PEDIATRIC ONCOLOGY 0031-3955/97 $0.00 + .

20

ACUTE LYMPHOBLASTIC
LEUKEMIA
Ching-Hon h i , MD

Childhood acute lymphoblastic leukemia (ALL), one of the first malignant

diseases for which large-scale therapeutic trials were conducted, has served as
a paradigm for cancer research for over four decades. At present, two thirds or
more of children with ALL can be cured with contemporary treatment plans
(Table 1).6*This remarkable success began with the identification of effective
antineoplastic drugs in the late 1940s and 1950s, followed by the development
of combination chemotherapy and subclinical central nervous system (CNS)
leukemia therapy in the 1960s. Refinements in the design and analysis of clinical
trials during the 1970s led to the recognition of clinical and laboratory features
that connote a poor prognosis, setting the stage for risk-directed therapy. In the
1980s, the following became clear: certain antileukemic agents, as well as cranial
irradiation, can produce serious late sequelae; many leukemias arise from non-
random cytogenetic abnormalities with therapeutic implications; intensive che-
motherapy can abolish the prognostic significance of certain adverse features;
and some cases of refractwy leukemia can be cured with allogeneic hematopoi-
etic stem cell transplantation. Together, these discoveries resulted in greater
refinement of risk-oriented therapy that, in time, advanced cure rates to their
present high levels. We recently entered the era of molecular medicine, in which
genetic probes are being used to recognize new disease categories and improve
treatment selection. Ultimately, dissection of ALL at the molecular level should
pinpoint sensitive and highly specific targets for therapeutic intervention, lead-
ing to treatments that are both safe and uniformly effective. This article empha-
sizes only recent advances in the management of childhood ALL.

This work was partially supported by grants PO1 CA 20180 and P30 CA 21765 from
the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

From the Department of Hematology/Oncology, St. Jude Children’s Research Hospital;

and the Department of Pediatrics, University of Tennessee, Memphis, College of
Medicine, Memphis, Tennessee

~ ~ ~~~~~~~

PEDIATRIC CLINICS OF NORTH AMERICA

VOLUME 44 NUMBER 4 * AUGUST 1997 831

832 PUI

EPIDEMIOLOGY

Acute lymphoblastic leukemia is the most common pediatric malignancy,

accounting for three fourths of all newly diagnosed leukemias and one fourth
of all cancers in childhood.33The incidence of childhood ALL in the United
States is approximately 3.4 cases per 100,000 children younger than 15 years of
age? with the peak incidence occurring between the ages of 3 and 4 years.i3 A
study by the Surveillance, Epidemiology, and End Results (SEER) Program,
which surveys cancer registries accounting for about 10% of the US population,
indicated a 20% cumulative increase in the incidence of childhood ALL from
1973 to 1991.Rh This finding was attributed to increased childhood or parental
exposure to environmental or occupational hazards, such as electromagnetic
fields, dietary nitrites, pesticides, and ionizing radiation, although none of these
factors have been conclusively linked to the development of ALL, to date.", 92
Part of the explanation may lie in changes in diagnostic specificity during
that survey period, resulting in recognition of not-otherwise-specified forms of
lymphoid leukemias as ALL.62 In the United States, the incidence of ALL is
higher in whites than in blacks (1.8 to 1) and in boys than in girls (1.2 to 1).
Worldwide, the frequency, age distribution, and subtypes of ALL show striking
geographic differences that could reflect variability in genetic susceptibility,
environmental factors, or 57 One study suggested an increased incidence

of infant leukemia in Greece owing to low-level intrauterine exposure to ionizing

radiation from Chern~byl?~ whereas larger investigations failed to show an
increased risk of childhood acute leukemia in regions affected by the nuclear
reactor
Numerous constitutional genetic defects (e.g., trisomy 21, congenital immu-
nodeficiency, and ataxia telangiectasia) have been linked to an increased risk of

Table 1. TREATMENT OUTCOME IN CHILDHOOD ACUTE LYMPHOBLASTIC

LEUKEMIA (ALL): RESULTS OF 11 INTERNATIONAL STUDIES

ChiIdren, Event-free Survival

Study n ( f SE), %
AIEOP ALL88 (1988-1992) 396 66.6 (2.4) at 5 y
BFM (1986-1 990) 998 72 (2) at 6 y
CCG 100 series (1983-1 989) 3465 67 (2) at 5 y
Dana-Farber 85-01 (1985-1987) 220 78 (3) at 7 y
DFW (1986-1 992) 243 66.6 (6.5) at 5 y
Dutch (1984-1 988) 291 72 (3) at 6 y
FRALLE 83 (1983-1 987) 559 57 (2) at 7 y
MRC UKALL X (1985-1990) 1612 62 (2) at 5 y
POG ALinC + T-cell +
infant protocols (1986-1990) 2404 66.4 (2.4) at 4 y
SJCRH XI (1984-1 988) 358 71% (4) at 8 y
TCCSG L84-11 (1984-1 989) 490 63.8% (3.2) at 7y

SE, Standard error; AIEOP. Associazione ltaliana Ematologia Oncologia Pediatrica; BFM, Berlin-
Frankfurt-Munster; CCG, Children's Cancer Group (Arcadia, CA); Dana-Farber, Dana-Farber Cancer
InstitutelChildren's Hospital Acute Lymphoblastic Leukemia Consortium (Boston, MA); DFW, Dallas-Ft.
Worth; Dutch, Dutch Childhood Leukemia Study Group; FRALLE, French Acute Lymphoblastic Leukemia
Cooperative Group; MRC, Medical Research Council (United Kingdom); UKALL X, United Kingdom
Acute Lymphoblastic Leukemia X; POG, Pediatric Oncology Group (Chicago, IL); ALinC, Acute Leuke-
mia in Childhood (protocol); SJCRH, St. Jude Children's Research Hospital (Memphis, TN); TCCSG,
Tokyo Children's Cancer Study Group.
From Pui C-H: Acute leukemia in children. Curr Opinion Hematol 3:249,1996; with permission.
 ACUTE LYMPHOBLASTIC LEUKEMIA 833

ALL in children.6’ However, in most instances, cases of ALL lack a plausible

causal explanation. A provocative suggestion is that childhood leukemias are
the consequence of rare, abnormal immunologic response to a common infection,
perhaps preceded by an initiating mutational event in utero.30,47 Finally, siblings
of children with ALL have a two to four fold increased risk of developing ALL
than do children in the general population, and the risk is much higher among
monozygotic twins, especially during the first few years of life. Intrauterine
metastasis through the shared placental circulation has been established as the
mechanism for the latter observation. Interestingly, a pair of identical twins
developed a late-onset concordant T-cell malignancy of monoclonal origin at 9
and 11 years of age, respecti~ely.~~This finding supports our speculation that
many ALLs arise in utero, with the most aggressive forms presenting clinically
in infants and the remainder appearing in later childhood.6L

CELL CLASSIFICATION BASED ON BIOLOGIC FEATURES

lmmunophenotype

Morphologic examination and cytochemical staining of blast cells are usu-

ally sufficient to distinguish ALL from acute myeloid leukemia; however, these
methods do not establish the cell’s immunologic subtype, a necessary consider-
ation in the comprehensive diagnosis. Most leukemic cells share features with
normal hematopoietic progenitors. By recognizing patterns of developmentally
relevant gene expression, one can classify leukemic cells according to their
normal maturation sequences. Because, with a few exceptions, cell-differentia-
tion antigens lack absolute lineage specificity, immunologic classification is usu-
ally based on reactivity with a panel of lineage-associated antibodieP (Table 2).
By this approach, ALL is broadly considered to have two lineages, B and T. B-
lineage cases can be subdivided into four distinct subtypes: early pre-B, pre-B,
transitional pre-B, and mature B ce1L6’Likewise, T-lineage ALL can be subclassi-
fied according to the stage of thymocyte differentiation or the stage of expression
65 For therapeutic purposes, however, one need
of the T-cell receptor pi-~tein.’~,
only distinguish T-cell and mature B-cell cases from those originating in B-cell
precursors.”’ Expression of ”myeloid-associated” antigens on otherwise typical
lymphoblasts has been recognized for over a decade. Although some investiga-

Table 2. IMMUNOLOGIC SUBCLASSES OF ACUTE LYMPHOBLASTIC LEUKEMIA

(ALL)
Frequency
Type Antigen Expression (%.)
Early pre-B cCD22+,CD79a, CD19+,CD22+,clg-(mu),slg- 57
Pre-B clg+(mu) 22
Transitional pre-B clg+(mu),slg’, slg-(kappa),slg-(lambda) 4
B cell slg’, slg+(kappa),or slg+(lambda) 2
T cell cCD3+,CD7+,CD5+,or CD2’ 15

”Based on 200 cases of newly diagnosed ALL studied at St. Jude Children’s Research Hospital
from 1993 to 1996.
cCD22, Cytoplasmic CD22; clg, cytoplasmic immunoglobulin; slg, surface immunoglobulin; mu,
mu heavychain protein; kappa, kappa light-chain protein; lambda, lambda light-chain protein; cCD3,
cytoplasmic CD3.
834 PUI

tors believe that myeloid-antigen positive ALL is associated with a poor

progn0sis,2~,~’~
we and others have found that this type of leukemia responds
well to contemporary risk-directed therapy.” b7, 78,I M

Genetic Features
Because gene alterations are at the base of all leukemia^,'^,^^ a cell classifica-
tion system may eventually become purely genetic. In fact, childhood ALL can
be readily classified according to specific chromosomal changes, now identified
in over 90% of cases.71Many of these abnormalities, especially the reciprocal
translocations, have been well-characterized molecularly and are thought to
have a central role in leukemogenesis. The clear correlation between nonrandom
chromosomal anomalies and blast cell biologic properties and presenting clinical
features (Table 3) attests to their prognostic significance, and hence their ultimate
worth in cell classification. Even so, there are compelling reasons to focus on
the molecular defects in leukemic cells. First, cases with clinically important
genetic rearrangements may be missed by routine karyotyping, even in centers
with a high rate of successful analysis. For example, whereas molecular re-
arrangements of the MLL gene (located at llq23) occur in approximately 80% of
infants with ALL, 60% or fewer have detectable llq23 chromosomal ab-
normalities.66,&s Second, rearrangements affecting the same chromosomal region
may involve different genes and represent clinically and biologically diverse
entities (e.g., gene rearrangements produced by the 1;19 translocation or 11q23
abnormalitie~).~~. 82 Third, molecular analyses can identify several critical submi-
croscopic genetic alterations not visible by karyotyping. In fact, TEL/”LI
fusion (also known as ETV6/CBFA2 fusi0n)9~and rearrangements of the TALI
gene2-the most common abnormality in B-lineage and T-lineage ALL,
respectively-as well as deletions of tumor suppressor genes such as ~ 2 are 6 ~ ~
generally detectable only at the molecular level. By combining cytogenetic and
molecular findings, one can successfully classify 75% or more of newly diag-
nosed ALL cases into prognostic and therapeutically relevant subgroups (Table 3).

MOLECULAR PATHOGENESIS
There are two general mechanisms of leukemia induction. The first involves
the activation of a proto-oncogene or the creation of a fusion gene with onco-
genic properties. In either case, the protein products are often transcription
factors, suggesting that alterations in master regulator proteins that control
hematopoietic growth and differentiation play a major role in leukemic transfor-
mation. Interestingly, various genetic rearrangements may exert their effects on
common signal transduction pathways. The second mechanism involves the loss
or inactivation of genes whose proteins suppress leukemia. Proto-oncogene
activation and loss of tumor suppressor genes either endow the leukemic cell
with a proliferative advantage or prevent its normal differentiation and pro-
grammed cell death. Readers are referred to several excellent reviews for more
91
detailed discussion of ALL molecular pathogene~is.’~,%,

PROGNOSTIC FACTORS AND THERAPEUTICALLY

RELEVANT RISK GROUPS
The cornerstone of the modem approach to ALL therapy has been careful
assessment of the failure risk, so that only high-risk cases are treated aggres-
Table 3. CLINICALLY AND BIOLOGICALLY RELEVANT GENETIC SUBGROUPS OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)’
~~ ~~

Estimated 5-y
Frequency Molecular Genetic Event-free
Chromosomal Abnormality (“/4 Alterations Associated Features Survival (%)
Hyperdiploidy (>50chromosomes) 27 Unknown 6-cell precursor phenotype; favorable age 80-90
(between 1 and 10 y); low leukocyte count
t(12;21)(p12-13;q22)t 21-24 . TEUAML7 fusion (also 6-cell precursor phenotype; pseudodiploidy; 85-90
known as E N 6 / favorable age (between 1 and 10 y)
CBFAP fusion)
t(1;19)(q23;p13.3) 5-6 E2MP6Xl fusion Pre-6 phenotype; pseudodiploidy; increased 70-80
leukocyte count
t(4;l l)(q21;q23) and other 1lq23 4-8 MLUAF4 fusion and CD10- 6-cell precursor phenotype; infant 20-30
translocations other MLL age group; hyperleukocytosis
rearrangements
t(9;22)(q34;ql1) 3 4 BCWA6L fusion 6-cell precursor phenotype; older age; 25-35
increased leukocyte count
t(1;14)(p34;qll) and TAL’ deletiont 3 TAL1 (SCL) CD10- T-cell phenotype; male 60-70
rearrangement predominance; hyperleukocytosis
t(8;14)(q24;q32.3), t(2;8)(ql2;q24), or 2 MYC (IgH, Ig[kappa], or B-cell phenotype; L3 morphology; male 70-80
t(8;22)(q24;qll) Ig[lambda]) predominance
t(l1;14)(p13;qll) 1 7 7 G X C R (delta) fusion T-cell phenotype; male predominance; 60
hyperleukocytosis; extramedullary disease
dic(9;12)(pl1-12;?~12) 1 Unknown 6-cell precursor phenotype; male 90
predominance
Hypodiploidy <45 (chromosomes) 1 Unknown None 20-30
and near-haploidy

‘Less common subgroups not listed.

tCryptic rearrangement requiring molecular detection.
$A local DNA deletion requiring molecular detection.
836 PUI

-
.-
a
others
(n=106)
2 40-
2
a 2o
- P<0.0001
I I I I I
0
0 2 4 6 8 10
Years From Diagnosis

Figure 1. Kaplan-Meier analysis of event-free survival according to presenting age and

leukocyte count in childhood B-cell precursor ALL cases treated in Total Therapy Study XI
(1984-1988) at St. Jude Children's Research Hospital.

sively and less toxic therapy, usually antimetabolites, is reserved for lower-risk
cases. Of the many variables that have been linked to ALL prognosis, treatment
has emerged as the most infl~ential.~~ For example, T-cell and B-cell ALL, once
associated with a dire prognosis, now have long-term response rates of 70% or
better with the use of intensive chem~therapy.~~, 83, e4, 93
Age and leukocyte count continue to be used for risk classification in
virtually every clinical trial involving B-cell precursor ALL. In a recent workshop
sponsored by the National Cancer Institute, participants agreed on a presenting
age between 1 and 9 years and a leukocyte count less than 50 X 109/L as the
minimal criteria for lower-risk ALL, with all other cases considered higher-ri~k.~~
By this standard, 60% to 70% of B-cell precursor cases would be classified as
lower-risk, with a long-term event-free survival probability of 70% to 85%; the
remaining 30% to 40% would have higher-risk disease and a survival probability
of 50% to 60% (Fig. 1).
Using genetic features, 'childhood B-cell precursor ALL can be classified
into three distinct subgroups (Fig. 2). Lower-risk ALL cases include patients
with hyperdiploidy (>50 chromo~omes),7~~ Io4 TELIAMLI fusion,51,89, 90 or the
dic(9;12).5All three genetic subgroups respond favorably to antimetabolite-based

3 4ol \
20
, 71 i 12

'I...........36i13
i
...............

''*
EA-PBX7 (n=14)

..BCR-ABL
*. ...............
**
(n=ll)

Reananged M L L (n=9)
I I I I 1
0'
0 2 4 6 8 10 12
Years From Diagnosis

Figure 2. Kaplan-Meier analysis of event-free survival according to selected genetic fea-

tures in childhood B-cell precursor ALL cases treated in Total Therapy Studies XI (1984-
1988) and XI1 (1988-1991) at St. Jude Children's Research Hospital.
 ACUTE LYMPHOBLASTIC LEUKEMIA 837

therapy. The biologic basis for the favorable prognosis of hyperdiploidy (>50
chromosomes) may stem from the tendency of hyperdiploid blasts to accumulate
increased amounts of methotrexate and its active polyglutamate metabo-
lites,10z,113
as well as the marked propensity of these cells for programmed cell
death (apoptosis)." The reason for a favorable outcome in cases with TEL/
A M L l fusion or the dic(9;12) is unknown. High-risk ALL cases are those with
rearranged MLL? 72 BCWABL fusion (Philadelphia chrornosome),2' or hypodip-
loidy (<45 c ~ ~ o ~ o s oThe ~ ~remaining
s ) . ~ ~cases, including those with the
t(1;19),8I can be classified as having intermediate-risk ALL.
The prognostic impact of age and, to a lesser extent, leukocyte count can be
explained by their association with specific genetic abnormalities. For example,
the overall poor prognosis of infants less than 12 months of age is due to the
very high frequency of MLL rearrangement in this age 88 It is well
recognized that hyperdiploidy (>50 chromosomes) ALL preferentially occurs in
children aged 1 to 9 years.79Recently, TEL/AMLl fusion rearrangements, another
highly favorable genetic abnormality, was found almost exclusively in this age
g r o ~ p . *Altogether,
~,~~ 70% of patients 1 to 9 years of age have one or the
other of these genetic abnormalities in their blast cells (Pui C-H, Unpublished
observation). Finally, rearranged MLL genes and BCWABL fusions are more
common in older children and typically are associated with high leukocyte
counts on pre~entation.~, 21, 72

CELL GROWTH AND DRUG-SENSITIVITY TESTING

The drug sensitivity of leukemic cells early in the clinical course is a

useful predictor of treatment outcome. Strategies used to assess early treatment
responsiveness include measurement of the clearance rate of circulating blasts
after single-agent or multiagent induction chemotherapy and the percentage of
bone marrow blasts during the early phase of remission induction therapy.',
26* loo Using semiquantitative polymerase chain reaction analyses or immunologic
methods, some investigators have correlated higher levels of minimal residual
leukemia in the immediate postinduction period with an increased likelihood of
relapse.14,
Recent studies suggest that leukemic cell growth in model systems has
prognostic significance in B-cell precursor ALL. In one study, patients whose
leukemic cells grew in mice with severe combined immunodeficiency had a
significantly higher relapse rate than did those whose cells failed to grow.'07 We
have found that higher rates of leukemic cell recovery after culture on stromal
cell layers confer a poor prognosis." Both systems can also be used to test the
drug sensitivity of leukemic cells. Other methods for testing drug sensitivity
include the 3-[4,5-dimethyl-thiazo1-2-yl]-2,5-diphenyltetrazolium bromide
(MTT) test, in which viable cells are identified by their ability to reduce MTT to
a colored formazan,60and the differential-staining cytotoxicity assay, in which
the staining properties of centrifuged samples of treated cells are used to distin-
guish viable from nonviable cells.9 The relative advantages and disadvantages
of these techniques remain to be established.

RISK-DIRECTED THERAPY

With the exception of B-cell ALL, which can be treated with short-term (<6
months) but very intensive chemotherapy, including high-dose cyclophospha-
mide, doxorubicin, vincristine, methotrexate, and cytarabine,'", 58, ** subtypes of
ALL require prolonged treatment for 2 to 2.5 ~ e a r s . 6Although
~ specific ap-
proaches to therapy may differ from center to center, contemporary protocols
invariably comprise four major elements: remission induction, intensification-
consolidation, prevention of overt CNS disease, and continuation of remission.
Induction treatment typically includes administration of a glucocorticoid (pred-
nisone and dexamethasone), vincristine, and L-asparaginase. The substitution of
dexamethasone for prednisone could reduce the risk of CNS relapse.40, In
theory, cancer chemotherapy would be curative if early treatment were sufficient
to eradicate malignant cells before they could acquire drug resistance. This
concept led to a successful series of clinical trials testing aggressive early therapy
with an increased number of agents, especially in patients with intermediate-
risk or high-risk ALL.* Contemporary treatment should induce complete remis-
sions in 98% to 99% of children with newly diagnosed ALL.
Most current trials specify a brief period immediately or soon after remis-
sion induction when patients receive intensification or consolidation therapy
designed to eradicate residual blast cells. This approach has been widely used
for high-risk patients and was recently credited with an improved outcome that
extended to intermediate-risk and lower-risk patients.I7,83, Io5
Effective therapy directed to subclinical CNS leukemia is an integral part of
curative treatment for ALL. Growing concern that cranial irradiation can cause
significant neurotoxicity and occasional brain tumors, especially in girls and
young children,18,63, 97, *lo has led many leukemia therapists to replace this mo-
dality with additional doses of intrathecal chemotherapy and more intensive
systemic treatment. Two recent studies suggested that this strategy is effective
in eradicating subclinical CNS leukemia, even in patients with intermediate-risk
or high-risk leukemia.20,35 Currently, cranial irradiation is reserved for patients
who have CNS leukemia at diagnosis or other very high-risk features (eg.,
hyperleukocytosis and Philadelphia chromosome).
Although continuation treatment with standard methotrexate and 6-mercap-
topurine secures long-term disease-free survival in most children with B-cell
precursor ALL, higher-risk cases and those with T-cell ALL benefit from more
aggressive therapy.70 Recent improvement in the outcome of such cases was
attributed to intensive use of L-asparaginase and doxorubicin in the Dana-Farber
85-01 to the introduction of high-dose methotrexate (5 g/mZ as a 24-
hour infusion) in the Berlin-Frankfurt-Miinster 86 ~ t u d y , "and~ to the addition
of the epipodophyllotoxins, cyclophosphamide and cytarabine, in the St. Jude
study Despite numerous innovations in postremission treatment, patients
with the Philadelphia chromosome and high leukocyte count,'2 and those with
the MLL rearrangement: 72 continue to have a dismal prognosis. Ongoing stud-
ies are testing the efficacy of allogeneic stem cell transplantation for this subset
of patients.

TREATMENT FOR RELAPSE

The bone marrow remains the most common site of relapse in ALL; in other
sites, such as the CNS and testes, the frequency of leukemia relapse has de-
creased to 5% or less. Available data suggest that for patients who develop
hematologic relapse on therapy or shortly thereafter, allogeneic hematopoietic

*References 13, 20, 27, 83,87, 93, and 101.

 ACUTE LYMPHOBLASTIC LEUKEMIA 839

stem cell transplantation is the treatment of choice,52,Io8 and that autologous

transplantation offers no substantial advantage over chemotherapy as postinduc-
tion treatment.6 For patients without histocompatible related donors, matched
unrelated transplantation is a reasonable option and has yielded some encourag-
ing results.22The efficacy of remission retrieval therapy for patients with an
isolated CNS relapse depends largely on whether they have received prior CNS
irradiation. Intensive chemotherapy and craniospinal irradiation can be expected
to secure long-term second complete remissions in about two thirds of the
previously unirradiated g r o ~ p . 485~ .Among patients with earlier exposure to
prophylactic radiation, this rate generally does not exceed 30%, even when
intensive chemotherapy and CNS irradiation are used to retrieve remis~ions.~~
Hematopoietic stem cell transplantation offers a reasonable option, especially if
the child has received intensive systemic therapy before relapse. Historically,
one third of patients with early testicular relapse and two thirds with late
recurrences in this site became long-term survivors with salvage chemotherapy
and bilateral testicular irradiati~n.~" Whether this experience can be extrapo-
lated to children who have received contemporary intensive treatment remains
uncertain. It will be difficult to test the efficacy of transplantation versus chemo-
therapy in a randomized trial because increasingly smaller numbers of patients
are relapsing in the testes.

LATE SEQUELAE

Each year approximately 1500 childhood ALL patients in the United States
become long-term survivors of their disease, emphasizing the need for a better
understanding of the pattern and magnitude of late complications. This informa-
tion is important not only to pediatric oncologists developing new protocols,
but also to primary physicians who care for these patients in their later life.
Few complications are as devastating as a second cancer, especially brain
tumors or acute myeloid leukemia. Children who received cranial irradiation at
5 years of age or younger are most susceptible to the development of brain
tumors.53, Acute myeloid leukemia has been linked to intensive treatment
with the epipodophyllotoxins (teniposide and etoposide), with the risk of disease
development apparently depending on treatment schedule and the concomitant
use of other agents.75,77
Treatment with the anthracycline components has been associated with
cardiomyopathy, especially when these agents are given to young girls at high
cumulative doses.47, Cranial irradiation has been implicated in a number of
late sequelae other than the development of brain tumors, including neuropsy-
chological deficitsI8,97, and endocrine dysfunction resulting in obesity, short
stature, precocious puberty, and osteoporosis.Z8,
38, w, 69,96 In general, these compli-
cations are seen in girls more often than in boys, and in young children more
often than in older ones. Many children with profound growth retardation due
to leukemia or its treatment are receiving growth hormone replacement therapy.
Recent emphasis on the intensive use of methotrexate and glucocorticoids has
led to an increased frequency of neurotoxicitp 115 and aseptic necrosis of
respectively, underscoring the need for judicious use of even seemingly benign
agents. As newer and more intensive regimens enter clinical trials, close monitor-
ing for long-term side effects will assume even greater importance, as indicated
by the numerous complications associated with allogeneic hematopoietic stem
840 PUI

cell transplantation, with or without total-body irradiation.* Effective counseling

and early psychoeducational intervention are also needed because adult survi-
vors of childhood ALL are at risk of emotional disturbance and unemploy-
ment.lI9
To close on a positive note, there have been no indications of increased
birth defects or cancers among offspring of adult survivors of childhood
ALL.32, 16. 37.42

SUMMARY

Advances in the molecular and immunologic characterization of leukemic

cells have greatly aided the diagnosis and risk assignment of ALL, as well as
the monitoring of bone marrow samples for minimal residual disease. Currently,
75% of childhood cases have biologically and therapeutically relevant genetic
abnormalities. Although gene discoveries in ALL have not been directly trans-
lated into effective therapy, there is every reason to believe that this disease will
eventually yield to molecular intervention.", 91 In the meantime, efforts are
being made to enhance the efficacy of existing regimens while reducing their
toxic side effects. We have learned, for example, the following: high-dose metho-
trexate is more effective than lower-dose methotrexate, especially for T-cell
ALL50,Io2; patients who need drastic adjustment of mercaptopurine dosage due
to thiopurine S-methyltransferase deficiency can be prospectively identified1I8;
dexrazoxane (ICRF-187)could reduce anthracycline cardiotoxicity1I2;granulocyte
colony-stimulating factor can shorten hospital stays for febrile neutropenia after
intensive remission induction therapy6R;and prolonged low-dose epipodophyllo-
toxin treatment may reduce the risk of therapy-induced acute myeloid leukemia
without compromising treatment efficacy.I6 The challenge now is to identify
specific treatments for genetically defined subtypes of ALL.

References

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outcome in children with T-cell acute lymphoblastic leukemia. Cancer 75:1684, 1995
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majority of patients with T-cell acute lymphoblastic leukemia? A Pediatric Oncology
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3. Bearman SI: The syndrome of hepatic veno-occlusive disease after marrow trans-
plantation. Blood 85.3005, 1995
4. Behm FG, Raimondi SC, Frestedt JL, et a1 Rearrangement of the M L L gene confers a
poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting
age. Blood 87:2870, 1996
5. Behrendt H, Charrin C, Gibbons B, et al: Dicentric (9;12) in acute lymphocytic
leukemia and other hematological malignancies: Report from a dic(9;12) study group.
Leukemia 9:102, 1995
6. Borgmann A, Schmid H, Hartmann R, et al: Autologous bone-marrow transplants
compared with chemotherapy for children with acute lymphoblastic leukaemia in a
second remission: A matched-pair analysis. Lancet 3462373, 1995
7. Borgstrom 8, Bolme P: Thyroid function in children after allogeneic bone marrow
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 ACUTE LYMFHOBLASTIC LEUKEMIA 841

8. Borowitz MJ, Shuster JJ, Land VJ, et al: Myeloid-antigen expression in childhood
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Address reprint requests to

Ching-Hon Pui, MD
Department of Hematology/Oncology
St. Jude Children’s Research Hospital
332 North Lauderdale Street
Memphis, TN 38105