Acute leukemia is the most common childhood malignancy, representing 30% of all

cancer in American children under the age of 15 years and 12% of cancer cases in those
ages 15 to 19 years old. In the United States, approximately 2500 new cases are
diagnosed annually; 80% of these are acute lymphoblastic leukemia, 15% are acute
myelogenous leukemia, and 5% belong to the chronic leukemia category. 1 The survival
rates of children with acute leukemia have increased dramatically in the last 40 years. 2-5
The most success in outcome has occurred in acute lymphoblastic leukemia, although
improvement is also being reported in acute myelogenous leukemia in the past f e w years.
Progress comes from treatment strategy modifications on the basis of observations made
in sequential large-scale therapeutic trials, an approach tha't serves as a paradigm for
research in other malignant diseases.

.11.

Acute Lymphoblastic Leukemia

Ka Wah Chan, MD

he incidence of childhood acute lymphoblastic
leukemia (ALL) in the United States is approx-
imately 3.4 cases per 100,000 children younger
than 15 years of age, with the peak incidence occur-
ring between 2 and 5 years of age. It is more common
in males and in whites. The incidence of ALL and of
the leukemia of infancy, but not other types of leuke-
mia in childhood, increased in the past two decades,
a change that appears to affect white children only.
Other than prenatal exposure to ionizing radiation and
specific genetic syndromes such as Down syndrome
and ataxia telangiectasia, little is known about the
cause of ALL. Epidemiologic studies so far have
failed to implicate any environmental factor (including
electromagnetic fields, radon exposure, pesticides, and
maternal smoking) as causative for this disease. 6"7
The clinical manifestations of childhood ALL are
protean. Symptoms and signs reflect the effects of
dysfunctional hematopoiesis (anemia, abnormal white
cell counts, fever, thrombocytopenia), and clonal pro-
From the Division of Pediatrics, The University of Texas MD Anderson
Cancer Center, Houston, Texas.
Curt Probl Pediatr 2002;32:40-49.
Copyright © 2002 by Mosby, Inc.
0045-9380/2002/$35.00 + 0 53/1/121790
doi:10.lO67/mps.2002.121790
liferation and infiltration of the leukemia cells (lymph-
adenopathy, hepatosplenomegaly, and bone pain).
These features are nonspecific in nature, and none is
found in more than two thirds of the patients. How-
ever, the constellation of abnormal findings should
raise the suspicion and prompt the ordering of labora-
tory testing. Ultimately a marrow aspirate is required
to establish a definite diagnosis.
Because a broad spectrum of peripheral blood ab-
normalities can be found at diagnosis, some common
pitfalls should be avoided. For example, not all pa-
tients have elevated blood counts; only half of the
patients have a leukocyte count of more than 10,000/
/zL. Thrombocytopenia is often present although
rarely as an isolated finding. Idiopathic thrombocyto-
penic purpura (ITP), a fairly common condition affect-
ing young children, is an important differential diag-
nosis of childhood ALL. This condition may even be
associated with an increase in the proportion of "im-
mune" lymphocytes in the peripheral blood. However,
a normal hemoglobin and differential leukocyte count,
and absence of hepatomegaly and lymphadenopathy
(splenomegaly may occur in ITP) should be reassur-
ing. The practice guidelines from the American Soci-
ety of Hematology suggested that a bone marrow
examination is not necessary in the initial workup of
ITP. s

40 Curr Probl Pediatr, February 2002

Biologic Features of ALL
Morphologic and Cytochemical Classification
The morphologic and cytochemical features of acute
lymphoblastic leukemia are not pathognomic. The
French-American-British working group had previ-
ously subdivided ALL into 3 types: L1, L2, and L3.
Although early trials suggested that L2 structure is
associated with a poorer prognosis, this distinction has
disappeared as more intensive therapy has been
used. 5"9 The L3 designation describes lymphoblasts of
mature B-cell stage that require a different treatment
strategy, namely therapy specifically for the Burkitt's
type lymphoma.
Immunophenoh/ping
Leukemia is a clonal disease resulting from the
genetic mutation and transformation of a single hema-
topoietic progenitor cell during its process of normal
maturation. Therefore the phenotypic characteristics
of the malignant population reflect the expression of
lineage-associated antigens of that stage. Approxi-
mately 85% of cases of ALL belong to the B-cell
lineage. Of these, 2% to 3% are mature B-cell ALL
that express surface immunoglobulin and are CD 20+.
Another 20% to 30% of cases have a pre-B-cell
phenotype: presence of cytoplasmic, but not surface
immunoglobulin. This represents an intermediate
stage of B-cell differentiation. The rest of the cases
belong to the early pre-B-cell type (B-precursor ALL).
They lack immunoglobulin expression but can be
identified by the common ALL antigen (CD10) and
terminal deoxynucleotidyl transferase (CD19) positiv-
ity. Likewise, the 15% of ALL derived from the T-cell
lineage reflects the stages of thymic differentiation.
Most cases are from the early thymocyte stage; this is
different from T-cell lymphoma, which tends to dem-
onstrate an intermediate or a mature phenotype. T-cell
ALL is most commonly found in teenage males with
leukocytosis, meningeal involvement, and mediastinal
lymphadenopathy. Once associated with a poor prog-
nosis, this subtype of ALL now has a prognosis equal
to that of B-cell precursor disease when treated with
appropriate risk-directed therapy. ~° With sensitive
monoclonal antibody technology, leukemia cells can
often be shown to express markers of different hema-
topoietic lineages. Between 7% and 25% of cases of
otherwise typical ALL also express myeloid markers.
With modem chemotherapy regimens, the presence of
CUrT Probl Pediatr, February 2002
this phenomenon does not appear to carry any prog-
nostic implication. Jl
Cytogenetics
A number of nonrandom genetic abnormalities have
been identified, and they bear significance in the
pathobiologic condition of childhood ALL. t2 The
advent of fluorescent in situ hybridization and molec-
ular diagnostic techniques has allowed more sensitive
and accurate detection of these genetic aberrations.
For example, it has recently been recognized that the
most common cytogenetic abnormality in childhood
ALL is the cryptic translocation t(12;22), not detect-
able by routine karyotyping analysis. ~3 This abnormal-
ity confers a good prognosis, as does hyperdiploidy
with 51 to 65 chromosomes. The numeric increase
most often affects chromosomes 4, 10, 17, and 21.12 In
the leukemia cells of these patients, intracellular ac-
cumulation of methotrexate polyglutamates is in-
creased, which results in prolonged retention of the
antifolate activity of methotrexate. ~4 The leukemia
cells also have a propensity to undergo apoptosis. ~5
Both of these cytogenetic subtypes of ALL are more
frequently found in children between 2 and 9 years of
age and are associated with a low leukocyte count.
These are also favorable prognostic factors and may
account for the high cure rate in these patients. On the
other hand, hypodiploidy with less than 45 chromo-
somes, particularly 24 to 28 chromosomes (near-
haploidy) is a significant adverse risk factor in spite of
contemporary intensive therapies. 16
A number of structural abnormalities of the chromo-
some band 1 lq23 have been identified, most of which
convey a worse prognosis. ~7 Seventy percent of in-
fants with ALL TM and 85% of those with secondary
leukemia after epipodophyllotoxin exposure have this
abnormality ~9 and carry a dismal prognosis. Other
children with this cytogenetic aberration have the
same prognosis as those in the same risk category.
Other cytogenetic features that portend a poor prog-
nosis and require different therapy are the transloca-
tions involving protooncogenes on chromosome 8, 9,
and 22. The hallmark of mature B-cell ALL is the
translocation of the MYC protooncogene from chro-
mosome 8 to an immunoglobulin gene, either the
heavy chain on chromosome 14 or the light chains on
chromosome 2 and 22, respectively. Patients with
B-cell ALL fare poorly with conventional ALL ther-
apy but have an 80% event-free survival rate when
41
TABLE 1. Prognosticfactors for childhood ALL
Age
WBC
Sex
Race
Fulky disease"
Extramedullary leukemia"
Morphology (FAB)"
Immunophenotype"
Cytogenetics
Hyperdiploidy (54-68 chromosomes)
Response to early treatment
(Day 7 or 14)
"Prognosticvalue modifiedby treatment.
treated with 3 to 6 months of rapid-sequence, intensive
chemotherapy. 2°
The Philadelphia (Ph) chromosome, with its t(9:
22)(q34;ql 1) translocation, is found in 3% to 5% of
childhood ALL and about 20% of adult ALL. The
translocation process leads to the juxtaposition of the
ABL and the BCR genes and the production of a
fusion protein (p185) with tyrosine kinase activity. It
is associated with a less than 20% disease-free survival
rate, even with intensive conventional chemothera-
py.2~ Allogeneic hematopoietic stem cell transplanta-
tion has recently been identified as the only current
therapy that has altered the long-term outcome of this
type of ALL.
Another translocation of prognostic significance is
the translocation t (l:19)(q23;p13) found in 25% of
cytoplasmic immunoglobulin M-positive pre-B-cell
ALL. 22 It is the most common cytogenetic abnormal-
ity of this subtype and is associated with a high
incidence of treatment failure if treated with a protocol
based on the patent's age and white blood cell (WBC)
count alone. However, intensification of chemotherapy
has improved the outcome of this subset of patients to
a rate similar to those without the cytogenetic abnor-
malities.
Principles of Risk-directed Therapy
Childhood ALL is a heterogeneous disease. A num-
ber of host-related and disease-related prognostic fac-
tors have been identified (Table 1); however, the
predictive strength of many of the original factors has
been overcome by modern programs of chemotherapy.
The type of treatment has emerged as one of the most,
42
Favorable Unfavorable
1-9 yrs <1, >10 yrs
<50,O00/#L >50,O00//~L"
Female Male
White Black, Hispanic
Absent Present
Absent Present
Lz L2, L3
B-Precursor B, T
t(12:21) Hypodiploidy (<45 chromosomes)
Philadelphia chromosome
11q23
t(1:19)"
Rapid Slow"
if not the most, important prognostic factors and is the
only one that can be modified. The current therapeutic
approach is stratification according to risk factors at
diagnosis and early changes in therapy for those who
do not respond well to induction. The concept of
altering therapy for patients who respond slowly, on
the basis of laboratory findings during the first 7, 14, or
28 days of induction therapy, has become a standard
practice and is described further in the Treatment
Strategies section b e l o w . 5"23"24 This principle applies
to all subgroups of ALL, with the exception of mature
B-cell-ALL, for which patients are treated with short-
term (less than 6 months) regimens of intensive
chemotherapy. On the other hand, the distinction of
"lymphoma/leukemia" syndrome (for patients with
bulky lymphadenopathy and massive hepatospleno-
megaly) has been dropped, and patients are treated
with identical risk-directed protocols.
There is no international consensus about risk as-
signment, and various groups have used different and
overlapping risk classification schema for treatment
decisions. As a result, it is often difficult to compare
outcome data from one group with another. The
National Cancer Institute sponsored a risk classifica-
tion workshop in 1993, and an agreement was reached
to use age and WBC count at diagnosis as the starting
point for risk assignment and reporting. 25 Children
ages 1 through 9 and with WBC count <50,000/~L
are considered to be at standard risk. This constitutes
about two thirds of all cases and has an estimated
event-free survival rate of more than 80%. The rest of
the patients (those younger than 1 year or older than 10
years of age or with a WBC count >50,000//zL)
belong to the high-risk group. They also generally
Curr Probl Pediatr, February 2002
have unfavorable cytogenetic and immunophenotypic
characteristics. Some, but not all, staging classifica-
tions also include genetic markers such as chromo-
somal analysis and leukemia cell DNA index to further
determine risk assignment.
Treatment Strategies
The standard elements of ALL treatment include
remission induction, prevention of leukemic infiltra-
tion of the central nervous system, and prolonged
maintenance therapy (for 2 to 3 years). This basic
approach has remained essentially unchanged for more
than 30 years, but a number of modifications have
been incorporated that account for the steady improve-
ment of treatment outcome. Current emphasis is fo-
cusing on intensification of chemotherapy in the early
postremission period on the premise that early and
extensive reduction of the leukemic burden will fore-
stall the development of drug resistance.
Induction
With a glucocorticoid, vincristine, and L-asparagi-
nase, with or without daunorubicin, all but 1% to 3%
of children with ALL achieve morphologic marrow
remission after 4 weeks. Early rapid response as
assessed by the rate of clearance of circulating or bone
marrow blasts after only l to 2 weeks of single-agent
or combination chemotherapy has a much better pre-
dictive value of long-term outcome than does response
after 4 weeks. Schrappe et a126 showed that among
patients with >1000 blasts//xL of blood after l week
of steroids and l dose of intrathecal methotrexate
event-free survival was 43% points lower than among
the "early responders." Similarly, patients with >25%
blasts in the bone marrow 7 days from the beginning
of treatment have a 5-year event-free survival rate of
only 42%. 24 These observations led to the strategy of
modifying treatment intensity according to the "early
response" criterion.
Central Nervous System Preventive Therapy
Treatment directed to eradicate occult leukemia cells
in the central nervous system (CNS) early after remis-
sion reduces the incidence of recurrence in this site.
Preemptive cranial irradiation is effective but produces
long-term adverse neurodevelopmental and endocrine
sequelae. A reduction of the dose of cranial irradiation
from 24 Gy to 18 Gy was equally effective, but
unfortunately modification did not prevent these late
Curr Probl Pediatr, February 2002
complications. 27 Intrathecal administration of one or
more chemotherapeutic agents at regular intervals
throughout the duration of leukemia therapy have been
shown to be as efficacious as radiation for CNS
prophylaxis. 28"29 It is also apparent that the CNS
relapse rate is, in part, dependent on the intensity of
concurrently administered systemic therapy. 3° For ex-
ample, high-dose intravenous methotrexate and cytar-
abine penetrate into the spinal fluid and help to control
leukemia cells in this and other sanctuary sites. Use of
dexamethasone instead of prednisone during induction
improved event-free survival rates and affords better
CNS protection. 3~ This is attributed to dexametha-
sone's longer half-life, increased affinity for steroid
receptors, and better CNS penetration. Cranial irradi-
ation is now reserved for patients with overt CNS
infiltration at diagnosis, or other very high-risk fea-
tures (eg, extreme hyperleukocytosis, and presence of
the Philadelphia chromosome, slow response to initial
therapy). The overall rate of relapse in the CNS is now
less than 5%. 28"29
The definition of CNS leukemia has also been a
point of controversy because of morphologic distor-
tion of white blood cells in the cerebrospinal fluid.
Five or more white blood cells//xL of cerebrospinal
fluid and the presence of blast cells is generally
accepted as diagnostic. 32 With intensive systemic
therapy and CNS radiotherapy, overt CNS leukemia at
presentation no longer has an adverse prognosis,
analogous to the diminished importance of many other
prognostic factors with better treatment strategies.
Intensification
Randomized trials have shown that giving one or
more courses of rotational, multiagent chemotherapy
during the first 6 to 8 months from diagnosis signifi-
cantly reduces the risk of relapse. The approach was
first found to work in patients with high-risk fea-
tures 33'34 but subsequent studies showed that patients
of all risk categories benefited, including those with
clinical features suggestive of a high probability of
c u r e . 9"35 There is wide variation among protocols in
the choice of drugs, the dose intensity, and the timing
of intensification treatments. Some introduce this
phase immediately after remission is achieved (con-
solidation) whereas others offer intensification after
completion of a short period of intrathecal prophylaxis
and oral maintenance (delayed intensification). How-
ever, there is no definitive evidence that any specific
regimen is superior. It has been suggested recently that
43
an additional course of intensive treatment (double
delayed intensification) at 9 to 10 months after diag-
nosis may improve the outcome of patients with poor
prognostic factors such as older adolescents and slow
"early responders" during induction. 33"34
Continuation Therapy
Prolonged maintenance therapy is still an integral
part of any ALL protocols. Timed from the end of
intensification, girls require 2 years of maintenance
therapy. For boys, this duration results in a higher
relapse rate. 36 When a third year of maintenance is
included for boys, males and females have similar
outcomes. 9 Attempts to reduce the duration of treat-
ment to less than 2 years, even with aggressive
chemotherapy up front, have been unsuccessful. 37 On
the other hand, prolongation of maintenance to beyond
3 years provides no advantage. There is no evidence
that treatment intensification at this stage is any more
effective than low-dose antimetabolite therapy. How-
ever, because of the variable bioavailability of oral
agents, maintaining a low neutrophil count of 750 to
1500//zL as a surrogate of adequate drug level is
important. 38 The addition of a dose of vincristine and
a 5-day course of steroid monthly improve the overall
outcomes, 39 whereas parenteral administration of 6
mercaptopurine or methotrexate has not been shown to
confer any advantage. 4° Current research focuses on
the choice of antimetabolite (mercaptopurine versus
thioguanine) and individualization of chemotherapy
dosage on the basis of drug clearance.41
Treatment of Very High-risk Patients in First
Complete Remission
Alternative treatment strategies have been advo-
cated for certain groups of patients with very high
risk of treatment failure, defined as an anticipated
event-free survival rate of less than 40% in spite of
modern therapy. For example, allogeneic hemato-
poietic stem cell (HSC) transplantation resulted in
the best outcome in patients with Philadelphia-
positive ALL. 21 In addition it has been suggested
that the graft-versus-leukemia effect may be more
prominent in this condition.
Acute lymphoblastic leukemia in infants is com-
monly associated with hyperleukocytosis and a pro-
pensity to have meningeal disease at diagnosis. Increased
treatment intensity has not affected the prognosis of the
70% to 80% of infants who have the mixed lineage
leukemia (MLL) gene rearrangement [most often in
44
association with t (4;11)]. Other patients who do poorly
include those who take more than 4 to 6 weeks to achieve
remission, and those with near-haploidy cytogenetic
abnormalities. Allogeneic HSC transplantation has been
tried with some success in these cases. 42"43 Recent
encouraging results with matched unrelated donors
(including umbilical cord blood units) suggest this ap-
proach can be considered when a sibling donor is not
available. 44.45
Treatment of Relapse
Although the outlook of childhood ALL has im-
proved in recent years, because of its relative fre-
quency, relapsed ALL remains a major problem in
pediatric oncology. Actually the number of such cases
is comparable to the number of children with newly
diagnosed brain tumors, the second most common
malignancy in childhood. Because most of the effec-
tive antileukemic agents are given during initial ther-
apy, retrieval therapy with essentially the same drugs
has a low success rate. Duration of first remission,
intensity of original therapy, and the site of relapse
appear predictive of the duration of second remission.
Bone marrow relapse is the principle form of treatment
failure. Patients who experience a relapse within the
first 18 months of diagnosis have little to no chance of
survival with conventional chemotherapy.44'45 Even
patients who relapse more than 3 years after initial
diagnosis have an event-free survival rate of only
30%. 46,47 Patients with combined marrow and ex-
tramedullary relapse have been reported to have a
somewhat better prognosis. 48
Thirty percent of all relapses appear to be isolated to
extramedullary sites, most commonly in CNS, testic-
ular, or ocular locations. 49 The prognosis of these
patients is better than that of patients with marrow
relapse, but many do have development of subsequent
systemic disease. The outcome is worse for CNS
relapse that occurs within 18 months of diagnosis,
similar to that of marrow relapse. Patients with iso-
lated testicular relapse fare the best with an event-free
survival rates exceeding 60%. 50 Because the incidence
of testicular relapse has decreased with contemporary
intensified systemic therapy and because of the lack of
predictive value of random testicular biopsy at the
conclusion of the maintenance phase, this procedure is
no longer recommended.
Curr Probl Pediatr, February 2002
AIIogeneic HSC Transplantation
The role of HSC transplantation in ALL remains the
subject of continued debate. Because of the excellent
results of modern chemotherapy, HSC transplantation
with its associated toxicity is not indicated in first
remission, with the exceptions of the conditions dis-
cussed above. Once the leukemia has relapsed, the
prognosis is drastically different. Chemotherapy pro-
duces an event-free survival rate of only 10% for
patients with bone marrow relapse, and 25% for those
with CNS relapse that occurred within 3 years from
diagnosis. High-dose chemoradiotherapy and allo-
geneic HSC transplantation has been shown to be
more effective in preventing further leukemia recur-
rence. 4648 Most series report a better event-free sur-
vival rate for recipients of matched sibling transplants
for early marrow relapses, although its benefit is less
definite for patients with relapses occurring more than
6 months after discontinuation of therapy. 47"51 Cur-
rently most centers have reserved transplantation for
patients with late relapses only if they respond slowly
to retrieval chemotherapy.
The risk of bone marrow transplantation relates to
toxicity of the preparative regimen and the harmful
effect of graft-versus-host disease. These complica-
tions are more pronounced with unrelated and par-
tially mismatched family donor grafts, the only stem
cell source available to three quarters of the patients
needing transplantation. 52"53 A high transplantation-
related mortality rate with these donors might ne-
gate the antileukemic potential of the procedure,
leading to greater uncertainty with regard to
whether HSC transplantation as a treatment modal-
ity can alter the overall outcome of relapsed ALL. 5
Recent technologic advances in alternative donor
HSC transplantation may have improved the patient
outcome to the same extent as in the sibling donor
group. 54,55
Autologous HSC transplantation, with the patient's
stem cells harvested in remission, is an alternative for
patients without an allogeneic donor. Purging with
chemotherapeutic agents or with antibody against
leukemia-associated antigens is often performed on
the stem cell collection to reduce tumor contamina-
tion. The procedure carries a lower morbidity rate, but
evidence so far has not shown any evidence that
autologous HSC transplantation is of benefit in re-
lapsed ALL.
Curr Probl Pediatr, February 2002
Recent Advances
Monitoring of Minimal ResidualDisease
With the success of risk-directed therapy, a logical
next step is to explore the ability to identify those
patients destined to have a relapse in spite of being in
apparent morphologic remission. Techniques such as
flow cytometry (to enumerate cells expressing leuke-
mic-associated antigens) and polymerase chain reac-
tion (to examine "patient-specific" T cell or immuno-
globulin gene receptor rearrangement pattern) can
detect one leukemic cell among 104 tO 105 cells,
several logs less in magnitude than that found at frank
relapse. 56 Cave et a157 recently reported that detectable
minimal residual disease (MRD) at levels higher than
l in 100 at the end of induction was associated with a
16 times higher risk of subsequent relapse compared
with lower MRD burden. After consolidation the
breakpoint of MRD burden for increased risk of
treatment failure was l in 1000. 57 The prognostic
significance of MRD was independent of other known
risk factors for relapse. Clinical trials are being de-
signed for patients with detectable MRD at defined
time points to receive augmented therapy. MRD is
also related to the outcome of HSC transplantation for
ALL. Patients with negative, low, and high levels of
MRD immediately before transplantation had an
event-free survival rate of 73%, 36%, and 0%, respec-
tively. 58 In another study the presence of MRD in the
first 3 months after transplantation increased the like-
lihood of subsequent relapse by 9-fold. 59
Genetic Polymorphisms
Race- and sex-associated genetic polymorphisms
can affect drug metabolism and detoxification enzyme
activities. For instance, genotype variations of N-
acetyltransferase, glutathione-S-transferase, and the
cytochrome P450 system enzymes may alter chemo-
therapeutic agent disposition and account for drug
resistance and toxicity. 6° This phenomenon may ex-
plain the prognostic differences in individual patients,
as well as among racial groups and sexes. A recent
development is the screening of gene expression
profiles by use of microarray techniques to better
define the prognosis and treatment strategies for indi-
vidual patients. 61
Complications of Treatment
Complications of antileukemia treatment can be
acute or of belated onset. Advances in supportive care
45
measures have helped to reduce the mortality and
morbidity rates of ALL therapy. Platelet and erythro-
cyte transfusions are often required, and all cellular
products should be irradiated to avoid the risk of
transfusion-related graft-versus-host disease. On the
other hand, administration of granulocyte colony-
stimulating factor during the intensive phase of che-
motherapy does not significantly reduce the duration
of neutropenia, rate of hospitalization, or delay in
therapy. 62
Metabolic derangement as a result of tumor lysis is
particularly common in patients with marked leukocy-
tosis (>100,000//~L), massive mediastinal lymphade-
nopathy, and T- or B-cell disease. Urate oxidase, a
recombinant enzyme that breaks down uric acid to
allantoin has been shown to rapidly and markedly
lower uric acid levels and avoid renal insufficiency.63
However, the nephrology service should be consulted
should dialysis become necessary. Induction chemo-
therapy should not be unduly delayed waiting for the
complete correction of the metabolic abnormalities.
Infections are the most common cause of death in
remission for children with ALL. This happens during
induction and intensification phase of chemotherapy.
Prompt administration of broad-spectrum antibiotic
therapy is essential for the treatment of the patient with
febrile neutropenia (<500 granulocytes/~L). During
maintenance therapy, patients are susceptible to pneu-
monits by Pneumocvstis carinii, although the risk can
be completely eliminated by prophylactic use of tri-
methoprim-sulfamethoxazole (given on 3 sequential
days per week). Disseminated varicella is also a
serious complication of ALL therapy. Administration
of zoster immunoglobulin within 72 to 96 hours of
exposure may attenuate the severity of subsequent
infection. Acyclovir is effective in limiting the sever-
ity of an established varicella infection. Immunization
of nonimmune household contact with the live, atten-
uated varicella vaccine is encouraged. Its use in the
patient with leukemia remains controversial. Measur-
able antibody production against the virus is found,
but maintenance chemotherapy has to be withheld for
several weeks before immunization.
Late effects of disease and therapy have become
increasingly recognized in survivors of childhood
ALL. 64 The cumulative incidence of second malig-
nancy 15 years after the diagnosis of childhood leu-
kemia is low, only 1.6% in the trials of the large U.S.
national cooperative groups. This occurs as a result of
an interaction between predisposing genetic factors
46
and treatment given for the primary tumor. Solid
tumors, especially brain tumors, are the most common
second malignancies in patients with ALL. One per-
cent of patients who received cranial irradiation will
have development of a brain tumor. The latency period
is 9 years for high-grade glioma and 19 years for
meningioma. 65 Secondary AML has developed after
regimens that include topoisomerase II inhibitor (epi-
podophyllotoxin) or alkylating agents. The risk for
topoisomerase II inhibitor-induced leukemia was
shown to be related to the treatment schedule of the
offending agents and concomitant use of other
drugs. ~9 The prognosis of secondary AML is ex-
tremely poor, and only allogeneic HSC transplantation
provides any chance of cure.
The neurocognitive development and academic
achievement of childhood leukemia survivors are
lower than that of control subjects and their normal
siblings. Cranial irradiation, especially in patients 5
years of age and younger, has the most deleterious
effect on neuropsychologic development. A dose-
response relationship has been observed between re-
duction in intelligence quotient points and the dose of
irradiation. 27 On the other hand, infants exposed to a
very high dose of systemic methotrexate and intrathe-
cal chemotherapy for CNS prophylaxis showed neu-
rodevelopmental testing scores normal for age. 66 Ra-
diation-induced hypothalamic-pituitary dysfunction
results in growth hormone deficiency but can also be
associated with accelerated skeletal maturation and
epiphyseal fusion. A complex of short stature, obesity,
and precocious puberty is recognized and is particu-
larly common among girls. Although most ALL sur-
vivors have normal sexual development, gonadal dam-
age can be demonstrated in some patients. This may
become more prevalent because the total dose of
cyclophosphamide has been escalated in the more
intensive regimens. Currently there is no evidence that
offspring of patients with leukemia have an increased
risk of congenital abnormalities.
Avascular necrosis of bone, with destruction of
weight-bearing joints, is a side effect of glucocorticoid
(especially high-dose dexamethasone) treatment. 67 It
affects mainly female patients older than 10 years of
age. Magnetic resonance imaging is the most sensitive
diagnostic study for this complication. Decreased bone
mineral density and osteoporosis has been observed in
all phases of treatment up to 20 years after diagnosis. 68
This leads to musculoskeletal pain, compression frac-
tures, kyphosis, and lordosis.
Curr Probl Pediatr, February 2002
 Each year more than 1500 children in this country
become long-term survivors of childhood ALL. They
return to the community and are monitored by their
local physicians. Late side effects are common among
these survivors, and the manifestations may be subtle
and take years to develop. Careful and regular (prob-
ably life-long) surveillance of these leukemia-free
children has become essential.
References
1. Smith MA, Gloeckler Ries LA, Gurney JG, et al. Leukemia.
In: Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T,
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49