Leukemia

https://doi.org/10.1038/s41375-018-0162-5

ARTICLE

Acute myeloid leukemia

Long-term recovery of quality of life and physical function over

three years in adult survivors of acute myeloid leukemia after
intensive chemotherapy
N. Timilshina1,2 H. Breunis1 G. A. Tomlinson1,2,3 J. M. Brandwein4 R. Buckstein5 S. Durbano1
● ● ● ● ● ●

S. M. H. Alibhai1,2,6

Received: 6 December 2017 / Revised: 7 March 2018 / Accepted: 13 April 2018

© Macmillan Publishers Limited, part of Springer Nature 2018

Abstract
We previously described impairments in quality of life (QOL) and physical function among acute myeloid leukemia (AML)
survivors between diagnosis and 1 year. The aim of the current study is to describe and compare to normative data QOL and
physical function recovery over 3 years from diagnosis and treatment with intensive chemotherapy (IC). At assessments done at
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baseline (pre-IC) and at 11 time points over 3 years, QOL, fatigue, and 3 physical performance measures (PPMs; grip strength,
6-min walk test (6MWT), and timed chair stands) were collected. Long-term recovery was defined by reaching scores within the
minimum clinically important difference of normative data. Global QOL recovery was seen in 79% at 1 year, 75% at 2 years,
and 86% at 3 years. At 3 years, the QLQ-C30 subscales with the greatest recovery were physical and emotional functioning. For
FACT-fatigue, recovery was seen in 68% at 1 year and 77% at 3 years. Recovery on PPMs was poorer on average, with only
17% on the 6MWT and 42% in grip strength returning to normal at 3 years. The vast majority of AML survivors after IC achieve
recovery in QOL and fatigue by three years. However, recovery in physical performance remained blunted.

Introduction AML has improved significantly over the past several

Acute myeloid leukemia (AML) is a life-threatening disease
whose incidence rises with age [1, 2]. The prognosis of
Electronic supplementary material The online version of this article
(https://doi.org/10.1038/s41375-018-0162-5) contains supplementary
material, which is available to authorized users.
* S. M. H. Alibhai
shabbir.alibhai@uhn.ca
1
Department of Medicine, University Health Network,
Toronto, ON, Canada
2
Institute of Health Policy, Management, and Evaluation,
University of Toronto, Toronto, ON, Canada
3
Dalla Lana School of Public Health, University of Toronto,
Toronto, ON, Canada
4
Division of Hematology, University of Alberta, Edmonton, AB,
Canada
5
Hematology/Oncology, Sunnybrook Odette Cancer Center,
University of Toronto, Toronto, ON, Canada
6
Department of Medicine, University of Toronto, Toronto, ON,
Canada
decades [3]. This improvement can be attributed to advan-
ces in intensive chemotherapy (IC) regimens, hematopoietic
stem cell transplantation (HSCT), and better supportive care
[4, 5]. Population-based studies from the US and Sweden
reported that 5-year and 10-year survival improved sig-
nificantly in all age groups over time, except for patients 80
and above [6, 7]. Similar data were reported by a Canadian
population-based study, with less improvement in long-term
survival among adults age 60 or older [8]. With a growing
number of long-term survivors, understanding the long-term
effects of AML and its treatment becomes increasingly
relevant.
We previously reported impairments in quality of life
(QOL) and physical function with AML at diagnosis and
over 1 year after IC [9, 10]. QOL and physical function
impairments were widespread and fatigue was almost uni-
versal at diagnosis. Survivors demonstrated significant
improvements in QOL, fatigue and physical function over
one year with similar trajectories for older and younger
patients [9]. However, fatigue remained common and phy-
sical function improved only slightly by 1 year.
To date, no study has reported long-term QOL and
physical function in AML patients undergoing IC. As
 N. Timilshina et al.

survival improves over time, long-term patient-reported Eligible Paents enrolled

at diagnosis
outcomes and survivorship issues become more important Excluded (n=120)
(n=237)
both to counsel patients, as well as to plan interventions Relapse= 2
BMT=39
to improve outcomes. Thus, our primary objective was to Deceased=60
Paents remaining on Withdrew/lost to follow up=19
measure QOL and physical function over 3 years in study at 12 months
survivors of AML treated with IC. A secondary objective (n=117)
was to investigate to what extent patients with
AML recovered in the domains of QOL, fatigue and
objective physical function compared to population nor- Declined to consent Paents re-consented for
long-term study at 1 year
mative data. (n=21)
(n=96)
Excluded (between reconsent
and 1 visit at 18 mo., n=25)
Relapse =13
BMT=5
Methods Follow up at 18 months
Deceased = 4
Withdrew/lost to follow up= 3
(n=71)
Adult AML patients (age 18+) undergoing IC without stem Excluded (n=5)
Relapse =1
cell transplant were enrolled in a prospective, longitudinal BMT=1
Deceased = 3
study. Assessments were done at baseline (pre-IC) and at 11 Follow up at 24 months Withdrew/ lost to follow up= 0
time points (end of cycle 1 of IC, end of cycle 2, end of (n=66)
Excluded (n=4)
cycle 3; and 6, 8, 10, 12, 18, 24, 30, and 36 months) over Relapse =0
BMT=0
the next 3 years. Follow up at 30 months
Deceased = 3
Withdrew/ lost to follow up= 1
(n=62)
Excluded (n=3)
Study design Relapse =0
BMT=3
Deceased = 0
Follow up at 36 months
Withdrew/ lost to follow up= 0
The study design has been described in detail in our pre- (n=59)
vious publications and is summarized here [9, 10]. A pro-
spective, longitudinal cohort study was conducted at the Fig. 1 Flow chart: patients flow chart
Princess Margaret Cancer Centre, a tertiary care AML
treatment referral center, and the Odette Cancer Centre, an
academic cancer center, both in Toronto, Canada. All study relapsed or underwent bone marrow transplant during
procedures were approved by the Institutional Research follow-up.
Ethics Board and all participants provided written informed
consent. Baseline measures

Subject recruitment At the baseline assessment (before or within 3 days of

Consecutive potentially eligible participants were identified
by the treating hematologists or by reviewing patient
admissions. Inclusion criteria were as follows: newly
diagnosed AML; initiating IC; ability to provide written
informed consent; and fluency in English or having both a
translator and questionnaires available in the patient’s first
language. Exclusion criteria included: another active
malignancy; prior chemotherapy (within 2 years of AML
diagnosis); life expectancy of <1 month (as determined by
the physician). Full inclusion and exclusion criteria, patient
recruitment and IC treatment details were described in our
previous publications [9, 11].
Consent for long-term follow-up
For the present study, one-year survivors from our origi-
nal study were re-consented for long-term follow up
(details in Fig. 1). Patients were excluded if they had
starting IC), both patient-reported outcomes (i.e., QOL and
fatigue), as well as objective physical function were asses-
sed. Additional measures included sociodemographic (age,
sex, education, marital status, smoking history) and disease
information (cytogenetics, relevant hematology and bio-
chemistry, performance status, and comorbidities).
Quality of life outcomes
We assessed QOL using the European Organisation for the
Research and Treatment of Cancer (EORTC) 30-item
questionnaire (QLQ-C30) and fatigue with the Functional
Assessment of Cancer Therapy Fatigue subscale (FACT-F)
at baseline and over three years of follow-up. The QLQ-C30
is scored from 0 to 100, with higher scores representing
better QOL. The FACT-F consists of 13 items, and overall
scores range from (0 maximal fatigue) to 52 (no fatigue)[12,
13]. Details regarding these psychometrically valid mea-
sures are described in our previous work [9, 10, 14].
Long-term recovery of quality of life and physical function over three years in adult survivors of. . .
Physical function tests
Three objective tests were used to assess various aspects of
physical function and fitness and were administered at the
same time points as QOL measures. To measure functional
endurance the 2-minute walk test (2MWT) was used from
baseline to 1 year, and the 6-minute walk test (6MWT) was
used subsequently [15]. Since there are no normative data
for the 2MWT and it was only measured in the first year, it
will not be discussed further. Grip strength, measured with a
Jamar dynamometer, was used to assess upper body mus-
cular strength [16, 17]. Lower body function was evaluated
with 10 timed chair stands [18]. Details regarding these
measures are described in our previous work [9–11].
Normative data
Normative data for QOL were obtained for the EORTC
QLQ-C30 from an analysis of six pooled European general
population normative studies including 16,151 participants
[19]. For all QOL outcomes, age-stratified and gender-
stratified normative data were used. Normative data for
FACT-F was obtained from the general United States
population [13, 20, 21]. For physical function tests, grip
strength reference values were obtained from the
2007–2013 Canadian Health Measures Survey [22] and
6MWT age-stratified and gender-stratified reference values
were obtained from reference equations which are com-
monly used in clinical practice [17, 23–25]. For the timed
chair stands test, population-based reference values strati-
fied for sex and 5-year age groups were used from Csuka
et al. [26, 27].
Minimally clinically importance differences (MCID)
Recovery on an outcome for an individual was defined as
reaching a value within the minimum clinically important
difference (MCID) of that individual’s age- and gender-
appropriate normative data on the outcome at that time
point. The MCID represents the minimum change in a given
measure that would be perceptible to the average patient
[28]. For all outcomes, we determined the MCID based on
published literature using methods described by Guyatt
et al. [29]. We used published MCIDs where possible [20,
23, 27, 29]. If no published MCID was available, we cal-
culated the MCID based on the 0.5-standard deviation rule
[29, 30].
In this study, recovery was defined as reaching within
one minimum clinically important difference (MCID) unit
for each outcome. Based on published literature, ten points
was considered to be the MCID for all of the QLQ-C30
scale scores, while it was four points for the FACT-F [20,
21, 31]. For physical function tests, 4.5 kg for grip
strength, 54 m (177.2 ft) for the 6MWT, and 3.4 s for timed
chaired stands were used [23–27]. We reported the pro-
portion of subjects (overall and by gender) who met the
definition of recovery at each time point for each of our
outcomes.
Statistical analyses
Descriptive statistics for continuous variables were reported
using means and standard deviations (SD) or medians with
inter-quartile ranges (IQR), as appropriate. Comparisons of
these variables between age groups were made using the
Student’s t-test. Categorical data are reported as counts and
percentages, and were compared between age groups using
Fisher’s exact test.
Results are presented for the total group and by gender.
Mixed-effect models for repeated measures (MMRM) with
compound symmetric structure were used to estimate effect
sizes and compare longitudinal changes in global QOL,
QOL subdomains, FACT-F and all three physical function
measures from 12 months to over 36 months. Differences in
recovery over time by median age (≤52 years vs. 52+
years), age group (≤60 years vs. 60+ years) and gender
were also evaluated using MMRM models. All analyses
were performed using SAS version 9.4 (SAS Institute, Cary,
NC).
Sensitivity analysis for missing data
It was assumed that certain missing values may suggest that
the patient’s underlying condition was worse than at visits
when values were obtained. To assess the impact of these
missing data on our results, a sensitivity analysis was per-
formed. Any patient who was unable to complete a physical
function test due to fatigue or illness was assigned a score
equal to the worst decile median score from the patient’s
age group at that particular visit and for that specific test.
Statistical analyses were then repeated using these imputed
data to determine whether the results were affected [32]. We
also performed a second sensitivity analysis using multiple
imputation to assign scores for any missing data (missing
value or missed visit) for all patients who remained eligible
at the assessment time point [33].
Results
Patients enrolled in the 0–12 month study have been
described previously [9]. Briefly, there were 237 partici-
pants, mean age 55 years, 44% female. At 1 year, 120
(51%) participants had early discontinuation due to death (n
= 60), receipt of HSCT (n = 39), withdrawal or loss to
 N. Timilshina et al.

follow-up (n = 19), and relapse (n = 2). Of the remaining Table 1 Demographic and disease characteristics at diagnosis among
patients consenting to the long-term follow-up study
117 patients, 96 (82%) patients were re-consented for long-
term follow-up. Baseline characteristic N = 71
Among 96 patients who were re-consented, between 12
Age, median (IQR) 52 (41–58)
and 18 months, 25 patients (26%) withdrew from the study,
Gender, female, n (%) 42 (59.2)
whereas 71 of 96 (74%) completed the assessment at
English as first language, n (%) 41 (57.8)
18 months and continued on study. At 24 months, 66 of 71
Body mass index, mean (SD) 27.7 (5.4)
patients completed the study (n = 5 were excluded), 62
Marital status, n (%) Married 53 (74.7)
completed assessments (n = 4 were excluded) at 30 months,
Divorced/separated 10 (14.0)
and 59 patients (n = 3 were excluded) were assessed at the
36–month visit (details in Fig. 1). These 71 one-year sur- Single 7 (9.9)
vivors had a median age of 52 years, the majority were Widowed 1 (1.4)
female (n = 42, 59%), and they were followed for up to 3 Race/ethnicity, n (%) White 45 (63.4)
years. Thirty six patients (51%) had never smoked, 27 Oriental 10 (14.1)
(38%) had normal cytogenetics, and a large majority of South Asian 10 (14.1)
patients (n = 59, 83%) had no other comorbidity at baseline Black 2 (2.8)
(Table 1). Other 4 (5.6)
Working situation, n (%) Still at work 36 (50.7)
Recovery in quality of life and fatigue scores over 3 Retired 19 (26.8)
years Unemployed 13 (18.3)
Sick leave 1 (1.4)
Table 2 shows the results of the QOL and physical function Other 2 (2.8)
test scores from one year to three years. Mean global QOL Smoking status, n (%) Never smoked 36 (50.7)
scores continued to improve over 3 years (74.3 at 1 year, Quit smoking 33 (46.5)
73.0 at 2 years, and 79.0 at 3 years, respectively, p = 0.039) Current smoker 2 (2.8)
and mean global QOL scores were above the reference ECOG performance status, n (%) 0 34 (47.9)
value after 2 years (reference value 75.7, Table 2, Supple- 1 25 (35.2)
mental Fig. 1 and Supplemental Table 1). QLQ-C30 sub- 2+ 12 (16.9)
scale scores were very close to reference values between 1 Karnofsky score (%), mean (SD) 83.0 (13.6)
year and 3 years, and over time there was no evidence for
Cytogenetic risk group, n (%) Favorable 24 (33.8)
further recovery in any QLQ-C30 subscale between 1 year
Intermediate 13 (18.3)
and 3 years (all p > 0.05, Table 2, Supplemental Fig. 1 and
Normal 27 (38.0)
Supplemental Table 1).
Unfavorable 5 (7.0)
Global QOL recovery was seen in 79% at 1 year, 75% at
Inconclusive 2 (2.8)
2 years and 86% at 3 years. At 1 year, the QLQ-C30 sub-
Mean hemoglobin, g/L (SD) 94.3 (17.8)
scales with the greatest proportion of survivors who had
returned to normal were physical function (72%) and Mean peripheral blast % (SD) 33.3 (31.3)
emotional function (72%), and at 3 years it was physical Mean bone marrow blast % (SD) 65.2 (28.3)
and social functioning (77% and 82%, respectively). In Mean platelet count (SD) 81.5 (75.9)
contrast, the domain with the fewest patients returning to Mean WBC count (SD) 20.1 (32.7)
normal was cognitive function (72%). For FACT-fatigue, Mean neutrophil count (SD) 3.1 (9.8)
68% of AML survivors had recovered at 1 year and 77% at Antecedent hematologic disorder, n (%) 18 (25.4)
3 years (Supplemental Table 2). Charlson score, n (%) 0 59 (83.1)
1 9 (12.7)
Recovery in physical performance measures over 3 2+ 3 (4.2)
years Hypertension, n (%) 16 (22.5)
Arthritis, n (%) 13 (18.3)
Objective physical function results are shown in Table 2. Thyroid disease, n (%) 10 (14.1)
Overall grip strength remained unchanged over time (mean Diabetes, n (%) 5 (7.0)
score 31.2 kg at 1 year and 32.0 kg at 3 years, p = 0.84) as Asthma, n (%) 3 (4.2)
did 6MWT distances (mean distance 1580 feet at 1 year and
ECOG Eastern cooperative oncology group, IQR interquartile range,
1705 feet at 3 years, p = 0.31)), whereas timed chair stands SD standard deviation, WBC white blood cell
significantly improved over time (mean score 35.0 at 1 year
Long-term recovery of quality of life and physical function over three years in adult survivors of. . .

Table 2 Raw QOL scores from 12 months to 3 years, all participants

Measurement (mean (SD)) Baseline 12 months 18 months 24 months 30 months 36 months p-Value*

Patient-reported outcomes
Global Health/QOL All 48.1 (25.3) 74.3 (17.0) 71.8 (19.7) (63) 73.0 (21.5) (64) 78.9 (17.8) (53) 79.0 (17.9) (56) 0.056
(N) (71) (68)
Male 48.8 (26.7) 77.1 (16.6) 75.0 (18.2) 73.3 (17.5) 79.8 (16.2) 82.9 (14.9)
Female 47.5 (24.6) 72.2 (17.2) 69.4 (20.7) 72.8 (24.1) 78.6 (19.3) 76.8 (19.6)
Physical functioning All 80.6 (23.8) 85.2 (16.7) 84.1 (17.4) (61) 82.5 (21.5) (63) 86.9 (17.4) (53) 88.3 (17.8) (56) 0.11
(N) (68)
Male 82.1 (21.2) 90.9 (10.6) 86.4 (14.8) 87.6 (15.0) 92.4 (8.7) 90.0 (18.2)
Female 79.5 (25.8) 80.9 (19.2) 82.7 (19.1) 78.9 (24.5) 83.2 (20.6) 87.1 (17.7)
Role functioning (N) All 50.7 (32.6) 80.9 (26.1) 83.6 (22.1) (63) 81.7 (26.7) (63) 88.1 (19.9) (52) 86.0 (23.7) (57) 0.38
(68)
Male 48.2 (34.3) 87.5 (20.6) 85.8 (20.5) 82.7 (26.8) 90.0 (19.0) 89.6 (21.3)
Female 52.6 (31.7) 75.6 (28.8) 81.9 (23.4) 81.1 (26.9) 86.9 (20.6) 83.3 (25.3)
Emotional All 68.3 (25.9) 80.6 (19.7) 81.7 (17.3) (62) 77.5 (24.2) (64) 85.9 (19.1) (52) 82.6 (22.8) (57) 0.11
functioning (N) (680
Male 72.6 (25.0) 84.5 (17.4) 82.1 (17.7) 82.7 (22.4) 86.5 (19.1) 82.9 (23.9)
Female 65.2 (26.5) 77.6 (21.0) 80.5 (17.0) 75.0 (25.3) 84.7 (19.4) 82.3 (22.3)
Cognitive All 77.1 (23.7) 81.6 (18.5)(68) 82.0 (19.2) (63) 81.2 (25.8) (63) 84.6 (18.4) (53) 83.3 (18.4) (57) 0.76
functioning (N) Male 80.9 (19.1) 84.5 (16.9) 87.0 (16.9) 88.0 (18.9) 87.3 (18.2) 82.6 (17.4)
Female 74.4 (26.4) 79.1 (19.4) 77.8 (20.3) 76.7 (28.9) 82.8 (18.7) 83.3 (19.5)
Social functioning All 49.2 (36.2) 82.8 (23.2) 85.8 (20.8) (61) 82.0 (27.0) (63) 86.8 (21.3) (53) 88.5 (22.4) (55) 0.30
(N) (67)
Male 45.2 (35.4) 85.1 (24.1) 89.1 (17.6) 83.3 (28.7) 87.3 (20.3) 89.1 (22.8)
Female 52.2 (36.9) 80.7 (22.7) 83.3 (22.9) 81.1 (26.1) 85.9 (22.0) 88.0 (22.4)
FACT-F score (/52) All 31.9 (12.9) 40.9 (9.8) (63) 41.9 (8.4) (63) 40.3 (10.8) (60) 44.0 (8.7) (53) 43.3 (8.5) (56) 0.14
(N) Male 31.9 (12.4) 43.6 (12.4) 43.3 (7.7) 42.1 (9.7) 45.5 (7.2) 45.0 (6.4)
Female 31.9 (13.3) 39.1 (10.2) 40.8 (8.9) 39.9 (11.3) 42.9 (9.4) 42.4 (9.8)
Physical functioning
Grip strength (kg) All 30.3 (12.5) 31.2 (13.7) 32.3 (13.4) (65) 31.8 (13.6) (62) 32.6 (14.4) (52) 32.0 (14.0) (55) 0.84
(N) (68)
Male 41.3 (10.1) 43.2 (10.5) 43.5 (10.9) 43.7 (12.2) 45.8 (12.9) 43.3 (13.8)
Female 22.1 (6.4) 22.8 (8.4) 23.9 (7.8) 23.9 (7.3) 24.4 (7.4) 23.9 (6.4)
Chair stands/min (N) All 25.6 (9.4) 35.0 (17.1) 35.2 (15.5) (59) 39.0 (20.4) (59) 38.3 (14.5) (50) 40.7 (18.4) (48) 0.002
(67)
Male 26.9 (9.4) 38.2 (19.5) 38.0 (18.4) 41.4(19.6) 39.4 (16.6) 44.9 (19.7)
Female 24.7 (9.3) 32.9 (15.1) 33.1 (12.9) 37.4 (21.1) 37.2 (13.2) 37.7 (17.2)
6-min walk distance All Not done Not done 1580 (301.3) 1566 (428.6) 1589 (424.4) 1705 (376.5) 0.31
(ft) (N) (60) (59) (51) (46)
Male Not done Not done 1658 (309.7) 1684 (389.4) 1756 (327.9) 1866 (337.3)
Female Not done Not done 1522 (284.7) 1492 (436.6) 1477 (455.9) 1589 (366.2)
Note: p-values are from mixed effects models for repeated measurements for longitudinal changes over 12 months to 36 months (included time
points 12, 18, 24, 30, and 36 months)
Values in parentheses in the upper row in each cell represent standard deviations

and 40.7 at 3 years, p = 0.002; higher scores indicate better
performance).
Recovery in PPMs was poorer on average than recovery in
QOL, with only 50% returning to normal in grip strength at 1
year and 53% at 3 years. For the lower body function mea-
sured with timed chair stands, 44% had returned to normal at 1
year whereas 64% had recovered at 3 years. Also, only 17% of
survivors returned to normal on the 6MWT at 3 years (Sup-
plemental Table 2). MMRM results showed lower extremity
function measured with timed chair stands was statistically
improved over time (p = 0.002, Table 2), whereas neither
other PPM demonstrated improvement over time (Table 2).
 N. Timilshina et al.

Table 3 Results of linear mixed effects model examining gender and years, respectively) although the result did not reach sta-
age effects from 12 months to 36 months
tistical significance (pinteraction = 0.075). Recovery in QOL
Patient-reported Time x Time x median Time x age- domains did not differ by gender (Table 3). For FACT-
outcomes gender age (<52 year vs. group (<60 year fatigue, only 67% of female survivors returned to normal
52+) vs. 60+)
compared to 91% among male survivors at 3 years (pinter-
p-Value p-Value p-Value
action = 0.075, Table 3 and Fig. 2).
Patient-reported outcomes Objective physical function results by gender are shown
Global health/ 0.075 0.083 0.14 in Fig. 3. Of the three PPMs, recovery only differed by
QOL gender for timed chair stands (pinteraction = 0.002, Table 3),
Physical 0.097 0.30 0.15 with female survivors improving more than male survivors
functioning over time.
Role functioning 0.42 0.46 0.32
Emotional 0.28 0.34 0.33 Impact of missing data
functioning
Cognitive 0.76 0.76 0.39
Attrition over 36 months is shown in Supplemental Table 3.
functioning
By the end of the 1-year follow-up, 82% of eligible patients
Social 0.39 0.45 0.65
functioning (96 of 117) remained on study. At baseline, QOL and PPM
FACT-F score 0.075 0.83 0.32 scores were not statistically significantly different between
Physical functioning
patients who were followed over 3 years and patients who
Grip strength (kg) 0.72 0.99 0.97
dropped out, died, or underwent HSCT (data not shown).
a b Results from the sensitivity analysis with imputed data for
Chair stands/min 0.002 0.018 0.010b
patients who were still alive but who missed one or more
6-min walk 0.32 0.32 0.27
distance (ft) study visits were similar to results from our primary ana-
a
lysis (Supplemental Table 4, Supplemental Fig. 2).
Females had greater improvement over time than males
b
Younger patients had greater improvement over time than older
patients
Discussion

Recovery of QOL and physical function by age and
gender
Analysis of recovery stratified by median age (52 years;
younger vs older) showed that recovery in neither global
QOL nor any QOL subdomain was different by age (all p
interaction > 0.05, Table 3). Recovery in PPMs (grip strength
and 6MWT) did not significantly differ by age (pinteraction >
0.05, Table 3) whereas timed chair stands did differ
(younger patients had significantly greater recovery,
pinteraction = 0.018, Table 3).
In this study, n = 17 (24%) patients (age 60+ years) and
n = 54 (76%) were aged <60 years. Analysis of recovery by
age group (<60 years vs. 60+ years) showed that recovery
in neither global QOL nor any QOL subdomain was dif-
ferent by age-group (all P interaction > 0.05, Table 3).
Recovery in physical function (grip strength and 6MWT)
also did not significantly differ by age-group (P interaction >
0.05, Table 3) whereas timed chair stands did differ by age-
group (<60 years age group had significantly greater
recovery, P interaction = 0.010, Table 3).
QOL and objective physical function results stratified by
gender are shown in Table 4 and Fig. 2. Global QOL
recovery was observed to be numerically lower in female
survivors compared to male survivors (72% vs. 87% at 3
In this prospective, longitudinal study, we investigated
recovery of QOL and physical function over 3 years in
AML survivors who had completed IC and remained in
complete remission. We found that QOL scores fully
recovered for a large majority of AML survivors, however
objective measures of physical function had limited to no
improvement over 3 years. For the most part, recovery in
QOL did not differ by age or gender, although women and
older adults both had less recovery in lower extremity
function compared to men and younger adults. These
findings provide a greater understanding of long-term
recovery after IC for AML and are thus important for
clinicians and patients.
Very few studies have reported the treatment impact of
AML on long-term QOL. Published studies of AML sur-
vivors include short follow-up, or feature small sample sizes
[9, 10, 34–39]. Our previous study reported on QOL in the
first year after diagnosis [9]. The current study includes a
much longer follow-up over 3 years and focuses, for the
first time, on recovery by comparing outcomes with popu-
lation normative data. Health-related QOL and other
patient-reported outcomes are crucial for a comprehensive
evaluation of treatment effectiveness [34]. Compared with
European normative data, global QOL recovered in a large
majority of both male and female AML survivors over 3
Long-term recovery of quality of life and physical function over three years in adult survivors of. . .

Table 4 Proportion of patients

Measurement (n (%)) Baseline 12 months 18 months 24 months 30 months 36 months
who achieved recovery (within
one MCID unit of normative Patient-reported outcomes
values) by gender
Global health/QOL Male 6 (22) 22 (79) 19 (70) 18 (69) 18 (86) 20 (87)
(MCID = 10 points) Female 9 (24) 27 (68) 24 (67) 25 (65) 25 (78) 24 (72)
Physical functioning Male 15 (54) 25 (89) 17 (65) 18 (69) 19 (91) 21 (88)
(MCID = 10 points) Female 22 (59) 24 (60) 21 (66) 21 (57) 23 (72) 23 (72)
Role functioning Male 5 (18) 21 (75) 19 (70) 17 (65) 17 (85) 20 (83)
(MCID = 10 points) Female 11 (28) 22 (55) 25 (69) 26 (70) 25 (78) 23 (70)
Emotional functioning Male 17 (61) 21 (75) 19 (70) 17 (65) 17 (85) 20 (83)
(MCID = 10 points) Female 18 (46) 28 (70) 25 (71) 22 (58) 27 (87) 25 (76)
Cognitive functioning Male 18 (64) 20 (71) 19 (70) 20 (80) 15 (71) 14 (58)
(MCID = 10 points) Female 17 (44) 17 (43) 12 (33) 19 (50) 14 (44) 18 (55)
Social functioning Male 6 (21) 20 (71) 19 (73) 18 (69) 15 (71) 19 (83)
(MCID = 10 points) Female 9 (24) 21 (54) 21 (60) 20 (54) 21 (66) 22 (69)
FACT-F score (/52) Male 9 (32) 21 (78) 19 (70) 18 (75) 18 (90) 21 (91)
(MCID = 4 points) Female 12 (32) 22 (61) 26 (72) 21 (58) 24 (73) 22 (67)
Physical functioning
Grip strength (kg) Male 16 (55) 15 (54) 16 (57) 13 (52) 12 (60) 13 (57)
(MCID = 4.5 kg) Female 19 (49) 19 (48) 18 (43) 15 (41) 17 (53) 16 (50)
Chair stands/min Male 5 (19) 13 (48) 12 (50) 15 (65) 10 (50) 13 (65)
(MCID = 3.4 s) Female 10 (30) 16 (41) 20 (59) 18 (51) 16 (55) 17 (63)
6-min walk distance Male Not done Not done 2 (9) 2 (9) 3 (15) 3 (16)
(ft) Female Not done Not done 3 (9) 5 (14) 5 (16) 5 (19)
(MCID = 54 m or
177.2 ft)
Note: Recovery on an outcome for an individual was defined as reaching a value within the minimum
clinically important difference (MCID) of that individual’s normative data on the outcome at that time point.
The MCID represents the minimum change in a given measure that would be perceptible to the average
patient. Numbers in each cell represent the number (and percentage) of individuals who recovered at that
time point

years. Among the QOL domains, physical, emotional and
role function recovered over 3 years in both male and
female survivors.
Previous studies suggest that patients generally return to
a satisfactory level of physical well-being, psychological
and emotional states [35, 37–41] However, prior studies
have not reported the long-term recovery of QOL and
physical function by comparing to population normative
data. We extended this prior literature by analyzing recov-
ery compared to normative data.
In this study we observed differences between recovery
defined by subjective measures and by objectively mea-
sured physical function in AML patients. A large majority
of AML survivors reported long term recovery using sub-
jectively measured quality of life, however, objective
measures show much poorer recovery among AML survi-
vors over 3 years. A meta-analysis by Cooper et al (2010)
reported that objective measures are better predictors of
long-term outcomes such as disability and mortality [42].
Our results suggest that subjectively measured (i.e., using
self-reported measures) recovery may have overestimated
true recovery, whereas objective measures show relatively
poor physical recovery over 3 years. This is one of the key
clinically relevant findings of our study, and suggests that
clinicians and researchers may be overestimating the
recovery of survivors of AML if only self-report (either in a
clinical interview or using validated questionnaires) is used.
In the present study self-reported cognitive functioning
was observed to have the lowest level of recovery among
long-term AML survivors. This has not been reported pre-
viously in this setting but suggests the presence of persistent
cognitive side effects after IC. However, our study did not
include any measures of objective cognitive functioning.
This is an important area for future research, since the
correlation of subjective and objective cognitive functioning
is modest in cancer survivors and cognitive impairment is a
common side effect of chemotherapy [43].
Fatigue appeared to improve slightly over 3 years (68%
recovery at 1 year and 77% at 3 years). Fatigue is one of
the most common symptoms, and both quantitative and
qualitative data have confirmed fatigue to be the most
common symptom among those recently diagnosed with

Fig. 2 Proportion of patients with recovery in QOL over 3 years by
gender Note: Recovery is considered reaching a value less than
10 points (the minimum clinically important difference) of the
AML [20, 44, 45] However, none of the studies examined
long-term recovery among AML patients. Our findings
confirm the importance of persisting fatigue in AML sur-
vivors. This is important for clinicians to recognize, since a
growing number of evidence-based therapies for cancer-
related fatigue exist [46].
Physical function recovery was significantly lower than
QOL recovery among AML survivors over 3 years. Lower
body strength worsened over time, whereas grip strength
and 6MWT distance remained relatively stable. Although
there are no published data on recovery of objective phy-
sical function in AML, prior literature suggests that cancer
and treatment-related toxicity can impact on physical
function not only during treatment, but also during recovery
following disease remission [47]. Published data also sug-
gest that declines in physical function in the first two years
after a breast cancer diagnosis are associated with mortality
[48]. Another study also reported an association between
physical function and early mortality among long-term
cancer survivors [49]. Importantly, reviews have suggested
that a physical exercise program during induction
N. Timilshina et al.
normative value for all quality of life scales except for the Functional
Assessment of Cancer Therapy Fatigue subscale (FACT-F), for which
it is 4 points
chemotherapy can be beneficial to physical function
recovery, especially reducing fatigue and distress [34, 35].
Multiple studies in other cancer sites both during and after
active treatment have also demonstrated improvements in
fatigue with exercise [50–54]. Collectively these data sug-
gest more attention needs to be paid to encouraging regular
exercise among AML survivors.
Recovery in objectively measured physical function was
strikingly poor, for example on the 6MWT. The 6MWT is a
submaximal aerobic capacity measure, is easy to use in
clinical trials and in rehabilitation settings, and can therefore
be used as a good measure for recovery in patients with
AML. The literature from breast cancer documented the
impact of treatment on fitness using the 6MWT as a sur-
rogate for formal exercise testing [55].
A previous study measured short-term changes in phy-
sical and cognitive function and emotional well-being of
older adults (aged 60 and older) receiving intensive che-
motherapy (IC) for AML. Outcomes were examined within
8 weeks after hospital discharge after IC [56]. This study
found that short term survivors of IC for AML had clinically
Long-term recovery of quality of life and physical function over three years in adult survivors of. . .

Note: 6-Minute Walk Test (6MWT) was not measured at 12 months

Recovery is considered reaching a value less than the minimum clinically

important difference (MCID) of normal. The MCID for each measure is as
follows:

4.5 kg for Grip strength

3.4 seconds for med chair stands

54m (177.2 ) for 6MWT

Fig. 3 Proportion of patients with recovery in Physical function over 3 minimum clinically important difference (MCID) of normal. The
years by gender Note: 6-Minute Walk Test (6MWT) was not measured MCID for each measure is as follows: 4.5 kg for Grip strength. 3.4 s
at 12 months. Recovery is considered reaching a value less than the for timed chair stands. 54 m (177.2 ft) for 6MWT

meaningful declines in physical function whereas quality of
life remained stable or improved. These findings support the
importance of interventions to maintain physical function
during and after IC. They also support our findings that over
1–3 years after diagnosis and treatment, subjective (self-
reported) and objective function measures diverge, with the
former showing greater ‘recovery’ compared to the latter.
This study emphasized the importance of interventions to
maintain physical function during and after IC. The findings
of the current long-term recovery study show that physical
function using objective measures still remained poor over
2–3 years. This provides stronger evidence to support the
findings of a previous study by Klepin et al. [56] and
highlights the importance of interventions to maintain
physical function during and after chemotherapy. And it
emphasizes that clinicians need to be aware of this ‘adap-
tation’ by AML survivors leading to overly positive views
of QOL recovery without recognizing ongoing physical
deficits that would benefit from exercise interventions to
improve long-term function and overall survival.
In this study, patients were censored beyond the time of
transplantation, and this study therefore cannot compare
quality of life and physical function data after BMT com-
pared to intensive chemotherapy. This is an important area
for future research. Watson et al.’s (2004) study from the
UK Medical Research Council AML 10 Trial data shows
that Allogeneic BMT was observed to have an adverse
impact on most quality of life dimensions compared with
intensive chemotherapy after 1 year from the end of treat-
ment [57].
Limitations
We recognize several important limitations to our study.
First, our study was limited by both referral and selection
bias, as all our patients received IC at specialized tertiary
care centers. We also had relatively few older long-term
AML survivors. Compared to younger patients, fewer older
patients receive IC on the basis of adverse disease biology
or comorbidity, and even fewer maintain long-term remis-
sion. Given the small sample size we could not analyze data
within different ethnic and educational groups or by
socioeconomic strata, but it is reasonable to assume that
differences in QOL or physical function recovery might
exist. This is an important area for future study. Second, this
study was affected by survivorship bias, and a relatively
small number of patients completed 3-year follow-up
assessment. However, most people who withdrew prema-
turely did so due to relapse, receipt of HSCT, or death. Few
withdrew from the study for non-clinical reasons. Thus we
believe our findings fairly represent the QOL and functional
recovery of AML survivors who remain in remission for 3
years. Third, the normative data we used are not Canada-
specific, although in other settings Canadian normative

QOL data are very similar to US and European cohorts [58–
60]. Finally, our modest sample size may have led to
missing potentially important differences in recovery by age
or gender. This area would benefit from further study.
Furthermore, our final sample represented a relatively small
fraction of the original cohort [9]. Given that participants
who remain on study tend to be healthier than those who
drop out, our results may overestimate true recovery in an
unselected sample of AML survivors.
Conclusion
The vast majority of survivors of AML after successful
conventional IC achieve important and sustained improve-
ments in global QOL and its domains, as well as fatigue,
with values similar to normative data by three years after
diagnosis. Recovery is generally similar by age and gender.
However, recovery in objective physical function remained
blunted and suggests the need for physical rehabilitation.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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