D RUG TH ERA PY

Review Article

Drug Therapy cytes are available,10 only a few of these molecules

A L A S T A I R J . J . W O O D , M. D. , Editor
A CUTE L YMPHOBLASTIC L EUKEMIA
CHING-HON PUI, M.D., AND
are truly lineage-specific. For this reason a panel of
antibodies is needed to establish the diagnosis and
to distinguish among the immunologic subclasses.
The panel used at St. Jude Children’s Research
Hospital includes at least one marker that is highly
sensitive (CD19 and CD7 for B-lineage and T-lin-
eage cells, respectively, and CD13 or CD33 for my-
WILLIAM E. EVANS, PHARM.D.
eloid cells) and one marker that is highly specific
(cytoplasmic CD79a and cytoplasmic CD3 for
B-lineage and T-lineage cells, respectively, and cyto-
plasmic myeloperoxidase for myeloid cells). On the
basis of these immunophenotypic analyses, a firm

A
CUTE lymphoblastic leukemia (ALL) is di-
agnosed in 3000 to 4000 persons in the
United States each year; two thirds of them
are children.1,2 The current rate of cure of nearly 80
percent in children attests to remarkable progress in Probability of Event-freeD 100
81±8%
the development of effective treatments for resistant XIIIA, XIIIB (n=366) 1991–1997
subtypes of the disease. Progress has been incremen- 80
Survival (%)

tal, from the introduction of combination chemo- 70±2% XI, XII (n=546) 1984–1991
60
therapy and central nervous system treatment for
53±2% X (n=428) 1979–1983
presymptomatic leukemia to newer, intensive treat-
40
ment regimens for patients at high risk for relapse 36±2%
V–IX (n=825) 1967–1979
(Fig. 1). In contrast, only 30 to 40 percent of adults
20
with ALL are cured.2,3 This discrepancy can be at- I–IV (n=90) 1962–1966
tributed in part to the higher frequency of adverse 9±3%
0
genetic abnormalities in the leukemic lymphoblasts 0 5 10 15 20 25 30 35
of adults.4-8 Here, we review advances in the classifi-
cation of lymphoblasts and in clinical management 100
that have contributed to recent gains in therapeutic
Probability of OverallD

86±6%
XIIIA, XIIIB (n=366) 1991–1997
outcome or that hold promise for the future. 80 81±2%
XI, XII (n=546) 1984–1991
Survival (%)

BIOLOGIC CHARACTERIZATION 74±2% X (n=428) 1979–1983

OF LEUKEMIC CELLS 60
V–IX (n=825) 1967–1979
ALL can develop from any lymphoid cell blocked 40 48±2%
at a particular stage of development, including prim-
itive cells with multilineage potential.8,9 In contrast 20
to acute myeloid leukemic cells, which can be readily 21±4%
I–IV (n=90) 1962–1966

identified in most instances by the presence of Auer 0

rods, myeloperoxidase, or monocyte-associated ester-
ases, leukemic lymphoblasts lack specific morpho-
logic or cytochemical features, so that the diagnosis
of ALL depends on immunophenotyping. Although
monoclonal antibodies against 166 different cluster-
of-differentiation (CD) molecules on human leuko-
From St. Jude Children’s Research Hospital (C.-H.P., W.E.E.) and
the Colleges of Medicine (C.-H.P., W.E.E.) and Pharmacy (W.E.E.), Uni-
versity of Tennessee, Memphis. Address reprint requests to Dr. Pui at St.
Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN
38105-0318.
©1998, Massachusetts Medical Society.
0 5 10 15 20 25 30 35
Years after Diagnosis
Figure 1. Kaplan–Meier Analyses of Event-free Survival (Top
Panel) and Overall Survival (Bottom Panel) in 2255 Children
with ALL in 13 Consecutive Studies Conducted at St. Jude
Children’s Research Hospital from 1962 to 1997.
The results demonstrate improvement in survival with the
introduction of therapy for subclinical disease of the central
nervous system (studies V to IX, 1967 to 1979); with early inten-
sification of systemic chemotherapy, including high-dose meth-
otrexate (study X, 1979 to 1983, and studies XI and XII, 1984 to
1991); and with reinduction treatment, early intensification of
intrathecal chemotherapy, and pulsed therapy with dexameth-
asone and vincristine (studies XIIIA and XIIIB, 1991 to 1997).
The mean (±SE) five-year survival probabilities are shown.

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 The Ne w E ng l a nd Jo u r na l o f Me d ic i ne

diagnosis can be made in 99 percent of cases. Al- RISK ASSESSMENT

though cases involving B-lineage and T-lineage cells
can be further subclassified according to the recog-
nized steps of normal B- and T-cell maturation,8 the
only distinctions with therapeutic importance are
those between the B-cell–precursor immunopheno-
type and the T-cell or mature–B-cell immunophe-
notype.
Depending on the criteria used and the number of
antigens tested, myeloid-associated–antigen expres-
sion can be detected in as many as one fourth of chil-
dren and one third of adults with ALL.7,8,11 This fea-
ture has no prognostic or therapeutic implications,11-13
but it can be useful in immunologic monitoring for
minimal residual leukemia.14 The few patients with
leukemic cells that express both lymphoid-associated
molecules (usually CD2 and CD7) and myeloid-
restricted molecules (such as myeloperoxidase) re-
quire treatment directed toward both lineages.11
Specific genetic abnormalities (e.g., chromosomal
gains or losses, resulting in hyperdiploidy or hypodip-
loidy, respectively; chromosomal translocations, lead-
ing to the formation of transforming fusion genes or
dysregulation of gene expression; and deletion or
functional inactivation of tumor-suppressor genes)
are found in the blast cells of 60 to 75 percent of pa-
tients with ALL (Fig. 2). The recognition of these
abnormalities has contributed greatly to our under-
standing of the pathogenesis and prognosis of the
disease.4,15
Although investigators agree that stringent evalu-
ation of the risk of relapse is needed at the time of
diagnosis to avert undertreatment or overtreatment,
there is considerable disagreement about risk criteria
and the terminology for defining risk subgroups. For
the purposes of this review, three categories of risk
— low, standard (average), and high — are consid-
ered. Many presenting clinical and biologic variables
initially thought to be useful predictors of outcome
have proved to be of little value as treatment has im-
proved.16 For example, patients with T-cell or B-cell
ALL, once thought to have a very poor prognosis,
now have as favorable an outcome as patients with
standard-risk B-cell–precursor ALL.2,3,12,17-22 Like-
wise, in two independent trials of more intensive
therapy,23,24 the poor prognosis previously associat-
ed with adolescent age or black race was not found.
Participants at a recent workshop25 agreed on cri-
teria for defining a low risk of recurrent disease in
children with newly diagnosed B-cell–precursor ALL:
an age of one to nine years and a leukocyte count of
less than 50,000 per cubic millimeter. Patients in oth-
er age groups or those with higher leukocyte counts
were considered to be at high risk.25 These prognostic
relations can be explained to a large extent by the
presence of specific genetic abnormalities.
For example, among children less than one year
old, in whom the prognosis is poor, 70 to 80 per-
cent have rearrangements of the MLL gene.26,27 In

HyperdiploidyD
(>50 chromosomes)D
E2A–PBX1D 6% ETV6–CBFA2D
t(1;19) t(12;21)D
2%
5% MYCD 3%
HyperdiploidyD 2% t(8;14), t(2;8), t(8;22) 4%
(>50 chromosomes)D
25% 4% TCRad 6%
14q11
3% 2% RandomD
ETV6–CBFA2D TCRbD 41%
t(12;21)D 7q35
22% 1% 4%
HypodiploidyD
(<45 chromosomes)

RandomD 6% MLL rearrangementsD 7% BCR–ABLD

28% t(4;11), t(11;19), t(1;11) t(9;22)D
25%
BCR–ABLD
t(9;22)D
4%
Children Adults
Figure 2. Estimated Frequencies of Specific Genotypes among Children and Adults with ALL.
The data are from studies at St. Jude Children’s Research Hospital4,8 and from the Groupe Français de Cytogénétique Héma-
tologique,5 Chessells et al.,6 and Copelan and McGuire.7

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 D R UG TH ERA PY

adolescent and adult patients, the frequencies of
MLL rearrangements and of BCR–ABL fusion, an-
other genetic abnormality associated with a poor
prognosis, are high.5,6,28 In contrast, two favorable
genetic abnormalities — hyperdiploidy (>50 chro-
mosomes per cell) and ETV6–CBFA2 (TEL–AML1)
fusion — occur mainly in children one to nine years
old; hyperdiploidy is associated with a low leukocyte
count as well.9,29,30
A risk-assignment system based on primary genet-
ic abnormalities has great intuitive appeal; however,
as shown in Figure 3, the predictive value of these
abnormalities is not high. For example, as many as
20 percent of children with ALL who have hyper-
diploidy or the ETV6–CBFA2 fusion gene eventual-
ly have a relapse.4,29,30 A useful measure in risk assess-
ment is the rate of clearance of leukemic cells from
the blood or bone marrow during the early phase of
therapy. In patients with B-lineage or T-lineage ALL,
slow clearance of the cells has proved to be an indi-
cator of poor prognosis.18,31,32
Another approach is to use the polymerase chain
reaction or immunologic methods to measure min-
imal residual disease soon after the induction of a
clinical remission, when some patients may still have
as many as 10 billion leukemic cells.14,33,34 Patients
who have a “molecular” or “immunologic” remission,
defined as leukemic involvement of less than 0.01
percent of nucleated bone marrow cells, are predict-
ed to have a better clinical outcome than those in
whom remission is identified solely on the basis of
morphologic criteria. On the other hand, the results
of qualitative assessment of some leukemia-specific
fusion transcripts in patients in remission do not re-
liably predict subsequent relapse.35 Additional stud-
ies are needed to establish the clinical utility of de-
termining drug sensitivity and growth characteristics
of leukemic cells in vitro.36-38
We propose a risk-classification system (Fig. 4) that
considers the blast-cell immunophenotype and geno-
type along with the presenting clinical features and
degree of early responsiveness to treatment. Although
the presence of BCR–ABL fusion in leukemic cells
usually indicates high-risk leukemia warranting hem-
atopoietic stem-cell transplantation, patients with this
genetic abnormality who have low leukocyte counts
at diagnosis or good early responses to prednisone
therapy may be cured by intensive chemotherapy
alone.39,40 Patients with near-haploid or markedly hy-
podiploid leukemic cells tend to have a poor progno-
sis and, regardless of their age or initial leukocyte
count, should undergo treatment at least as aggressive
as that given to patients with standard-risk leukemia.41
Patients with B-cell–precursor ALL with MLL gene
rearrangements, especially infants with the t(4;11)
translocation and MLL–AF4 fusion, usually have a
poor response to chemotherapy.28,42 However, there
is a subgroup of patients with MLL rearrangements
who have a good response42 (Fig. 3): those with
T-cell leukemia with the t(11;19) translocation and

100
HyperdiploidyD
(>50 chromosomes)D
(n=193)
80 ETV6–CBFA2 (n=82)
Event-free Survival (%)

E2A–PBX1 (n=34)

60

BCR–ABL (n=30)
40
MLL rearrangements (n=30)

20

0
0 2 4 6 8 10 12 14

Years after Diagnosis

Figure 3. Kaplan–Meier Analysis of Event-free Survival According to Genetic Features of Blast Cells
in 369 Children with ALL Treated at St. Jude Children’s Research Hospital from 1984 to 1997.
The relatively good survival of patients with BCR–ABL fusion reflects successful treatment of a sub-
group with low leukocyte counts at diagnosis. The E2A–PBX1 abnormality, once associated with poor
survival,8 now is associated with the same favorable prognosis as the ETV6–CBFA2 (TEL–AML1)
abnormality.

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 The Ne w E ng l a nd Jo u r na l o f Me d ic i ne

T cell B-cell precursor

Other genotypes orD Hyperdiploidy (>50D

BCR–ABL fusion orD CNS or testicularD chromosomes) orD
MLL rearrangement leukemia ETV6–CBFA2 fusion

BCR–ABL fusion andD Age <1 or »10 years,D

Age 1 to 9 yearsD
leukocyte countD OtherD leukocyte countD
and leukocyte countD
>25,000/mm3 or MLLD presentations »50,000/mm3, or CNSD
<50,000/mm3
rearrangement in infants or testicular leukemia

ProvisionalD ProvisionalD ProvisionalD

standard risk standard risk low risk

Poor earlyD
response orD Good earlyD Failure ofD Poor earlyD Good earlyD Failure ofD Poor earlyD Good earlyD
failure ofD response induction response response induction response response
induction

High risk Standard risk Low risk

Figure 4. Proposed Risk-Classification System for ALL According to Immunophenotype and Genotype, Age, Leukocyte Count, Early
Response to Treatment, and Presence or Absence of Extramedullary Disease (in B-Cell–Precursor Disease).
All patients with T-cell ALL are considered to have a standard risk of relapse, except those without a good response to remission-
induction therapy. Among patients with B-cell–precursor ALL, the high-risk group is defined by the presence of the BCR–ABL fusion
gene and a high leukocyte count or a poor early response to chemotherapy induction, MLL rearrangements (in infants), or lack of
response to induction therapy. Patients with low-risk ALL have a B-cell–precursor immunophenotype with hyperdiploidy (>50 chro-
mosomes), the ETV6–CBFA2 (TEL–AML1) fusion gene, or an age of one to nine years and a leukocyte count of less than 50,000 per
cubic millimeter, with a favorable early response to chemotherapy. All other patients with B-cell–precursor ALL are considered to
have a standard risk. Antimetabolite therapy with dexamethasone and vincristine pulses is sufficient for treatment of low-risk
leukemia, whereas standard-risk leukemia requires more intensive multidrug therapy. Patients with high-risk ALL are candidates for
hematopoietic stem-cell transplantation. Gradations of color within a box indicate the estimated proportions of patients in each of
the three risk categories. CNS denotes central nervous system. Patients with mature–B-cell ALL are not included in this classifica-
tion because of their requirement for highly specialized therapy.

MLL–ENL fusion (unpublished data). Although

T-cell ALL is treated as standard-risk leukemia at TABLE 1. COMPARISON OF TREATMENT OUTCOMES ACCORDING TO
DISEASE SUBTYPE IN ADULTS AND CHILDREN WITH ACUTE
virtually all centers, patients with high leukocyte LYMPHOBLASTIC LEUKEMIA.*
counts (>100,000 per cubic millimeter) or delayed
early responses require even more intensive central
nervous system–specific therapy than do other pa- SUBTYPE ESTIMATED EVENT-FREE SURVIVAL (%)

tients with this immunophenotype.43 The presence ADULTS CHILDREN

of any leukemic cells in the cerebrospinal fluid at di- B cell (rearranged MYC ) 50–55 at 4 yr 75–85 at 5 yr
agnosis may indicate that intensive intrathecal treat- B-cell precursor†
Hyperdiploidy (>50 chromosomes) 30–50 at 3 yr 80–90 at 5 yr
ment is needed to prevent relapse of central nervous ETV6–CBFA2 (TEL–AML1) Unknown 85–90 at 5 yr
system disease.44 E2A–PBX1 20–40 at 3 yr 70–80 at 5 yr
In adults, the frequency of the BCR–ABL fusion BCR–ABL <10 at 3 yr 20–40 at 5 yr
MLL–AF4 10–20 at 3 yr 10–35 at 5 yr
gene is higher and the frequency of favorable genetic Hypodiploidy (<45 chromosomes) 10 at 3 yr 25–40 at 3 yr
changes is lower than in children (Fig. 2).2,3,5-7 Even T cell 50 at 3 yr 65–75 at 5 yr
for the same genetic subtypes of ALL, survival rates
*This analysis reflects the results of nine studies.4-12
are lower in adults than in children (Table 1). Thus,
†The four fusion genes listed here arise from the following alterations:
although several risk models have been proposed for ETV6–CBFA2, t(12;21)(p13;q22); E2A–PBX1, t(1;19)(q23;p13); BCR–
adults with ALL,2 the prevailing view is that most af- ABL, t(9;22)(q34;q11); and MLL–AF4, t(4;11)(q21;q23).

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fected adults should be considered to have a high
risk of recurrence and should be treated accordingly.
Adults younger than 30 years of age have a better
prognosis than those 30 to 59 years old, who in turn
have a better prognosis than patients who are 60 or
older.2,3,6 Adults with some types of ALL require
treatment modification: those with B-cell disease,
because of its unique sensitivity to therapy19,20; those
with Philadelphia-chromosome–positive disease, be-
cause of its resistance to chemotherapy alone5,6; those
with pre–T-cell (CD7+, CD2¡, CD5¡) leukemia,
because the response to chemotherapy is not as
good as that in patients with leukemia of a more ma-
ture T-cell phenotype7; and elderly patients, who tol-
erate treatment poorly.3
SUPPORTIVE CARE
At least half the patients with ALL present with
fever. Often the fever is induced by pyrogenic cyto-
kines released from leukemic cells, including inter-
leukin-1, tumor necrosis factor, and interleukin-6,45
but in about a third of the patients it is due to infec-
tion. Therefore, broad-spectrum antibiotic therapy
should be initiated in patients with fever, especially
those with neutropenia, until a diagnosis of infec-
tious disease has been excluded. At most centers, all
patients are treated prophylactically for Pneumocystis
carinii pneumonia with trimethoprim–sulfameth-
oxazole, given three days per week.46 Alternative
treatments for patients with intolerance to trimeth-
oprim–sulfamethoxazole include aerosolized pen-
tamidine, dapsone, and atovaquone.
In patients with B-cell or T-cell ALL or B-cell–
precursor leukemia with a large burden of leukemic
cells, hyperuricemia, hyperkalemia, and hyperphos-
phatemia with secondary hypocalcemia are common,
TABLE 2. TREATMENT STRATEGIES ASSOCIATED
STRATEGY
Fractionated high-dose cyclophosphamide,
high-dose methotrexate (3 to 8 g/m2),
and cytarabine
Intensive induction treatment with four
or more drugs
Dexamethasone for subclinical central
nervous system involvement
Intensification (consolidation) therapy
shortly after induction of remission
High-dose methotrexate (5 g/m2)
Increased exposure to systemic metho-
trexate
Reinduction treatment
Early and intensive intrathecal chemother-
apy for subclinical central nervous sys-
tem involvement
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D R UG TH ERA PY
even before chemotherapy is initiated. These pa-
tients should be given intravenous hydration, sodi-
um bicarbonate to alkalize the urine, allopurinol to
treat hyperuricemia, and aluminum hydroxide or
calcium carbonate (if the serum calcium concentra-
tion is low) to treat hyperphosphatemia. Allopuri-
nol, by inhibiting purine synthesis in leukemic blast
cells, may reduce the peripheral blast-cell count
before chemotherapy is begun.47 Nonrecombinant
urate oxidase, available in France and Italy, converts
uric acid to allantoin (a readily excreted metabolite
that is 5 to 10 times as soluble as uric acid) and
decreases the serum uric acid concentration more
rapidly than allopurinol; however, it can cause acute
hypersensitivity reactions and, in patients with glu-
cose-6-phosphate dehydrogenase deficiency, can cause
methemoglobinemia or hemolytic anemia.48
For patients with extreme leukocytosis (leukocyte
count, >200,000 per cubic millimeter), either leu-
kapheresis or exchange transfusion (in small chil-
dren) may be used to reduce the burden of leukemic
cells,49 although the short- and long-term benefits
of these procedures remain in question.50 Emergen-
cy cranial irradiation has no therapeutic role in these
patients.49,50 Other supportive care measures, includ-
ing the use of indwelling catheters and psychosocial
support, are important, but their discussion is be-
yond the scope of this review.
TREATMENT
The improved rate of cure of ALL can be attrib-
uted in large measure to the development of more
effective multidrug regimens in well-designed clinical
trials. Table 2 summarizes several treatment strate-
gies that have been found to have a particularly im-
portant effect on outcome.
WITH IMPROVED OUTCOMES IN CLINICAL STUDIES OF ALL.
TYPE OF DISEASE REFERENCE
Mature–B-cell ALL in chil- Soussain et al.,19 Hoelzer et al.,20 Reiter et al.,21 Patte 22
dren and adults
ALL in children Reiter et al.,18 Rivera et al.,51 Niemeyer et al.,52 Gaynon et al.53
ALL in children Bostrom et al.,54 Veerman et al.55
ALL in children and young Schorin et al.,17 Reiter et al.,18 Rivera et al.,51 Niemeyer et al.,52
adults Gaynon et al.,53 Veerman et al.,55 Rohatiner et al.,56 Ma-
honey et al.,57 Chessells et al.,58 Hoelzer et al.59
T-cell ALL in children Reiter et al.18
ALL in children Evans et al.60,61
ALL in children and adults Reiter et al.,18 Hoelzer et al.,59 the Childhood ALL Collabo-
rative Group,62 Tubergen et al.,63 Nachman et al.64
ALL in children and adults Reiter et al.,18 Veerman et al.,55 Cortes et al.,65 Nachman
et al.,66 Pui et al.67
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 The Ne w E ng l a nd Jo u r na l o f Me d ic i ne
At virtually all centers, patients with mature–B-cell
ALL are treated with short-term (two-to-eight-
month) regimens of intensive chemotherapy that in-
clude fractionated high-dose cyclophosphamide, high-
dose methotrexate, and cytarabine.19-22 Some studies
have suggested that the addition of ifosfamide, eto-
poside, or both to these regimens may improve the
cure rate further.20-22 In a French study of 102 chil-
dren, a seven-drug regimen including high-dose
methotrexate (8 g per square meter of body-surface
area), cytarabine, cyclophosphamide, and etoposide
led to a cure rate of 85 percent,22 a standard against
which other trial results are now measured. Because
of their poor prognosis, infants with ALL are often
considered a unique subgroup and treated with mul-
tiple drugs given at high dosages, but no cranial ir-
radiation.26
For all other patients, the basic approach to ther-
apy consists of a relatively brief remission-induction
phase, followed by intensification (consolidation)
treatment and then prolonged continuation therapy.
Treatment for subclinical leukemia of the central
nervous system is initiated early and is given for
varying lengths of time, depending on the treatment
protocol.
Induction of Remission
The first goal of therapy in patients with leukemia
is to induce complete remission with restoration of
normal hematopoiesis. The induction regimen in-
variably includes a glucocorticoid (prednisone or
dexamethasone) and vincristine, as well as asparagin-
ase for children or an anthracycline for adults.2,3,7,16
With improvements in chemotherapy and support-
ive care, the rate of complete remission now ranges
from 97 to 99 percent in children and from 75 to
90 percent in adults. Nonetheless, attempts are be-
ing made to intensify induction therapy, especially
for patients with standard-risk or high-risk disease,
on the premise that more rapid and complete reduc-
tion of the leukemic-cell burden may forestall drug
resistance in leukemic cells, leading to improvements
in long-term outcome. Indeed, intensive induction
regimens with four or more drugs have been credit-
ed with improving outcomes in several trials in chil-
dren.18,51-53 Efforts to intensify induction therapy in
adults have been limited by severe drug toxicity2,3,7;
however, in one study, high-dose cytarabine may
have preferentially improved the outcome in adults
with T-cell ALL.56 Administration of granulocyte
colony-stimulating factor may hasten recovery from
neutropenia and reduce the complications of inten-
sive chemotherapy, but it does not improve the event-
free survival rate in either children or adults.68-70
Perhaps because of its increased penetration into
cerebrospinal fluid and its longer half-life,71 dexa-
methasone, when used in induction and continua-
tion regimens, provides better protection than pred-
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nisone against relapse of central nervous system
disease in children with ALL.54,55 Three forms of as-
paraginase, each with a different pharmacokinetic
profile, are available. In one randomized trial, the
outcome in patients treated with asparaginase de-
rived from Escherichia coli was better than that in pa-
tients treated with Erwinia carotovora asparaginase,
which has a shorter half-life in plasma.7 The efficacy
of various anthracyclines in adults with ALL has
been similar.73,74
Intensification (Consolidation) Therapy
With restoration of normal hematopoiesis, pa-
tients whose disease is in remission become candi-
dates for intensification (consolidation) therapy. Such
treatment, administered shortly after the induction
of remission, includes several drugs, most often meth-
otrexate given in high doses with or without 6-mer-
captopurine18,51,55,57; asparaginase given in high doses
for an extended period17,52; an epipodophyllotoxin
plus cytarabine51,58; or a combination of vincristine,
dexamethasone, asparaginase, doxorubicin, and thio-
guanine given with or without cyclophosphamide.18,53
This phase of therapy has been credited with im-
proving outcomes, even in patients with low-risk
ALL.58 Very high doses of methotrexate (5 g per
square meter) appear to improve the outcome in pa-
tients with T-cell ALL.18 This conclusion is con-
sistent with data indicating that T-lineage blast cells
accumulate methotrexate polyglutamates (active me-
tabolites of the parent compound) less avidly than do
B-lineage blast cells,75 so that higher serum concen-
trations of methotrexate are needed for adequate ac-
cumulation of methotrexate polyglutamates.76 Indeed,
the conventional dose of methotrexate of 1 g per
square meter may be too low for many patients with
B-cell–precursor ALL.60
The value of intensification treatment is less cer-
tain in adults with ALL because randomized trials
have not been performed and because some studies
have used suboptimal continuation regimens.2,3 How-
ever, the results of several nonrandomized studies
have suggested that intensive multidrug therapy be-
gun after induction of remission results in longer-
lasting remissions, especially in young adults; that
patients with T-cell ALL benefit from cyclophospha-
mide and cytarabine therapy; and that high-dose cy-
tarabine therapy improves outcome in patients with
standard-risk or high-risk ALL.2,12,56,59
Continuation Treatment
With the exception of those with mature B-cell
leukemia, children with ALL require prolonged con-
tinuation treatment for reasons that are poorly un-
derstood. Perhaps long-term drug exposure or the
host immune system is needed to kill residual, slowly
dividing leukemic cells or to suppress their growth,
allowing programmed cell death to occur.16 In one
 D RUG TH ERA PY
trial, attempts to shorten the duration of moderately
intensive chemotherapy to 18 months or less result-
ed in a high rate of relapse after the cessation of
treatment; however, according to a meta-analysis of
42 studies, there is no advantage to prolonging
treatment beyond three years.62 Hence, the general
rule is to discontinue all therapy in children whose
disease remains in remission two and a half to three
years after therapy is begun. It remains unclear
whether the duration of therapy can be shortened
for patients receiving intensified chemotherapy. It is
also uncertain whether adults with ALL require pro-
longed continuation therapy. In two trials of the ef-
ficacy of post-remission treatment given for 5 to 10
months, the median durations of remission ranged
from 9 to 12 months.73,77 These poor results may re-
flect inadequate treatment for induction of remission
or inadequate consolidation treatment.
A combination of methotrexate administered week-
ly and mercaptopurine administered daily constitutes
the usual continuation regimen for children with
ALL. Accumulation of higher intracellular concen-
trations of the active metabolites of methotrexate
and mercaptopurine and administration of this com-
bination to the limits of tolerance (as indicated by
low leukocyte counts) have been associated with an
improved clinical outcome.78-80
A few children (1 in 300) have an inherited defi-
ciency of thiopurine S-methyltransferase, the en-
zyme that catalyzes the S-methylation (inactivation)
of mercaptopurine. In these children the standard
doses of mercaptopurine have potentially fatal hema-
tologic side effects, but the drug can be given safely
in much smaller doses.81 Furthermore, about 10 per-
cent of children are heterozygous for this deficiency
and thus have intermediate levels of enzyme activity;
they may require moderate dose reduction to avert
side effects. Recent identification of the genetic basis
of this autosomal codominant trait has made possi-
ble the molecular diagnosis of these cases.82 In addi-
tion, because mercaptopurine has an apparent circa-
dian effect, treatment outcome improves when the
drug is given in the evening.83 With methotrexate,
the advantages of oral as compared with parenteral
administration are uncertain, but the parenteral
route circumvents problems of decreased bioavail-
ability and poor compliance. Prolonging exposure
to methotrexate by giving it orally in divided doses
over a 36-hour period has proved to be less effective
than giving a higher-dose intravenous infusion over
a 24-hour period.57
The addition of intermittent pulses of vincristine
and a glucocorticoid to the antimetabolite continu-
ation regimen has been shown to improve results62
and has been widely adopted in the treatment of child-
hood ALL. Another integral component of many
protocols is reinduction therapy introduced early af-
ter the first induction of remission (for example, at
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Copyright © 1998 Massachusetts Medical Society. All rights reserved.
four months). This treatment, which relies on the
same drugs that were given during the first induction
phase, has improved results in children and in adults
with ALL.18,59,62 Prolonged intensification including
a second reinduction phase or rotational administra-
tion of non–cross-resistant drug pairs during contin-
uation treatment may further improve outcome in
patients with standard-risk or high-risk ALL.64,84
Therapy Directed toward the Central Nervous System
Realization that the central nervous system can be
a sanctuary for leukemic cells has prompted the devel-
opment of presymptomatic therapy directed toward
the central nervous system in patients with ALL. Be-
cause of concern that cranial irradiation can involve
substantial neurotoxicity and can occasionally cause
brain tumors, many therapists instead administer in-
tensive intrathecal or systemic chemotherapy early in
the treatment course. The results of chemotherapy
are excellent: rates of relapse of central nervous sys-
tem disease of 2 percent or less have been achieved
in several studies.43,55,65-67
Whether certain groups of patients at high risk
should be treated with cranial irradiation is unclear.
In one study, among children with T-cell ALL and
a leukocyte count of at least 100,000 per cubic mil-
limeter, those receiving intensive intrathecal therapy
alone had an outcome that was inferior to that of
children given cranial irradiation,43 but the chemo-
therapy in the two groups was not identical. None-
theless, in the context of effective systemic chemo-
therapy, a radiation dose of 12 Gy, rather than the
conventional dose of 18 Gy, appears to provide ade-
quate protection against central nervous system leu-
kemia, even in patients at high risk.43
Allogeneic Stem-Cell Transplantation
Transplantation of allogeneic stem cells is usually
indicated for patients who do not have a response to
the initial induction treatment and those who have
a second remission after a hematologic relapse.85
However, for children with late relapses after anti-
metabolite treatment (more than 36 months after
induction), transplantation may be deferred until a
subsequent relapse, because these patients have a
reasonable chance of cure with retrieval chemother-
apy alone.86,87 Transplantation during the first remis-
sion remains controversial. However, because of their
unfavorable prognosis, patients with the BCR–ABL
or MLL–AF4 fusion gene are commonly treated
with allogeneic stem-cell transplantation during the
first remission.7,39,40,85,88
For patients who require allogeneic stem-cell
transplantation but lack suitable family donors, al-
lografts from matched unrelated donors are a rea-
sonable option and have yielded encouraging re-
sults.89,90 In one study, transplantation of grafts from
unrelated donors was as effective as transplantation
Vol ume 33 9 Numb e r 9 · 611
 The Ne w E ng l a nd Jo u r na l o f Me d ic i ne

of matched-sibling–donor grafts.90 Transplantation covorin rescue is inadequate.92,93 Although thought

of umbilical-cord blood or autologous bone marrow to have few life-threatening side effects, prednisone
has also been attempted.7,85,91 Preliminary results in- was implicated as a central nervous system toxin in
dicate that transplantation of cord-blood stem cells one recent study.94
is feasible, especially in children; an advantage of this Acute myeloid leukemia may develop in some pa-
approach is that it does not require the same degree tients who have received intensive treatment with
of histocompatibility as transplantation of hemato- topoisomerase II inhibitors, primarily etoposide and
poietic stem cells from adults.91 Whether the lower teniposide. The latency period is relatively short (me-
risk of graft-versus-host disease might be offset by a dian, three years), and the risk appears to be related
diminished graft-versus-leukemia effect and hence a to the treatment schedule and concomitant use of
higher risk of relapse remains to be determined. other drugs.95,96 The long-term survival rate of pa-
tients with this complication is very low, even with
LATE SEQUELAE allogeneic stem-cell transplantation.96 Treatment with
Each year, at least 1500 children in the United anthracyclines at high cumulative doses and rapid
States become long-term survivors of ALL, a group rates of administration can result in cardiomyopathy,
at risk for the late adverse effects of treatment (Table especially in young girls.97 Studies are under way to
3). Cranial irradiation has been implicated in the de- determine whether cardioprotective agents such as
velopment of brain tumors (with a median latency dexrazoxane can reduce the frequency of this com-
of 10 years), neuropsychological deficits, and endo- plication without loss of the therapeutic benefits of
crinopathy leading to short stature, obesity, preco- anthracyclines. There have been no indications that
cious puberty, and osteoporosis.4 Many children the incidence of cancer or birth defects is increased
with profound growth retardation due to cranial ir- among the offspring of adult survivors of childhood
radiation or intensive chemotherapy receive growth ALL.98-100
hormone therapy after completing antileukemic
therapy. An adequate final height can be attained in FUTURE CONSIDERATIONS
most cases with growth hormone therapy, which Despite the high rate of cure of childhood ALL,
does not appear to increase the risk of leukemic re- resistant forms of the disease still represent a leading
lapse (unpublished data). However, the long-term cause of cancer-related deaths in children. Efforts are
consequences of growth hormone deficiency in being made to identify new antileukemic drugs and
these patients and the extent to which these effects new approaches to therapy. Arabinosylguanine has
can be reversed by continued replacement therapy shown considerable promise, inducing complete re-
remain to be determined. missions in 44 percent of adults and children with
Encephalopathy, with or without seizures, can be refractory T-cell ALL in one small series.101 Recent
induced by methotrexate, usually after intravenous insights into the mechanisms by which tumor-specif-
administration of high doses but in some cases after ic cytolytic cells are produced have opened the way
oral administration of low doses (e.g., 25 mg per for the development of targeted immunotherapy.102
square meter every six hours for four doses), if leu- Several strategies for gene therapy have also been
developed and include the use of antisense oligonu-
cleotides and ribozymes to disrupt oncogene expres-
sion and the use of genes encoding cytokines and
human leukocyte antigens to induce an immune re-
TABLE 3. LATE COMPLICATIONS OF INTENSIVE CHEMOTHERAPY sponse against leukemic cells.103 In another poten-
FOR ALL. tially useful approach, small cell-permeable mole-
cules may be designed to inhibit the transcription of
COMPLICATION ASSOCIATED TREATMENT specific genes.104 The recent finding that ALL is
angiogenic suggests that antiangiogenic drugs also
Brain tumor Cranial irradiation
Acute myeloid leukemia Epipodophyllotoxins, alkylating
may have a therapeutic role.105
agents, anthracyclines These and related therapies may soon offer treat-
Cardiomyopathy Anthracyclines ment options that are more specific and hence less
Encephalopathy Cranial irradiation, methotrexate, toxic than conventional chemotherapy. However,
glucocorticoids
many remarkable advances in curative therapy for
Avascular necrosis of bone Glucocorticoids, local irradiation
childhood ALL (Fig. 1) have been achieved in the
Osteoporosis Cranial irradiation, glucocorticoids,
antimetabolites past 20 years through more effective use of antileu-
Short stature Cranial irradiation, glucocorticoids, kemic drugs that first became available decades ago.
intensive chemotherapy Indeed, it may be possible to improve existing ther-
Obesity Cranial irradiation apeutic regimens further by adjusting dosages on the
Thyroid dysfunction Cranial (and neck) irradiation, inten-
sive chemotherapy
basis of pharmacokinetic characteristics in individual
patients.61 Thus, further modifications of contempo-

612 · Augus t 2 7 , 19 9 8

The New England Journal of Medicine

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Copyright © 1998 Massachusetts Medical Society. All rights reserved.
 D RUG TH ERA PY
rary treatment protocols, coupled with systematic
evaluation of novel biologic strategies, may provide
uniformly effective therapy for children with ALL
and begin to improve the generally unfavorable out-
look for adults with this disease.
Supported in part by grants (PO1 CA-20180, R37 CA36401, RO1 CA-
78224, and P30 CA-21765) from the National Cancer Institute, by a
Center of Excellence grant from the state of Tennessee, and by the Amer-
ican Lebanese Syrian Associated Charities.
We are indebted to Dieter F. Hoelzer, M.D., Hagop Kantarjian,
M.D., and Richard A. Larson, M.D., for helpful comments regard-
ing the manuscript, and to J.R. Gilbert for medical editing.
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