors of ALL had a significantly
higher (worse) HOMA-IR when compared to females in the DHS, while females
with a history of CRT had the highest levels of insulin resistance (CRT females,
mean HOMA-IR = 4.6; no CRT females, mean HOMA-IR = 3.3; DHS females, mean
HOMA-IR = 2.4). Male survivors of ALL also had a significantly higher mean HOMA-IR
(CRT, 4.0; no CRT, 3.4) compared to males in DHS (2.3) [13].
Obesity is a well-known risk factor for insulin resistance and Type 2 DM and is
highly prevalent among ALL survivors. ALL survivors in the Childhood Cancer
Survivors Study (CCSS) with a history of cranial radiation have a significantly
higher BMI when compared to non-cancer siblings [14]. Nevertheless, obesity does
not account for all of the increased risk of insulin resistance in ALL survivors. In the
ALLIFE study (comparing ALL survivors to non-cancer participants in the DHS),
male survivors of ALL were not more obese, but did show increased risk of insulin
resistance [13]. Further, a comparison of survivors of pediatric ALL in the CCSS
and their non-cancer siblings found that ALL survivors were more likely to report a
history of diabetes mellitus even after controlling for body mass index (RR 1.8) [16].
Numerous mechanisms have been proposed to explain obesity and insulin resis-
tance among ALL survivors, although no single explanation is entirely satisfactory.
As in other pediatric survivors, the causes of obesity in ALL survivors may include
reduced physical activity, familial risk factors, and early adiposity rebound [25–27].
Additional factors may be at play among ALL survivors in particular. Glucocorticoid
administration during the first 4 weeks of ALL therapy results in derangements
in glucose levels, weight gain, and height loss. Further, steroids can alter appetite
regulation and result in decreased physical activity [28, 29]. The metabolic and
anthropomorphic changes in ALL survivors frequently persist long after corticos-
teroid therapy has stopped.
Abnormalities of growth hormone or leptin may contribute to insulin resistance
in ALL survivors. Growth hormone (GH) deficiency has been repeatedly implicated
in insulin resistance and visceral obesity, and GH deficiency is the most common
endocrinologic disorder after CRT [30, 31]. Leptin, a hormone secreted by adipo-
cytes, is important in appetite and physical activity (Fig. 7.1). We have described
leptin dysregulation, which may contribute to insulin resistance, in ALL survivors
[32]. Some evidence suggests that a biologic interaction between leptin receptor
activity, CRT, and obesity may exist; a polymorphism of leptin receptor activity
(Gln223Arg) interacts with CRT in its association with insulin resistance and is
independently associated with obesity among women [26].
Prior evidence suggests that ALL survivors are more likely to be physically inactive
than controls, and women treated with CRT are especially inactive [33]. Inactivity
in this population may be a result of muscle strength deficits. In a study of 75 adult
survivors of childhood ALL treated between 1970 and 1986, Ness and colleagues
found decreased muscle strength and mobility compared to population normative
values. The ALL survivors took longer to complete the “Timed Up and Go” test and
walked shorter distances. Furthermore, males had 4.5% more body fat and females
had 2.3% more body fat (as measured by dual energy X-ray absorptiometry) than
population normative values. In that study, a history of treatment with CRT and
growth hormone (GH) deficiency were associated with lower body weakness among
females [34].
As noted, CRT plays an important role in the increased risk of obesity among ALL
survivors. In the Childhood Cancer Survivor Study, ALL survivors who received
18 Gy or more of CRT were found to be at increased risk for obesity [14].
Women and those who were treated before age 5 were at the highest risk [12].
Fig. 7.1 The leptin–adiponectin system
In the ALLIFE Study, described above, higher BMI after CRT was associated with
loss of lean body mass and increased fat mass [30, 35]. Subjects with a history of
CRT had higher fat mass, subcutaneous adiposity, and visceral adiposity; the
effect of CRT on visceral adiposity was most pronounced. A recent comparison of
childhood cancer survivors and non-cancer siblings found that CRT was associated
with higher total fat and trunk fat, but not BMI, among both male and female
survivors [10].
The impact of CRT extends beyond obesity to insulin resistance as well. As
described above, female ALL survivors in the ALLIFE Study who had been treated
with CRT had the highest levels of insulin resistance when compared to females
without a history of CRT and male ALL survivors [13]. CRT is associated with
growth hormone deficiency, which is independently associated with insulin
resistance. Nonetheless, a history of CRT does not explain all of the observed
risk for obesity and insulin resistance among ALL survivors [13, 14, 30, 36–38].
As in the case of patient HT, many ALL survivors did not receive CRT yet have
obesity and insulin resistance [39]. Importantly, this finding suggests that although
CRT is currently used in only 5–15% of children with ALL, this population of survivors
will remain at increased risk of obesity and insulin resistance in the future.
Although the young woman presented in this case has a satisfactory blood pressure
and is exercising vigorously several days a week, she meets criteria for the metabolic
syndrome. Among adults, the metabolic syndrome is defined by the American Heart
Association as including three of the following five diagnostic criteria: elevated
blood pressure (³130 mm Hg systolic blood pressure of ³85 mm Hg diastolic blood

pressure), elevated fasting triglycerides (³150 mg/dL), elevated fasting glucose
(³100 mg/dL), low HDL-C (<40 mg/dL in men or <50 mg/dL in women), and
increased waist circumference (³102 cm in men or ³88 cm in women) [40]. The
1999 World Health Organization guidelines included microalbuminuria [41], while
the most recent harmonized guidelines from the World Health Organization,
International Diabetes Federation, and the American Heart Association/National
Heart Lung and Blood Institute include ethnicity-specific guidelines regarding the
waist circumference limits [42, 43]. Obesity is a critical determinant of the metabolic
syndrome, operating through a number of influences that include reduced insulin
sensitivity and changes in fatty acid metabolism. Variations in the nature and magnitude
of the dyslipidemia seen in this setting are due to the interaction of genetic factors
with environmental influences, most notably diet and physical activity, and possibly
stress. This patient should be treated aggressively with risk factor modification and
encouraged to continue her exercise routine.
KL is a 28-year-old survivor of T-cell ALL who was treated beginning at age 8 with a regimen
that included cranial radiotherapy (CRT) at a dose of 1,800 cGy, plus cyclophosphamide,
daunorubicin (360 mg/m2) and prednisone. Approximately 1 year into treatment, KL
relapsed in his bone marrow and required a hematopoietic stem cell transplant. At that time,
he was given total body irradiation (TBI) of 1,500 cGy and a testicular boost of 400 cGy.
During his visit in the long-term follow-up program, he is found to be 168 cm tall with a
weight of 85 kg; his BMI is 30 kg/m2. His fasting glucose is 105 mg/dL, triglycerides are
211 mg/dL, AST is 72 mg/dL, and ALT is 101 mg/dL all of which are elevated.
KL is a patient with multiple treatment-related risk factors for obesity and insulin
resistance. As described previously, many survivors of childhood ALL are at increased
risk for obesity and insulin resistance, regardless of treatment history. Furthermore,
KL received CRT during his initial treatment, which increases the risk of obesity
and insulin resistance as discussed above. Finally, KL required TBI at a dose of
1,500 cGy in preparation for his hematopoietic stem cell transplant. Stem cell trans-
plant, especially following TBI, has been associated with impaired glucose metabolism
and increased risk of cardiovascular disease [44–46]. Patient KL now appears to
have obesity, impaired fasting glucose, hypertriglyceridemia, and most likely non-
alcoholic fatty liver disease (steatohepatitis).
Several investigators have reported an increased prevalence of insulin resistance,
Type 2 DM, or impaired glucose metabolism following pediatric hematopoietic
stem cell transplant. A history of TBI has emerged as a particularly important risk
factor in this setting. Depending on the setting of the study, the prevalence of
impaired glucose tolerance and overt Type 2 DM ranges from 42% to 64% of stem
cell transplant survivors with a history of treatment with TBI [47–51]. In an analysis
of participants in the Childhood Cancer Survivor Study, compared to non-cancer
controls, a history of treatment with TBI was associated with dyslipidemia, DM,
and a clustering of cardiovascular risk factors consistent with the metabolic
syndrome [52]. Interestingly, the link between obesity (particularly if measured by
body mass index) and insulin resistance is not as clear in the TBI population. Many
hematopoietic stem cell transplant survivors are normal or underweight by body
mass index [16]. Among 1,089 survivors of adult and pediatric stem cell transplants
in the Bone Marrow Transplantation Survivor Study, participants with a history of

TBI were found to be at increased risk for DM when compared to non-cancer
siblings, even after adjustment for BMI [51].
Recently, Chemaitilly and colleagues reported the results of metabolic testing
among ten adults with a history of receiving TBI before the age of 21 years. Subjects
were known to have endocrine late effects, including hypergonadotropic hypogo-
nadism (n = 6), growth hormone deficiency (n = 3), and hypothyroidism (n = 1), but
no subject was known to have DM or to be taking insulin-sensitizing medication.
Investigators measured the homeostasis model assessment of insulin resistance
(HOMA-IR) from fasting blood glucose and insulin levels; HOMA-IR values above
2.6 (75th percentile) were considered abnormal. Of the ten subjects in the study,
three were obese (BMI ³ 30) and two were overweight (BMI between 25 and
29.9 kg/m2). Nonetheless, all subjects had excess abdominal fat and five subjects
were insulin resistant on laboratory testing.
A study in Sweden measured body fat by dual energy X-ray absorptiometry
(DXA) along with HOMA-IR, growth hormone, leptin, and adiponectin in 18 young
adults who had a history of treatment with hematopoietic stem cell transplant
and TBI during childhood. Subjects were compared to age- and gender-matched
controls. Eight survivors were found to be insulin resistant (defined as HOMA-IR ³ 2.86)
compared to none of the controls. As noted, although survivors were more likely to
be insulin resistant, they did not on average have higher body mass index. Instead,
survivors tended to be shorter than controls, with lower BMI. Importantly, when
body composition was measured with DXA, survivors were found to have higher
fat mass and lower lean body mass than non-cancer controls. Further, leptin was higher
and adiponectin was lower in survivors compared to controls, even after adjustment
for fat mass [44].
These studies suggest that TBI followed by hematopoietic stem cell transplant
may result in a form of lipodystrophy. In this setting, impaired subcutaneous fat
accumulation may lead to increased free fatty acids in the circulation and accumula-
tion of fat in visceral tissue [53, 54]. According to this line of reasoning, impaired
glucose tolerance results when subcutaneous adipose tissue is unable to expand
because pre-adipocytes cannot proliferate (due to history of radiation treatment).
Increased leptin, as described in the Swedish study and among ALL survivors in the
ALLIFE Study [32, 44], may be an attempt by the body to recruit progenitor adipo-
cytes from the bone marrow pool, although this hypothesis needs to be tested [54].
Accumulation of adipocytes in the liver, as suggested in the case of KL, is a likely
natural consequence of changes in fat accumulation and failure of subcutaneous
adipocyte expansion following TBI.
2.2 Craniopharyngioma
TC is a 22-year-old survivor of craniopharyngioma, diagnosed just before his 5th birthday,

and treated with partial surgical resection plus radiation; he received 4,500 cGy to the
suprasellarmass followed by 540 cGy cone-down to the tumor bed. He has panhypopituitarism
and has been followed since treatment by a pediatric endocrinologist. On transition to the
adult program, he requires daily thyroid hormone replacement, hydrocortisone, testosterone,
and DDAVP. He describes his diet to you: breakfast is waffles, cereal, or eggs and sausage;
lunch is often a cheeseburger and French fries; dinner is prepared by his mother and includes
chicken, rice, corn, and green vegetables. He also drinks a half-gallon of fruit juice daily
and frequently snacks on chips, cakes, and candy. On exam, he is 165 cm tall and weighs
86 kg; his BMI is 31 kg/m2.
Central nervous system (CNS) tumors are the second most common malignancy
among children, following ALL [7], and endocrinologic abnormalities among this
group of patients are common during and following treatment. Growth hormone
deficiency, hypothyroidism, diabetes insipidus, ACTH deficiency, and gonadotropin
deficiency as a result of damage to the hypothalamic–pituitary axis and precocious
puberty (likely due to disinhibition of cortical control of the hypothalamus) are all
common late effects seen in CNS tumor survivors. As described in the ALL cases,
growth hormone deficiency may result in insulin resistance and the metabolic
syndrome [55]. In addition to the additional risk for obesity associated with the
lower doses of cranial radiation and described among ALL survivors, craniopharyngioma
survivors are at particular risk for an unusual form of obesity, termed hypothalamic
obesity (described below).
Craniopharyngioma is a relatively rare form of CNS tumor, representing 6–10%
of all childhood CNS tumors and most commonly seen in children 5–14 years old
[56]. They typically arise in the pituitary stalk or the floor of the third ventricle.
While histologically benign, craniopharyngiomas can be extremely aggressive
clinically and can result in endocrine dysfunction at presentation. Treatment
typically involves surgery and radiation.
As mentioned above, many patients treated for craniopharyngioma go on to
develop an unusual form of obesity termed hypothalamic obesity, which is thought to
be caused by destruction of the ventromedial hypothalamus (VMH). In the healthy
brain, the VMH regulates energy balance by interpreting hunger and satiety signals
from circulating leptin, ghrelin, pancreatic polypeptide 3–36 and insulin [57, 58]
(Fig. 7.1). Damage to the VMH can result in excessive calorie intake and decreased
caloric expenditure, either by inducing hyperphagia that results in obesity and insulin
resistance (as may be the case in this patient), or via overactive vagal neural trans-
mission resulting in excessive insulin secretion from the b-cell of the pancreas [38].
Treatment decisions for craniopharyngioma affect the likelihood and severity of
subsequent obesity. Surgical excision of the tumor without radiation generally
results in severe hypothalamic obesity and typical adult BMI >50 or 60. In the case
of TC, he received subtotal surgical resection and radiation therapy, which typically
results in less damage to the VMH and lower average BMI. Unfortunately, weight
gain in the setting of hypothalamic obesity can be intractable and difficult to treat.
In 2003, researchers from the University of California, San Francisco and St. Jude
Children’s Research Hospital in Memphis, Tennessee, conducted a randomized,
double-blind, placebo-controlled trial of octreotide therapy for pediatric hypotha-
lamic obesity following treatment for CNS tumor. In this study, 18 subjects (13 with
a history of craniopharyngioma) with an average body weight of 100 kg and BMI
Fig. 7.2 Body mass index (BMI) in adult survivors of childhood acute lymphoblastic leukemia
following cranial radiotherapy (CRT)
of 37.1 kg/m2 received octreotide or placebo for 6 weeks. Octreotide is known to

bind to the somatostatin receptor-5 on the b-cell membrane, limiting insulin release.
Subjects who received octreotide stabilized their weight gain over time, while those
on placebo continued to gain weight at the same rate. Insulin hypersecretion was
improved, and the magnitude of insulin response correlated with improvement in
quality of life as well [58]. Since that study, further studies in adults with hypothalamic
obesity who were not CNS tumor survivors have also found that octreotide can
stabilize weight gain [59], while another study has found a benefit to a combination
of metformin and diazoxide in this population [60]. Further studies of these potential
treatments are needed.
2.3 Osteogenic sarcoma
PJ is a 36-year-old survivor of osteogenic sarcoma of the right tibia. She was diagnosed at
age 17 and underwent limb-sparing surgery followed by cisplatin, methotrexate, and doxo-
rubicin (471.5 mg/m2). At the time of her treatment she was obese with a BMI of 32 kg/m2.
In the adult long-term follow-up program today she is 158 cm and weighs 91 kg; her BMI
is 39 kg/m2. Since the last visit in the program, she lost 5 kg and has been walking for exercise.
Nonetheless, she has been diagnosed with hypertension, type 2 diabetes mellitus, and
hypercholesterolemia.
Unfortunately, PJ was obese at the time of her treatment and has become more
obese since completing treatment. Pediatric obesity is a challenging problem of
increasing prevalence. Recent data from the National Health and Nutrition
Examination Survey reveals that in 2003–2004, 17.1% of US children and adoles-
cents were obese (at or above the 95th percentile of the sex-specific BMI for age).
Among girls, the prevalence of obesity increased from 13.8% in 1999–2000 to
16.0% in 2003–2004. Among boys, the prevalence increased from 14.0% to 18.2%
over the same time period [61]. While the etiology of pediatric obesity is not
completely understood, several specific behaviors have been shown to contribute
to childhood obesity: a history of being fed with formula in infancy; increased con-
sumption of sugar-sweetened beverages; low levels of physical activity; and
increased time in sedentary behavior (such as watching TV) [62]. Additionally, recent
evidence suggests duration of sleep may be important for maintaining a healthy
weight in childhood [63]. Family factors including maternal obesity and sedentary
behavior are likely to be important contributors as well [64]. Unfortunately, childhood
obesity is likely to persist into adulthood [65]. Furthermore, childhood obesity is
associated with many of the common comorbidities, such as fatty liver and Type 2
DM, that are found in obese adults [62, 63, 66, 67]. Obese children and adolescents
who are diagnosed with cancer are likely to be obese following treatment as well;
in a study of ALL survivors conducted by Razzouk and colleagues, being obese at
presentation was strongly correlated with obesity following treatment [68].
A recent study of 32 survivors of childhood sarcoma, a median of 17.3 years
from diagnosis, found that survivors had a higher prevalence of the metabolic
syndrome than age- and gender-matched controls.[69] Survivors of childhood
osteosarcoma may be at particular risk for obesity and insulin resistance due to
physical limitations and resultant sedentary lifestyle. In 2005, Ness and colleagues
reported the prevalence of performance limitations and participation restrictions
among a cohort of long-term survivors of childhood cancer and their non-cancer
siblings from the Childhood Cancer Survivor Study. Participants were asked whether
over the past 2 years physical activities (ranked from vigorous to slow) had been
limited by health. Survivors below the 10th percentile distribution of responses
from the sibling group were categorized as having a performance limitation.
Participation restrictions were evaluated in three categories: limited personal care
skills; limited routine activities; poor health preventing school or work attendance.
Survivors of bone cancer including osteosarcoma were more likely to report
performance limitations when compared with their siblings (risk ratio, 3.8). Further-
more, 36.9% of bone cancer survivors reported performance limitations, more than
any other diagnosis group [70]. Unfortunately, these restrictions and limitations
appear to result in inactive lifestyle among many bone cancer survivors; other studies
have confirmed an increased risk for inactive lifestyle among osteosarcoma survivors,
which is likely treatment related [71, 72].
For patients such as PJ who are overweight or obese at diagnosis, the physical
challenges of posttreatment recovery make weight-loss intervention extremely difficult.
Studies among obese children without a history of cancer have suggested an
increased risk for aberrant lower limb mechanics [73], which could be worsened by
postsurgical changes among sarcoma survivors. Prosthetic malfunction, including
endoprosthetic loosening, mechanical failure, or fracture of the allograft, are more
likely in the setting of growth and weight gain and can require surgical revision
[74, 75]. Survivors with a history of amputation who gain weight may be at risk
for prosthesis-related injury including skin breakdown and ill-fitting prosthesis
and should be referred for refitting [76]. As a result of the biomechanical and
musculoskeletal risks, recommendations for physical activity in patients such as
PJ can be challenging. Providers should seek specialized exercise programs in a
setting familiar with posttreatment challenges.
3 Interventions
Despite the increased risk of obesity and insulin resistance among many survivors
of childhood cancer, there have been few studies of physical activity and dietary
interventions in this population. Although recruitment and retention of subjects are
the primary obstacles with most intervention studies in this group, targeted inter-
ventions appear to have the potential to be successful.
In 1993, Sharkey and colleagues reported the results of a cardiac rehabilitation
intervention after cancer therapy in children and young adults. The strategy in this
study included both home-based and institutionally based exercises [77]. Functional
capacity, exercise time, and exercise tolerance all improved. A few years later, Collett
and colleagues reported via abstract that randomly assigned supervised exercise
sessions were not superior to written exercise materials across several outcomes
[78]. Although there was a difference in ages in the two groups, supervision did not
improve results over written materials. These findings suggest that among motivated
adults, lifestyle changes may be easier to accomplish in a home-based regimen.
However, these and other studies [77–79] report that participant recruitment and
retention can be challenging.
As noted above, diet is an important contributor to becoming overweight, obese,
and insulin resistant. Several studies examining diet in survivors of childhood
cancer have noted low fruit and vegetable intake and high fat intake [80–82]. In 2008,
Robien and colleagues reported results of a Childhood Cancer Survivor Study ancillary
study evaluating whether the diets of adult survivors of childhood ALL are consistent
with guidelines from the USDA Food Guide, the Dietary Approaches to Stop
Hypertension (DASH) diet, or the 2007 World Cancer Research Fund/American
Institute for Cancer Research (WCRF/AICR). ALL survivors met, on average, 3 out
of 8 USDA guidelines, 3.6 out of 11 DASH guidelines, and 2.9 out of 7 WCRF/
AICR guidelines [81]. These results suggest that the diet of ALL survivors is inferior
to their non-cancer peers, but further study is needed.
Poor dietary habits that precede cancer diagnosis or develop during treatment
may persist into adulthood; these habits may be amenable to targeted intervention.
Yet, to date, no study has reported a targeted dietary intervention among adult
survivors of pediatric and young adult cancer. At the After Completion of Therapy
(ACT) clinic of St. Jude Children’s Research Hospital, Hudson and colleagues
initiated a multibehavior intervention based on the Health Belief Model among
adolescents who had survived cancer (12–18 years old). Their intervention included
modules for smoking, sun protection, self-examination, diet, and exercise. Participants
chose one behavior on which to focus. At 1 year follow-up, investigators found no
significant differences between the standard care and intervention groups in health
knowledge, perceived susceptibility, knowledge of barriers to and benefits of health
behaviors, or in the behaviors themselves, which were assessed via a summative measure
[83]. Although the initial published results did not show any effect of the interven-
tion, a reanalysis looking at the individual health behaviors rather than the summary
measure found that the treatment group showed a significant increase in health knowl-
edge, a maintenance of smoking abstinence among former smokers and nonsmokers,
and, importantly, a decrease in so-called junk food consumption [84].
The recently reported FRESH START trial may offer a model for future studies
among survivors. This trial tested the effect of a 10-month program of tailored
mailed print materials promoting fruit and vegetable consumption, reducing total
and saturated fat intake, and increasing exercise, compared to the effect of more
generic diet and exercise materials available in the public domain. Participants were
adult survivors of breast and prostate cancer. On average, all groups improved lifestyle
behaviors, but greater gains occurred in the FRESH START (tailored materials)
intervention compared to the control arm (P < 0.001 for practice of two or more goal
behaviors) [85]. Although not yet duplicated in a population of pediatric cancer
survivors, results of the FRESH START study suggest that mailed tailored print
materials may be successful in this group as well.
4 Future Directions
Further studies to elucidate the unique causes of obesity and insulin resistance
among survivors of childhood cancer and intervention trials in this population are
needed. A history of treatment for acute lymphoblastic leukemia, with or without
cranial radiotherapy, a history of total body irradiation, a history of treatment for
craniopharyngioma, and a history of pretreatment obesity are all known risk factors
for obesity and insulin resistance among adult survivors of childhood cancers.
Nonetheless, strategies to reduce adult obesity and insulin resistance, including
studies of exercise or dietary intervention, have been lacking. Unfortunately,
improvements in cancer therapy are not likely to ameliorate the epidemic of obesity
among survivors. Future studies should focus on whether diet and exercise behaviors
differ between survivors and non-cancer populations, and should test targeted
interventions in this at-risk group.
Several animal studies implicate diet, especially dietary fat, in the emergence
of insulin resistance among non-cancer individuals. The mechanism of free fatty
acid-induced insulin resistance was suggested more than 30 years ago; essentially,
free fatty acids compete with glucose for substrate oxidation [86]. In rats, diets
high in saturated, monounsaturated, or polyunsaturated (omega-6) fatty acids
lead to severe insulin resistance [87], while trans-fatty acids may be particularly
deleterious [88]. Interestingly, some animal studies suggest that diets high in omega-
three polyunsaturated fatty acids, such as in fish oil, may protect against insulin
resistance [88, 89]. While animal studies have been intriguing, results in smaller
human studies have had mixed results, possibly due to small sample sizes. A 2008
review of the evidence in humans of the effect of dietary fat on insulin sensitivity
described twelve available studies that found no effect. Most of these trials,
however, were of 4 weeks duration and enrolled fewer than 25 subjects [90]. In
contrast, a five-city study of 162 subjects, in which dietary fats were carefully
controlled using centrally produced margarines and cooking fats showed more
promising results. Insulin sensitivity (by intravenous glucose tolerance test) was
significantly worse on a diet high in saturated fatty acids (−10%, p = 0.03), com-
pared to a diet high in monounsaturated fatty acids. Omega-three fatty acids from
fish oil did not impact insulin resistance, however, and that study was limited by its
use of centrally produced fats [91]. These studies could inform a fat-based dietary
intervention among survivors of childhood cancer.
Other recent evidence suggests that added sugar, especially in the form of
sugar-sweetened beverages, may be contributing to the rising prevalence of
obesity. A rapid increase in the consumption of sugar-sweetened beverages,
especially among adolescents, has been well documented [92]. At the same time,
an analysis of food consumption in the United States has suggested that all of the
weight gain that has been observed in the general population since 1970 can be
attributed to consumption of an additional 300 kcal per day [93]. Sugar-sweetened
beverages are widely available and are aggressively advertised to young consumers
[94]. Although replacement of sugar-sweetened beverages with artificially sweet-
ened beverages is somewhat controversial [95], a trial among adolescents of
free home delivery of noncaloric beverages (intended to displace sugar-sweetened
beverages and therefore decrease consumption) found that sugar-sweetened
beverages could be almost completely eliminated from the diet. Furthermore, among
adolescents who were the heaviest at the start of the trial, the substitution resulted
in weight loss [96].
In conclusion, adult survivors of childhood cancer, especially those who were
treated with specific therapies or who were obese prior to treatment, are at increased
risk for obesity and insulin resistance. The mechanisms of obesity in this population
are still being elucidated. In the meantime, studies which will lead to improvements
in physical activity, reduced sedentary behavior, and less dietary fat and sugar
consumption are greatly needed.
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Chapter 8
Physical Activity and Recovery
from Hematological Malignancy
Luisa Soares-Miranda, Carmen Fiuza-Luces, and Alejandro Lucia
Abstract Traditionally, physicians would recommend cancer patients to rest during

and after treatments and to avoid activity. However, recently, physical activity has
been associated with benefits during and after cancer treatments. There is growing
interest in physical activity interventions as a way to ameliorate the side effects of
cancer treatments. Studies have shown that physical activity is safe and feasible dur-
ing and after hematological cancer treatments. Improvements in aerobic capacity,
muscular strength, body composition, fatigue, depression, and quality of life were
observed in hematological cancer patients engaging in physical activity interven-
tions. However the optimal physical activity dose for these patients is not known
and further research is needed.
1 Introduction
Although traditionally clinicians have recommended that cancer patients rest and
avoid activity, emerging research supports that cancer patients should be as active as
possible during and after treatments. This chapter provides an overview on how
exercise has an important role for cancer patients and survivors of hematological
malignancies. To put this information into perspective, we will first present
general concepts about exercise and cancer, and then focus on exercise and hemato-
logical malignancies.
L. Soares-Miranda
Research Center in Physical Activity, Health and Leisure,
Faculty of Sport, University of Porto, Porto, Portugal
C. Fiuza-Luces • A. Lucia (*)
Exercise Physiology, Universidad Europea de Madrid,
Madrid, Spain
e-mail: alejandro.lucia@uem.es
160 L. Soares-Miranda et al.
Interest in physical activity and cancer has primarily focused on its potential to
ameliorate the side effects of the treatments [1]. It is known that physical activity
has the potential to impact a broad range of physiological systems and functions,
including the central nervous and cardiorespiratory systems, the skeletal muscle tis-
sue, and inflammation and oxidative pathways. Physical activity can improve blood
oxygenation (which depends on pulmonary function), blood oxygen carrying capac-
ity (which depends on cardiac output) and muscle function. Furthermore, it is capa-
ble of increasing the peak cardiorespiratory capacity (commonly expressed as peak
oxygen uptake, VO2 peak), in virtually all population groups [2]. As a result, regular
exercise increases the ability to handle the physical activities of daily life more eas-
ily and effectively.
The American College of Sports Medicine (ACSM) and the American Heart
Association recommend that every adult engage in moderate-intensity aerobic
physical activity for a minimum of 30 min on most, if not all, days of the week, or
in vigorous-intensity aerobic physical activity for a minimum of 20 min on 3 days
each week [3]. Additionally, they recommend activities to maintain or increase
muscular fitness (e.g., weight training) a minimum of 2 days per week [3].
Anticancer treatments have opposing effects on the body compared to physical
activity. Radiotherapy often results in lung fibrosis, which decreases lung capacity
and function [4]. Chemotherapy causes anemia, thereby decreasing blood oxygen
transport. It can also decrease cardiac function, which reduces cardiac output, and
skeletal muscle mass, leading to muscle atrophy [5]. Additionally, chemotherapy
induces gastrointestinal toxicities that can interfere with the diet [6, 7]. Hematopoietic
stem cell transplantation is usually associated with further side effects, such as graft
versus host disease and infections, more marked loss of physical activity/fitness,
fatigue, distress, emotional problems, and immunological and hematological
changes [8]. Cancer patients are usually exposed to successive courses of chemo-
therapy, radiotherapy, and/or biologic therapy that produce acute as well as late and
long-term adverse physiologic and psychological effects, leading to physical decon-
ditioning and consequently to diminished quality of life. Thus, these patients have
low cardiorespiratory fitness and low muscle strength [9]; as a result, they can expe-
rience fatigue even in normal daily life activities [5]. Thus, there are a large range of
late and long-term effects of cancer treatments that may be positively affected by
physical activity (Table 8.1).
With the improvement of cancer treatments in general and hematological malig-
nancies in particular, the numbers of survivors have increased. Often, these patients
have poor physical condition and low energy in normal daily activities. Up to 70%
of patients during treatment and 30% of cancer survivors suffer from one or more of
the aforementioned side effects of treatment [10, 11]. Thus, physical activity could
play an important role in these patients, both during and after treatment, to attenuate
these side effects. Additionally, with improvements in early diagnosis, more effec-
tive treatments, and better surveillance, many cancer survivors die from noncancer
causes, predominantly those associated with the cardiovascular system [12].
Thus, in the last decades exercise has emerged as having an important role in cancer
8 Physical Activity and Recovery from Hematological Malignancy 161
Table 8.1 Late and long-term effects of cancer treatment that may be positively affected by physical
activity (modified from Physical Activity Guidelines Advisory Committee Report 2008)
Cancer treatment Physical changes
Surgery Pulmonary function
Radiation Cardiac function
Chemotherapy Muscle mass
Immunotherapy Fat Mass
Hormone therapy Weight or body mass index
Decreased muscle strength/power
Inflammation
Immune function
Bone health
Trauma and scarring
Lymphatic function (lymphedema)
Psychological and behavioral changes
Exercise/physical activity
Physical symptoms and pain
Depression
Cognitive function
Quality of life (multiple domains)
prevention and control [1]. A sign of that recognition is the fact that physical activ-
ity has been acknowledged as an important intervention by the American Cancer
Society’s guidelines for cancer prevention and for cancer survivors [13, 14].
In 2007, Courneya and Friendenreich proposed a physical activity and cancer-
control framework that emphasizes specific time periods in the cancer continuum
where physical activity has an important and plausible role [13] (Fig. 8.1).
In the framework, two periods before diagnosis and four after are illustrated, and
physical activity has a specific role in each of them [13]. The logic of this framework
is the implementation of specific physical activity programs according to the time
period of the patient’s disease. For example, in the treatment-preparation/coping
phase, physical activity may help patients deal physically and emotionally with the
disease. Furthermore, improving fitness may allow more demanding treatments, and
might even delay the need of treatments by managing the disease and its symptoms.
In the treatment effectiveness/coping period, physical activity might be important to
control treatment side effects and toxicities, to preserve physical function and mus-
cle strength, and to prevent weight gain. In this specific time period, physical activ-
ity is also important to improve mood and quality of life and to potentiate cancer
treatments. In the survivorship phase, which incorporates the recovery/rehabilitation
and prevention/health promotion time periods, physical activity has an important
role (1) to help recovery from the side effects of the treatments, such as fatigue, fat
gain, and bone loss; and (2) to prevent the development of other chronic diseases for
which survivors might be at risk, such as heart disease and diabetes. Additionally, in
this phase physical activity might reduce the odds of having tumor recurrence [13].
DIAGNOSIS
CANCER CONTROL CATEGORIES
Prevention Derection Treatment Treatment Recovery/ Disease Prevention/ Palliation Survival

Preparation/ Effectiveness/ Rebabilitation Health Promotion
Coping Coping
Prescreening Screening Pretreatment Treatment Survivorship End of Life
PREDIAGNOSIS POSTDIAGNOSIS
CANCER-RELATED TIME PERIODS
Fig. 8.1 Physical activity and cancer control framework (Reprinted from Courneya KS, Friedenreich
CM. Physical activity and cancer control. Semin Oncol Nurs. 2007;23(4):242–52. Copyright 2007
Elsevier. Used with permission)
There is a worldwide proliferation of exercise programs for cancer patients;

additionally there are a growing number of studies suggesting that exercise can
reduce the odds of having certain cancers [15, 16]. It is believed that regular physi-
cal activity has the potential to influence cancer risk; however, the mechanisms
involved are not well understood [17]. Possible mediators are reductions in body
mass and/or adiposity, reductions in reproductive hormone levels, altered growth
factor milieu, enhanced antioxidant defense mechanisms, and changes in immune
function, including reduced inflammation and enhanced antitumor immunity [17].
Physical activity has been studied in relation to incident cancers at many sites,
though the evidence for a protective effect is strongest for overall cancer risk and for
cancers of colon and breast, specifically [15, 18]. Additionally there is a growing
evidence that increased physical activity may reduce the risk of endometrium and
lung cancer [15]. Evidence supports that exercise may also increase survival in
breast and colon cancer [19–22].
The guidelines on exercise for cancer patients and survivors are very recent. In
2008, the United States Department of Health and Human Services released guide-
lines indicating that subjects with a chronic condition as cancer “should be as physi-
cally active as their abilities and condition allow” when not capable of achieving
the general recommendations on physical activity [15]. In 2010 the American
College of Sports Medicine (ACSM) roundtable published one statement on
Exercise Guidelines for Cancer Survivors in which the role of exercise in cancer
control and survivorship was emphasized. These guidelines highlight that exercise
prescription in cancer survivors should be individualized according to the pretreat-
ment aerobic fitness, medical comorbidities, response to treatment, and side effects
of treatment.
According to ACSM the aims of exercise prescription in adult cancer survivors
are (1) to recover and increase physical function, aerobic capacity, strength, and
flexibility; (2) to improve body image, body composition, and quality of life (QOL);
to improve cardiorespiratory, endocrine, neurological, muscular, cognitive, and
psychosocial outcomes; (3) to decrease tumor recurrence or second primary

cancer; (4) to improve the ability to physically and psychologically bear the ongo-
ing anxiety regarding recurrence or a second primary cancer; (5) to attenuate and
decrease long-term and late side effects of cancer treatment; and (6) to improve
physiologic and psychological ability to deal with any current or future cancer treat-
ments [16]. It is recommended in those guidelines that the exercise intervention
begin after enough time to heal from surgery is given to the patients, and that sub-
jects with extreme fatigue, anemia or ataxia should not exercise [16]. In general it is
suggested that cancer survivors should avoid inactivity; they should return to nor-
mal daily activities as fast as possible after surgery, and continue normal daily
activities and exercise as much as possible during and after treatments [16]. However,
subjects with known metastatic bone disease will require specific adaptations in
their physical activity programs to avoid fractures; individuals with cardiac condi-
tions, which can be consequence of cancer or not, may also require modifications
and greater supervision for safety [16]. Hematologic patients with multiple myeloma
should be treated as osteoporosis patients when exercise is being prescribe [16].
Regarding the safety of exercise during and after treatments it is believed that exer-
cise is harmless either during and after treatments, including during demanding
treatments as bone marrow transplant [16]. Resistance and flexibility training are
also suggested for cancer survivors, however some changes are recommended for
patients with and at risk for lymphedema as well as at risk for facture and infection
(or immune-compromised because of treatments) [16]. The ACSM roundtable rec-
ommended changes to United States Department of Health and Human Services
guidelines on physical activity for specific cancer survivors. While the recommen-
dations on physical activity for adult hematological patients not receiving
hematopoietic stem cell transplantation (HSCT) are the same as for their healthy
age group, adult survivors that received HSCT have different recommendations.
According to ACSM, daily, lighter intensity aerobic exercise is recommended, with
a lower progression of intensity, and specific attention to avoid overtraining [16].
The recommendations regarding resistance and flexibility training in these patients
are the same as age-appropriate guidelines [16]. Special attention to platelet count,
fever, bleeding, severe pain, and hemoglobin level should take place when hemato-
logical patients undergo an exercise intervention, especially under hospitalization
conditions [8].
Exercise guidelines for the general population include detailed recommendations
regarding aerobic, strength and flexibility, yet, at present this is not feasible for
hematologic cancer patients undergoing any treatment regimen. First, an insuffi-
cient number of studies have evaluated the risks or benefits of flexibility interven-
tions. This is clearly an area for future research. Also, research evaluating the effects
of resistance training alone is clearly merited. Evidence suggests that resistance
training is beneficial and safe, but as most interventions also include an aerobic
component, it is difficult to parse out the effects of the training type [23–26].
Nevertheless, it is noteworthy that no study has reported adverse outcomes associated
with supervised progressive resistance training, including in young survivors.
Furthermore, exercise programs did have demonstrable benefits.
The subsequent paragraphs are dedicated specifically to exercise and hemato-

logical malignancy and they are presented to the readers in two major groups, adult
and pediatric.
2 Physical Activity Interventions in Adults
Studies conducted in adults recovering from hematological malignancy have focused

on a variety of health outcomes such as fatigue, QOL, body composition, physical
fitness/physical performance, and emotional well-being. In the following para-
graphs we will overview the main studies conducted in this field and their results. In
order to simplify the information, and given the deleterious effects of HSCT on
physical function, we will make a distinction between studies on adults who did and
did not receive HSCT.
2.1 Physical Activity Interventions in Adults

Not Receiving HSCT
A growing interest in exercise on adults with and recovering from hematological

malignances exists [27–33]. Of those, only a few were randomized controlled trials
(RCTs). In the next paragraphs we will focus on the main results.
Chang et al. [29] showed in a RCT that a 3-week walking intervention was
capable of reducing fatigue and improving cardiorespiratory fitness in adults survi-
vors of acute myeloid leukemia receiving chemotherapy. Blaauwbroek et al. [28]
reported that a short-time, contact pedometer-based intervention could significantly
improve physical activity and diminish fatigue in adult survivors of childhood can-
cer (~60% of which were hematological malignancies). Battangili et al. [27] indi-
cated that a combined aerobic and strength intervention in adults with acute leukemia
undergoing chemotherapy treatments was able to reduce fatigue and to increase
cardiovascular endurance. Oldervoll et al. [34] observed that a home-based exercise
intervention improved fatigue, physical functioning, and maximal aerobic capacity
in chronically fatigued Hodgkin’s disease survivors. In contrast, in a low-intensity
RCT intervention consisting of seven weekly yoga sessions in lymphoma survivors,
no effect on fatigue, depression, or anxiety was observed [33]. A large RCT (N = 122)
conducted by Courneya [30] provided, perhaps, one of the most important eviden-
tial supports for the health benefits of exercise interventions in adult survivors of
hematological cancer not receiving HCST. Their study indicated that progressive
aerobic activity thrice weekly for 12 weeks produced significant improvements in
fatigue and cadiorespiratory fitness in Hodgkin lymphoma/non-Hodgkin lymphoma
survivors, without interfering with medical treatments or response [30]. In addition
to these findings, they also found that several months after the intervention, the
improvements remained borderline or significantly superior compared with the
control group [30]. Other studies also found that cardiovascular endurance increased
with regular exercise either in adults with acute myeloid leukemia [27] or with vari-
ous types of hematological cancer receiving aggressive chemotherapy [32].
The existing evidence on the relationship between physical activity interventions
and depression in cancer patients is not totally consistent. Neither Chang et al. [29]
nor Cohen et al. observed significant exercise effects on depression [29, 33], though
both interventions involved relatively low-intensity activity, which might have limited
the results. Conversely, Courneya [30] found improvements in depression and happi-
ness with a progressive aerobic activity intervention, which remained significant 6
months after the end of the intervention. Battaglini et al. [27] also found a reduction
in depression scores in patients with acute leukemia undergoing chemotherapy treat-
ments in an intra-hospital exercise program. Neither the study by Courneya’s group
or the one by Cohen and colleagues reported an effect of exercise on anxiety [30, 33].
However, the report by Cohen et al. (which used a Tibetan Yoga intervention) showed
significant improvements in sleep-related outcomes in lymphoma survivors [33].
The study by Courneya et al. [30] was the only study to examine global QOL and
physical function. They found that after a 12-week progressive aerobic activity
intervention in Hodgkin lymphoma/non-Hodgkin lymphoma survivors, QOL had
significantly improved [30]. In a follow-up assessment 6 months after the interven-
tion, the aforementioned improvements remained in the exercise-training group, but
not all of them remained significantly different. A subsequent analysis in the same
study, found that the intervention effect on QOL was mediated by marital status,
with unmarried survivors having better outcomes than their married peers [31]. The
authors explain this fact given that unmarried patients probably have less social sup-
port at home, then they possibly will benefit more from the social aspects of the
physical activity intervention [31]. Courneya et al. [30] also reported significant
improvements in body composition, particularly in lean body mass. However, the
aforementioned beneficial effects in body composition were lost 6 months after the
end of the intervention.
A recent pilot trial, which evaluated the feasibility of intense, supervised ergom-
eter training in patients with severe pancytopenia and undergoing high-dose chemo-
therapy, showed that exercise does not cause problems in patients with median
platelet count and hemoglobin levels of 27,000/ml and 9.2 g/100 ml [32]. Platelet or
blood transfusions were recommended before training when platelet count and
hemoglobin levels were below 10,000/ml and 8 g/100 ml, respectively.
2.2 Physical Activity Interventions in Adults Receiving HSCT
HSCT is a very demanding experience, associated with physical, psychological and

psychosocial stress [8]. Others sources of stress include common side effects, such
as nausea, diarrhea, pain, etc., as well as hospitalization [8]. Such stress sources
might be reduced with physical activity interventions due to its multidimensional
effects [8].
Exercise intervention programs for HSCT survivors have been conducted during
the hospitalization period [35–37], started during hospitalization and continued
after discharge [23, 24, 38–42], and in the outpatient or home based setting [43–49].
One study conducted an intervention spanning the entire clinical course before, dur-
ing, and after HSCT [50]. Many interventions were aerobic and successfully
increased the functional capacity and/or aerobic fitness of the participants, or at
least attenuated the lost of functional capacity associated with HSCT [24, 38, 39,
43, 47, 49, 50].
There is a substantial interest in the capability of physical activity to change
blood markers in HSCT patients, though results are inconclusive. An aerobic exer-
cise intervention during the inpatient period induced a considerable pre–post change
in hemoglobin concentration [36]. The same group had shown some years earlier
that, in patients randomized to the experimental group (who had performed daily
endurance training during hospitalization), the duration of the neutropenic phase
was significantly reduced [51]. In this study they also observed improved results in
the intervention group, for some treatment-related complications such as severity of
diarrhea, severity of pain and duration of hospitalization [51]. Kim et al. reported
that a RCT of 6 weeks of supervised bed exercises during hospitalization produced
significant improvements in lymphocyte count [37]. Hayes et al. found that a
3-month combined aerobic and resistance training intervention (beginning inpatient
and continuing after discharge) did influence immune recovery [42].
The benefits of supervised interventions exclusively in the outpatient setting on
fitness outcomes appear to be established, with one uncontrolled trial showing
increased endurance fitness after a 12-week program consisting of three weekly
sessions of 30 min exercise [43]. Home-based interventions seem less successful to
improve fitness since two studies failed to find improvements in endurance [44, 47].
Nevertheless, Shelton et al. [48] compared a supervised and a home-based interven-
tion and found that patients obtained functional benefits from exercise training
independent of how the training program is supervised. However, the exercise tar-
gets in the two intervention groups differed, which makes it difficult to make com-
parisons between groups [48].
Some studies evaluated the effects of physical activity interventions on body compo-
sition in HSCT patients. In a home-based 6-month aerobic and resistance training inter-
vention, Coleman et al. found that controls lost lean body weight whereas intervention
participants maintained lean body weight [44]. Hayes et al. reported that a 3-month
moderate intensity, mixed-type exercise program reduced the percentage of body fat
and increased fat-free mass, though no changes were observed in weight, body mass
index or fat mass [41]. They also reported a significant increase in total energy expendi-
ture in the intervention group, compared with pretreatment [41]. Conversely, Cunningham
et al. found no significant changes in body composition after a 6-week resistance train-
ing intervention [35]. Additionally, Wilson et al. reported with a home-based aerobic
exercise program an increase in physical performance and an improvement in fatigue in
survivors after HSCT, but no change in body mass index [52].
In other cancer populations, QOL is an outcome showing improvements in most
exercise intervention studies [53]. The results for HSCT patients are less clear,
though they suggested an overall positive benefit of exercise interventions on QOL.
In an intervention setting after HSCT, Hayes et al. found an increase in QOL in the
intervention group, but not in the control group [23], though the between-group
difference was not significant. Wilson et al. found significant improvements in QOL
after a home-based intervention for some physical function-related QOL subscales
and a decrease in fatigue severity [52]. DeFor et al. in a RCT also suggested that an
aerobic intervention lasting for the first 100 days after transplant significantly
improved physical and emotional well-being [38]. Carlson et al. found no significant
change in anxiety and depression after outpatient intervention, but vigor increased
and fatigue decreased [43]. In contrast, Coleman and colleagues found no significant
change in fatigue after a combined aerobic and resistance training intervention
[44, 46]. A recent RCT with a large sample size (N = 105) showed that a partly super-
vised exercise intervention that started before HSCT and continued after patient dis-
charge significantly reduced cancer related fatigue and improved physical capacity,
functioning, anger/hostility, pain and global distress [50]. Additionally, this study
suggested that physical exercise is feasible and beneficial for patients before, during
and after HSCT, even when the intervention is only partially supervised [50].
2.3 Summary
Growing evidence supports the notion that physical activity programs have a benefi-
cial effect on body composition of adults suffering from hematological malignan-
cies. Promising evidence exists that exercise training induces improvements in
cardiorespiratory fitness, fatigue, muscle strength, physical functioning, depression
and QOL during or after treatment for hematological malignancies. Evidence is
insufficient to conclude on the effects of exercise on sleep and anxiety. Research
suggests that benefits are more likely when activity occurs at least 3 days per week.
The mechanisms for the benefits of physical activity in this population are not clear
so, more research is needed.
Published data show that exercise interventions are feasible both during and
after cancer treatments, which provides an enormous range of potential benefits to
patients.
3 Physical Activity Interventions in Children
Assessing the effects of exercise in children with or recovering from hematological

malignancies is very challenging. Compared with adults, pediatric cancer is rela-
tively rare and often involves debilitating treatments, both of which cause severe
recruitment difficulties. Thus, studies performed to assess the effects of regular
exercise training in pediatric cancer patients or survivors are relatively scarce. It is
known that for both adult and pediatric cancer patients, bed rest exacerbates the low
physical capacity and function as well as muscle atrophy that are already induced by
cancer treatments. In the following paragraphs we will review the main studies con-
ducted in pediatric ages.
3.1 Physical Activity Interventions in Children

Not Receiving HSCT
A large number of the programs reported in the literature derive mainly from physi-
cal therapy programs that are part of the standard care in many non-US countries.
These programs characteristically involved limited doses of supervised outpatient
physical activity (generally very light resistance training), supplemented with home-
based activities (usually aerobic activity). These types of interventions usually failed
to show significant benefits in children surviving from acute lymphoblastic leuke-
mia and lymphoma (ALL), especially those that are home based.
In a 12-week intervention in a physical therapy setting after treatment, Marchese
et al. reported that supervised resistance training with home-based aerobic activity
induced no significant change in ankle strength in ALL survivors (4–15 years), but
a significant improvement was observed in the ankle dorsiflexion active range of
motion in the intervention group [54] (Note that ankle dorsiflexion range of motion
is an important function for normal gait and navigating stairs). In a similar interven-
tion lasting 12 weeks and involving 45 min of supervised resistance training two
times per week followed by twice per week home-based aerobic activity, Takken
et al. found no effect on strength in ALL survivors (6–14 years) [55]. These physical
therapy programs showed no improvements in physical function [54] or functional
mobility [55]. On the contrary, in-hospital individually supervised physical activity
programs appear to be beneficial for young ALL survivors. San Juan et al. reported
that a 16-week combined aerobic and resistance training intervention three times
per week (session duration of 90–120 min) significantly improved muscle strength
in very young (4–7 years) pediatric ALL survivors in the maintenance phase of
treatment [56]. Improvements in muscle strength were evident after the first 8 weeks
of training [57] and remained after a 20-week detraining period that followed the
16-week training program [56]. This program also produced a significant increase
in functional mobility [56], though it failed to significantly improve ankle dorsiflex-
ion range of motion. A 20-week aerobic intervention consisting of 30–40 min ses-
sions thrice weekly after treatment improved fitness in Hodgkin lymphoma survivors
[34]. In a 12-month home-based aerobic and resistance training RCT, Moyer-Mileur
et al. [58] found a significant increase in self-reported physical activity and fitness,
but no increase in objectively measured physical activity (pedometer-measured
steps). A small intervention study that included supervised and home-based exer-
cise successfully improved physical activity levels [59]. Shore and Shepard [60]
reported that a 12-week aerobic intervention of 30 min partially supervised (that is,
by a fitness professional once per week and by parents twice per week) significantly
improved fitness in three pediatric ALL survivors (13–14 years old) compared to 3
controls, within 4 weeks of the conclusion of induction therapy. A recent community-
based intervention showed improvements in physical activity levels and physical
fitness in adolescents surviving cancer, though they returned to low physical activity
levels shortly after they finished the program [61]. Despite the improvements, some
interventions induced in fitness, some interventions did not improve children’s body
composition [34, 59, 62].
There is growing interest in the effects of exercise on blood markers in pediatric
patients with hematological malignancies. Marchese et al. [54] found no changes in
hemoglobin levels in ALL survivors (4–15 years) participating in aerobic and resis-
tance training. In contrast, Shore and Shepard [60] reported that aerobic exercise
tended to decrease CD3, CD4, and CD8 counts, though the change was not clini-
cally significant, and included only three pediatric ALL survivors. Ruiz et al. [25]
recently reported no alterations in growth hormone, insulin-like growth factor-1
(IGF-1) and IGF-binding proteins with a combined (aerobic and resistance) training
program in young (4–7 years) ALL survivors during maintenance treatment. Though
preliminary, these findings may prove important, as elevated levels of IGF-1 have
been previously linked with increased cancer risk [63, 64] including leukemia [65].
In a sample of older (7–18 years) ALL survivors, Ladha et al. [66] reported no effect
of a single acute bout of exercise on white blood cells, monocytes, or eosinophils,
suggesting no adverse immune response to acute exercise.
Although physical therapy interventions appear to be ineffective in improving
QOL [54], a recent community-based physical activity intervention showed
improvements in QOL in adolescent survivors of cancer [61]. In contrast, the in-
hospital intervention of San Juan et al. [56] showed no effect on QOL. As with other
outcomes, interventions with limited supervision of training sessions, such as that
of Takken et al. [55], failed to show an improvement in fatigue. However, a 20-week
aerobic intervention of thrice weekly activity for 30–40 min after treatment reduced
fatigue in Hodgkin lymphoma survivors [34]. Finally, the Shore and Shepard study
[60] reported that the aforementioned 12-week, partially supervised aerobic inter-
vention three times per week significantly improved anxiety.
3.2 Physical Activity Interventions in Children

Undergoing HSCT
Intervention studies in pediatric HSCT patients are scarce [26, 67]. Although more
research in this field is desired, the existing preliminary data are promising. In ALL
and acute myeloid leukemia pediatric survivors who received HSCT within the pre-
vious year, an 8-week in-hospital intervention combining aerobic and resistance
exercises produced a significant increase in muscle strength, functional mobility,
aerobic fitness, and QOL [26]. A recent aerobic and resistance training intervention
during inpatient hospitalization for HSCT resulted in significantly increased fitness
and body mass with no deleterious effect on immune cell recovery [67]. Though
more research is needed to corroborate these preliminary data, exercise training dur-
ing the neutropenic phase after HSCT (neutrophil count of 0.5 × 109/l) did not
increase risk of adverse events [67].
3.3 Summary
Exercise interventions are safe in children during and after therapy for hematologi-
cal malignancies, and there is strong evidence for a benefit on cardiorespiratory
fitness and especially muscle strength. Individual supervised interventions have
shown, to date, greater benefit than home-based programs. Based on the available
research data, which is small, we can conclude that supervised exercise interven-
tions should be ideally performed inside the treating hospital, in part to overcome
the safety concerns expressed by some parents. Physical activity interventions can
begin not only during the maintenance phase but also earlier in the treatment proto-
col (with more gradual habituation to exercise in the more debilitated children).
Each session should be closely supervised by instructors (at least one instructor for
every two children). We recommend that instructors are qualified professionals who
can be classified as “fitness specialists,” i.e., professionals involved in prescription
of physical activity for preventive and rehabilitative purposes (see for example
http://www.acsm.org). Given the emphasis that should be put in strength exercises,
hospitals should ideally be equipped with a gymnasium specially built for children
(see Fig. 8.2). Once children have reached normal (or close to normal levels) of
muscle strength for their age (which can be reasonably achieved within 2–3 months
of inpatient training), children should be encouraged to follow an active lifestyle on
their own in the transition from the inpatient to the outpatient condition. We believe
that an overprotective attitude of parents/guardians and teachers (especially in
Physical Education classes) is detrimental for children who are in the last phases of
treatment or have completed the treatment.
Finally, the molecular mechanisms by which exercise training exerts its benefi-
cial effects in the pediatric cancer population remain to be clearly elucidated. For
instance, whether the beneficial effects of regular physical exercise in cancer
patients/survivors are associated with decreased production of pro-inflammatory
cytokines remains to be determined.
4 Side Effects of Exercise Testing and Training

in Hematological Cancer Survivors (Adults and Children,
HSCT or Not) Undergoing Treatment
Since hematological patients suffer from a severe loss of physical capacity and
function during treatments, many of these patients may not be able to complete
exercise tolerance testing until the treatment is over [47]. It is known that survivors
may need to suspend their participation in the exercise intervention due to
treatment-related side effects [38]. Consequently, achieving the study dose for
physical activity can be challenging. Participants may also need to give up physical
activity programs due to medical complications [35]. Unfortunately, the effects of
these interruptions on the study outcomes are generally discussed in minimal detail
Fig. 8.2 Example of intrahospital gymnasium in the Children’s Hospital Niño Jesús (Madrid,
Spain). The weight training machines that are specially built for children were donated by Strive
Inc (Canonsburg, PA, USA)
and are not empirically evaluated [36]. Very little data are available on the ability of
exercise training to affect treatment tolerance or efficacy. Courneya and colleagues
[68] showed aerobic training had no effect on treatment efficacy in a population of
lymphoma survivors. They also reported that the intervention had no effect on the
reappearance of disease, but the study was not designed to examine recurrence as an
end point. DeFor et al. [38] also found no survival or length of stay effect of an
intervention that began while survivors were admitted for allogeneic HSCT.
Coleman et al. [45] found an exercise intervention decreased the number of transfu-
sions needed in myeloma survivors. Thus, further studies which explore and discuss
potential side effects of exercise in these populations are needed.
5 Conclusions
The existing evidence suggests that bed rest that has been traditionally recom-
mended for cancer patients likely results in an exacerbation of some of the side
effects of cancer treatments, particularly loss of physical function and muscle
strength. In contrast, regular physical activity plays an important role in preventing,
attenuating, and rehabilitating mid- and long-term effects of cancer treatment [15];
as such, physical activity programs emerge as a promising intervention during and
after cancer treatment. Oncologists have acknowledged that cancer diagnosis is a

strong life-changing period, in which promotion and acceptance of healthier behav-
iors might be very useful [69]. Regular physical activity practice is one of such
behaviors. In addition, because professionals and family members taking care of
patients with cancer often turn out to be long-term providers, they are in an excep-
tionally privileged position to promote healthy lifestyle interventions, best exempli-
fied by regular physical activity [12].
We hope that this book chapter increases the awareness of health professionals
and those working with cancer patients that physical activity has an important role
in the treatment and recovery of cancer patients.
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Index
A obesity, 52
Absorption, 98, 124 patients outcomes, 137
ACSM. See American College of Sports Q-test, heterogeneity, 19
Medicine (ACSM) T-cell ALL and high-risk, 119
Acute lymphoblastic leukemia (ALL) Adipocytes
and AML pediatric survivors, 170 accumulation, 147
and APL, 52 adipocyte-derived hormone (see Leptin)
BMI, adult survivors, 145, 149 adiponectin, 82
childhood, 18 aging and nutrition
CRT, 144–145 bone marrow microenvironment,
description, 16 36–37
diagnosis, 56 thymic microenvironment, 37
DXA, 147 BMSC, 33
glucocorticoids, 51 IL-6, 35
heavy babies, 17 marrow, 32
IGF-1R, 59 microenvironment
insulin, 143 bone marrow, 53
KL and TBI, 146 hematologic malignancies, 53, 54
leptin-adiponectin system, 144, 145 pre-adipocytes, 35
LGA and AGA babies, 17 protection, leukemia cells
metabolic syndrome, 145–146 adiponectin, 56
mouse models, 53 IGF-1, 59
obesity, 50, 51, 144 leptin, 55–56
optimal birth weight calculation, 18 MCP-1, 58–59
pharmacokinetic study, 117 obesity, 53
prognosis, 48 SDF-1a, 58
retrospective study, 116, 117 stem cells, 55
survivors, 168, 169 VEGF, 57
survivors, childhood, 143 visfatin, 57–58
T-cell, 119 Adipogenesis
Acute myelogenous leukemia (AML) bone marrow, 53
characterization, 51 cellular progenitors, stromal level
chemotherapy, 51 ASC, 33–34
high birth weight and childhood, 19 BMSCs, 32–33
leptin receptors, 55–56 thymic stromal cells, 34
obese patients, autologous HCT, 133 hematopoietic regulatory factors, 35
Energy Balance and Cancer, DOI 10.1007/978-1-4614-2403-1,
178 Index
Adipogenesis (cont.) B
lipid ligands, 35–36 BAT. See Brown adipose tissue (BAT)
transcriptional regulators, 34 Birth weight
Adipokines, 36, 56, 57, 81 description, 4
Adiponectin IGF1 levels, 59
BMSC adipogenesis, 36 BM. See Bone marrow (BM)
levels, 56 BMI. See Body mass index (BMI)
obesity, 82 BMSC. See Bone marrow mesenchymal
paracrine factor, 35 stromal/stem cells (BMSC)
serum, 56 Body mass index (BMI)
Adipose adolescent, 4
ASC, 33–34 adult
BAT (see Brown adipose tissue (BAT)) and CLL/SLL, 8
mammary adipose tissue, 32 and DLBCL, 7, 8
peripheral tissue and hematopoiesis, 37–38 and FL, 9
tissue, 54, 57, 58, 99 and lymphoma-NHL, 6
tissue deposits, 81 adult leukemia
WAT (see White adipose tissues (WAT)) AML, 14
white adipose, 81 CML, 13
Adult hematologic diseases, 51 dose-response relationship, 14, 15
Aging and nutrition, adipocytes and Q-test, heterogeneity, 12
hematopoietic organs ALLIFE study, 145
bone marrow microenvironment early-life, 5, 8
adipose tissue accumulation, 36 epidemiologic studies, 142
bone mineral density (BMD), 37 and Hodgkin lymphoma, 10–11
marrow adiposity, 36 and NHL, 6
thymic microenvironment, 37 patients categorization, 133
Alkylating agents and toxicity, 101, 117, 118, 120, 121
bifunctional, 132 and VEGF concentration, 48
busulfan, 105, 115 Bone marrow (BM)
cyclophosphamide, 115–116 adipocytes, 35, 53
ifosfamide, 116 bone marrow biopsy, 86
ALL. See Acute lymphoblastic children, 56
leukemia (ALL) mesenchymal stem cells
American College of Sports Medicine (see Bone marrow mesenchymal
(ACSM) stromal/stem cells (BMSC))
and American heart association, 160 microenvironment, 36–37, 49, 53, 54
goal, 163 plasma cells, 83
lighter intensity aerobic exercise, 164 plasma leptin levels, 56
published exercise guidelines, cancer progenitor cells, 12
survivors, 163 volume and birth weight, 21
AML. See Acute myelogenous Bone marrow mesenchymal stromal/stem
leukemia (AML) cells (BMSC)
Amyloidosis hematopoiesis, 33
description, 74 osteoblasts, 32
WM (see Waldentröm’s transplantation studies, 32
macroglobulinemia (WM)) Brown adipose tissue (BAT), 32
Anthracyclines, 118–119 Busulfan, 105, 115, 132
Antimetabolites
cytarabine, 116–117
mercaptopurine, 117 C
methotrexate, 117–118 Cancer survivors
Autologous hematopoietic stem cell ACSM, 163–164
transplantation (AutoHCT), 89 bone, 150
Index 179
exercise guidelines, 163 Distribution

exercise prescription, 163 hemodynamic changes, drugs, 88
hematological, 171–172 lipophilic drugs, 99
pediatric, 142, 143, 152 volume of, 98, 116, 117, 120, 131
resistance and flexibility, 163 Down syndrome, 101
Cardiovascular disease, 135, 142, 143, 146 Doxorubicin, 118–119
Chemotherapy. See also Leukemia
chemotherapy
conditioning regimen pharmacodynamics, E
HCT, 133–134 Epidemiology
dosing, HCT setting, 132 obesity
obesity and toxicity, 51 adolescents, 3
vincristine, 58 birth weight, 4
Childhood cancer, obesity Brazil, 3
ALL, 143–147 “built” environment, 4–5
animal studies, 153 “fast” food, 5
craniopharyngioma, 147–149 heredity, 4
and insulin resistance, 142, 153 men and women, 2
interventions, 151–152 prevalence, 1–2
osteogenic sarcoma Surveillance Epidemiology and End
childhood cancer survivor study, 150 Results (SEER) Registry
pediatric obesity, 150 data, 75, 76
PJ, 149, 150 Etoposide, 120–121
postsurgical changes, 151 Excretion, 99–100
and overweight, 142 Exercise
sugar-sweetened beverages, 153 behaviors, 152
treatment, 141–142 programs, 151
Childhood hematologic malignancies
biologic mechanisms
bone marrow volume, 21 G
IGF-1, 20 Graft-versus-host disease (GVHD), 49, 135,
IGF-II gene, 21 137, 138, 161
maternal weight, 21 GVHD. See Graft-versus-host
methodological considerations, 20 disease (GVHD)
Chronic diseases, 162
Chronic lymphocytic leukemia (CLL)
and adult BMI, 8 H
IGF-1R expression, 569 HCT. See Hematopoietic cell transplantation
and SLL, 12 (HCT)
CLL. See Chronic lymphocytic leukemia (CLL) Health belief model, 152
Coronary artery disease, 143 Heart disease, 162
Corticosteroids, 122 Hematological cancer
Cranial radiotherapy (CRT) multiple myeloma
ALL, 143 (see Multiple myeloma)
GH deficiency, 145 physical activity and recovery
role, 144 (see Physical activity
CRT. See Cranial radiotherapy (CRT) and recovery, hematological
Cyclophosphamide, 115–116 malignancy)
Cytarabine, 116–117 Hematologic diseases, 51
Hematopoiesis
and adipogenesis, 34
D formation, IGF-1 role, 20
Dasatinib, 121–122 IL-6, 83
Daunorubicin, 118–119 peripheral adipose tissue, 37–38
180 Index
Hematopoietic Incidence
HCT (see Hematopoietic cell AL amyloidosis, 74
transplantation (HCT)) APL, 52
leptin, 82 BMI and leukemia, 12
malignancies, 48–50 cancer, 55, 57, 59
precursors, 55, 58 childhood leukemia, 59
stem cells (see Hematopoietic stem leukemia, 54
cells (HSC)) multiple myeloma, 75–76, 78
toxicity/interval, 40 NHL, NIH-AARP Diet and Health
transplant, 49 Study, 6
Hematopoietic cell transplantation (HCT) obesity, 53–54
allogeneic treatment-related morbidity and
AML, 137 mortality, 51
BMI and clinical outcomes, 137–138 Insulin-like growth factor-1 (IGF-1)
AutoHCT, 89 bioactive levels, 59
autologous birth weight, 20
prognostic factors, 136 childhood growth, 5
TBI and BMI, 135–136 explanted leukemic cells, 12
chemotherapy dosing, 132 hematopoiesis formation, 20
conditioning regimens, 130–131 and insulin signaling, 60
obesity and outcomes signals stimulation, 59
evaluation, 134 Insulin-like growth factor receptors
prognostic factors, 135 biological accessibility and activity, 80
pharmacodynamics, conditioning regimen bone remodeling., 81
chemotherapy, 133–134 Insulin resistance
Hematopoietic stem cells (HSC) homeostasis model assessment, 147
CD34+ putative, 33 and inflammation, 57
hematopoiesis, 36 and obesity, 142–146, 148, 150–153
lineage determination, 34 obesity-induced, 59–60
Hematopoietic stem cell transplantation Interleukin 6 (IL-6)
(HSCT) Hodgkin lymphoma, 10–11
allogeneic, 172 multiple myeloma, 82–83
physical activity interventions myeloma bone disease, 83
adults, 166–167 single nucleotide polymorphisms, 11
children, 170 International Classification of Disease for
Hepatic venoocclusive disease, 115 Oncology, Second and Third
HL. See Hodgkin lymphoma (HL) Editions (ICD-O-2 and-3), 5
Hodgkin lymphoma (HL)
aspirin users, 85
birth weight, 11 K
obesity, 10–11 Kahlers diseases. See Multiple myeloma
Hodgkin’s disease, 112, 165
Homeostasis model, 143, 147
HSC. See Hematopoietic stem cells (HSC) L
HSCT. See Hematopoietic stem cell l-asparaginase
transplantation (HSCT) monotherapy, 54
use, 122
Leptin
I adipocytes, microenvironment, 54, 56
Idarubicin, 118–119 defined, 55
Ifosfamide, 116 obesity, 81–82
IGF-1. See Insulin-like growth factor-1 (IGF-1) Leukemia. See also Obesity and leukemia
IL-6. See Interleukin 6 (IL-6) prognosis
Imatinib, 121–122 adult, 12–15
Index 181
chemotherapy (see Leukemia Microenvironment

chemotherapy) adipocytes, leukemia, 53
childhood bone marrow, 36–37
ALL, 16–18 thymic, 37
AML, 18–19 Migration
overall, 16 granulocyte-CSF (G-CSF), 36
high birth weight, 20 hematopoietic cells, marrow, 36
Leukemia chemotherapy HSC, 38
and obesity, size descriptors leukemia cell, 58
cancer outcomes, 101–104 Monoclonal gammopathy of undetermined
effect, pharmacokinetic parameters, significance (MGUS)
105–114 obesity, 79–80
retrospective cohort studies, 101, 105 Monocyte chemotactic protein 1
weight descriptors, BSA (MCP-1), 58–59
calculation, 100 Mouse models, 53
pharmacokinetics and dosing Multiple myeloma. See also Obesity
acute leukemias treatments, 122 amyloidosis
alkylating agents, 105–116 description, 74
anthracyclines, 118–119 WM (see Waldentröm’s
antimetabolites, 116–118 macroglobulinemia (WM))
corticosteroids, 122 cells migration, 58
plant alkaloids, 120–121 description, 73
platinum compounds, 119–120 diagnosis
tyrosine kinase inhibitors, 121–122 chromosomal abnormalities, 87–88
Lymphomas computed tomography and MRI, 86
adult NHL, 5–10 diagnostic criteria, 86, 87
B and T-cell, 53 FISH and CGH, 87
childhood, 15–16 immunoglobulin, 73
diffuse large B-cell lymphoma pathogenesis
(DLBCL), 7, 8, 10 incidence, USA, 75–76
Hodgkin lymphoma obesity, 76–80
(see Hodgkin lymphoma) premalignant stages, 74
and leukemias, 105 recipients, autologous HCT, 135
non-Hodgkin, 52 treatment, 89
obese patients, 101 Myelodysplastic syndrome, 103
WM, 74 Myriad diseases, 135
M N
Malignant disease, 130, 137, 138 NF-kB. See Nuclear factor-kB (NF-kB)
Mercaptopurine, 117 NHL. See Non-Hodgkin lymphoma (NHL)
Mesenchymal stem cells. See Bone marrow Nilotinib, 121–122
mesenchymal stromal/stem cells Non-alcoholic fatty liver disease, 146
(BMSC) Non-Hodgkin lymphoma (NHL)
Metabolic syndrome, 143, 145–146, adult
148, 150 adulthood BMI, 6–8
Metabolism description, 5
arachidonic acid, 35 early adulthood BMI and height, 8–10
cancer cell, 57 IGF-1, 5
drug, 131 aspirin users, 85
fatty acid, 146 Nuclear factor-kB (NF-kB)
glucose, 146 aspirin use and MM risk, 85–86
lipid, 36 cell cycle regulators, 84
Metastatic bone disease, 163 cytokines and chemokines, 84
182 Index
O Obesity and leukemia prognosis

Obesity adipocytes
anthropometric measures and adult NHL microenvironment, 53
adult BMI and NHL, 6 protection, leukemia cells, 55–59
early adulthood body mass index and changes, mammals, 60
height, 8–10 leukemia outcome
histologic subtype, 5 chemotherapy pharmacokinetics and
IGF-1, 5 individual tolerance, 49
recent adulthood body mass index, 6–8 and chemotherapy toxicity, 49–51
birth weight effects, hematologic malignancies,
childhood leukemia, 16–19 49, 50
childhood lymphoma, 15–16 factors, hematopoietic cancers/
BMI therapies, 49, 50
and adult leukemia, 12–15 and leukemia relapse, 51–53
and Hodgkin lymphoma, 10–11 mechanisms, cancer, 47, 48
and cancer risk Overweight
meta-analysis, 71, 72 adults, 3
Million Women Study, 72 BMI (see Body mass index (BMI))
physical activity, energy balance and “built” environment, 4–5
cancer risk, 72–73 children, 117
childhood cancer (see Childhood leukemia, 12, 14
cancer, obesity) mortality, 72
diet-induced, 34, 37 and normal-weight women, 119
epidemiology and obese lymphoma patients, 136
adolescents, 3 and obese patients, 52
birth weight, 4 and obesity, 142
Brazil, 3 outcomes, 137
“built” environment, 4–5 prevalence, 1–2
“fast” food, 5
heredity, 4
men and women, 2 P
prevalence, 1–2 Peroxisome proliferator activated receptor g
hematologic malignancies (PPARg), 34, 35
and anthropometric measures, 22, 23 Pharmacodynamics
childhood (see Childhood hematologic conditioning regimen chemotherapy,
malignancies) HCT, 133–134
MGUS, 79–80 parameters, 98
multiple myeloma risk Pharmacokinetics (PK)
adipokines, 81 anticancer agents, 88
adiponectin, 82 chemotherapeutics, obesity setting, 131
cohort studies, 78 and dosing (see Pharmacokinetics and
diagnosis, 86 dosing, obesity)
IL-6, 82–83 Pharmacokinetics and dosing, obesity
insulin-like growth factor absorption, 98
receptors, 80–81 cancer chemotherapy, 122, 123
Iowa Women’s Health Study, 77 distribution, 98–99
Japan Collaborative Cohort Study, 77 excretion, 99–100
leptin, 81–82 leukemia chemotherapy
NF-kB, 84–86 acute leukemias treatments, 122
somatogram-depicted body shape, 79 alkylating agents, 105–116
standardized morbidity ratio anthracyclines, 118–119
(SMR), 76–77 antimetabolites, 116–118
TNF-a, 83–84 corticosteroids, 122
treatment effect, 88–89 plant alkaloids, 120–121
Index 183
platinum compounds, 119–120 Recovery

size descriptors, 100–105 hematopoietic, 51
tyrosine kinase inhibitors, 121–122 physical activity and (See Physical
metabolism, 99 activity and recovery,
parameters, 98 hematological malignancy)
Physical activity
ALL survivors, 144
breast and colon cancer, 72–73 S
and dietary interventions, 151 SDF-1a. See Stromal-derived factor 1a
lack of, 4 (SDF-1a)
multiple myeloma, 73 Sinusoidal obstruction syndrome, 115, 132
and recovery (see Physical activity SMM. See Smoldering multiple
and recovery, hematological myeloma (SMM)
malignancy) Smoldering multiple myeloma
weight, 58 (SMM), 89
Physical activity and recovery, Stem cell transplantation
hematological malignancy AutoHCT, 89
ACSM, 163–164 HCT
benefits, 160 allogeneic, 137–138
and cancer control, 162 chemotherapy dosing, 132
cancer survivors, 171–172 conditioning regimens, 130–131
chemotherapy, 160–161 obesity and outcomes, 134–135
HSCT, 164 outcomes, autologous, 135–137
interventions, adults pharmacodynamics, conditioning
depression, cancer patients, 165 regimen chemotherapy, 133–134
HSCT, 166–167 hematopoietic, 89
QOL, 165, 168 pharmacokinetics, chemotherapeutics, 131
RCTs, 164–165 Stromal-derived factor 1a
interventions, children (SDF-1a), 58
ALL, 168–169 Sunitinib, 121–122
HSCT, 170 Survivors
QOL, 169–170 adolescent, 169
late and long-term effects, cancer adult cancer, 143, 163
treatment, 161 ALL, 142–145, 151, 168–169
role, 162 AML pediatric, 170
PK. See Pharmacokinetics (PK) bone cancer, 150
Plant alkaloids and cancer patients, 159, 163
etoposide, 120–121 chronic disease, 162
teniposide, 121 hematological cancer, 171–172
Plasma cells Hodgkin and non-Hodgkin
bone marrow plasma cells, 83 lymphoma, 165
dyscrasias, 74 Hodgkin’s disease, 165
multiple myeloma, 5 HSCT, 166
myeloma, 73 long-term, 135, 141, 143, 150
TNF-a, 83–84 non-cancer siblings, 142
Platinum compounds, 119–120
Pulmonary disease, 135
T
Teniposide, 121
R Thymus, 34
Radiation TNF-a. See Tumor necrosis factor-a
cranial, 144, 148 (TNF-a)
leukemia, 12 Tumor necrosis factor-a (TNF-a), 83–84
and surgery, 148 Tyrosine kinase inhibitors, 121–122
184 Index
V W
Vascular endothelial growth factor (VEGF) Waldentröm’s macroglobulinemia
defined, 57 (WM), 74
receptors, 57 WAT. See White adipose tissues (WAT)
VEGF. See Vascular endothelial growth White adipose tissues (WAT), 31–32
factor (VEGF) WHO. See World Health Organization
Veno-occlusive disease, 132 (WHO)
Ventromedial hypothalamus (VMH), 148 WM. See Waldentröm’s macroglobulinemia
Vincristine (WM)
chemotherapy, 58 World Health Organization (WHO)
treatment, 54–55 classification scheme, 12
Visfatin, 35, 57–58 microalbuminuria, 146
VMH. See Ventromedial hypothalamus (VMH) overweight estimation, 3

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Energy Balance and Cancer

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The Many Roles of Obesity in Hematologic Malignancies:

Los Angeles, CA, USA Steven D. Mittelman

1 The Epidemiology of Obesity and Hematologic

Index ................................................................................................................ 177

Tracey Beason Division of Public Health Sciences, Department of Surgery,

Kevin C. Oeffinger Department of Pediatrics, Memorial Sloan-Kettering Cancer

Lauren R. Teras and Alpa V. Patel

1 The Epidemiology of Obesity

Obesity in the United States (US) is now universally recognized as epidemic.

L.R. Teras, Ph.D. (*) • A.V. Patel, Ph.D.

BMI (kg/m2) BMI Class

2 Anthropometric Measures and Adult Non-Hodgkin

ADULT BMI AND LYMPHOMA-NHL

2.1 Recent Adulthood Body Mass Index

2.2 Early Adulthood Body Mass Index and Height

2.3 Summary and Future Directions

3 BMI and Hodgkin Lymphoma

important players as associations of both IL-6 single nucleotide polymorphisms and

4 BMI and Adult Leukemia

Leukemias are a group of cancers that are characterized by increased numbers of

Fig. 1.7 Previous epidemiologic studies of BMI and adult CML

Fig. 1.8 Previous epidemiologic studies of BMI and adult AML

Fig. 1.9 Previous epidemiologic studies of BMI and adult ALL

5 Birth Weight and Childhood Lymphoma

6 Birth Weight and Childhood Leukemia

6.1 Overall Leukemia

6.2 Acute Lymphoblastic Leukemia

6.3 Acute Myeloid Leukemia

Although AML is the second most common type of childhood leukemia, it is

7 Other Considerations in Childhood Hematologic

7.1 Methodological Considerations

Methodological differences may explain some of the inconsistency in measured

7.2 Biologic Mechanisms

7.3 Maternal Weight

Maternal characteristics have also been studied in relation to childhood hematopoi-

7.4 Conclusions and Future Directions

In summary, the research conducted to date supports a 30–40% higher risk of

Table 1.1 Summary of associations between anthropometric measures and hematologic

8 Summary of Obesity and Hematologic Malignancies

Numerous studies have examined anthropometric measures in relation to adult and

13. Thorburn AW (2005) Prevalence of obesity in Australia. Obes Rev 6(3):187–189

Abstract The physiology and pathology of adipogenesis and hematopoiesis are

J.M. Gimble, M.D., Ph.D. (*)

adipokines such as adiponectin, leptin, and resistin as well as hematopoietic/

2 Adipogenesis: Cellular Mechanisms

2.1 Cellular Progenitors at the Stromal Level

with multilineage differentiation potential (adipogenic, chondrogenic, osteogenic),

2.2 Transcriptional Regulators: Common Themes Between

Adipogenesis is positively regulated directly by the helix–loop–helix family members,

2.3 Adipogenic-Related Hematopoietic Regulatory Factors

2.4 Lipid Ligands

lipid mediators such as lysophosphatidic acid act as lymphoid chemotactic factors,

3 Aging and Nutrition: Impact on Adipocytes and

3.1 Bone Marrow Microenvironment

Adipose tissue accumulates in the bone marrow microenvironment with advancing

for hematological disorders in anorexia nervosa; however, recent murine studies

3.2 Thymic Microenvironment