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1516 Part XI: Malignant Lymphoid Diseases Chapter 91: Acute Lymphoblastic Leukemia 1517

Intensification (Consolidation) Therapy After normal hemato- Patients diagnosed with ALL between the ages of 16 and 39, often
poiesis is restored, patients in remission become candidates for inten- considered together as adolescents and young adults, are commonly
sification therapy. Such treatment, administered shortly after remission treated by either adult or pediatric hematologists. Several retrospective
induction, refers to readministration of the induction regimen or to comparative analyses have reported that adolescents and young adults
high doses of multiple agents not used during the induction phase. with ALL treated on pediatric protocols have had superior event-free
Although there is no dispute on the importance of this treatment in and overall survival rates when compared with similar patients enrolled
childhood ALL, there is no consensus on the best regimen and dura- on adult ALL trials. Preliminary data suggest that these patients have
tion of treatment. More commonly used regimens for childhood ALL better outcomes when treated with pediatric-inspired regimens, and
include high-dose methotrexate with or without mercaptopurine, high- that excess toxicity is not observed. 153,155–162
dose l-asparaginase given for an extended period, or a combination of Continuation Therapy Although unnecessary for cure of mature
dexamethasone, vincristine, l-asparaginase, and doxorubicin, followed B-cell leukemia, continuation therapy for 2 to 3 years is an integral part
by thioguanine, cytarabine, and cyclophosphamide. 107,108,121,137,141,142 This of pediatric and adult ALL regimens. Attempts to shorten the duration
phase of therapy has improved outcomes, even for patients with low- of treatment have led to inferior outcomes in both childhood and adult
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risk ALL. Patients with ETV6-RUNX1 have an especially good out- ALL, although as many as two-thirds of childhood cases might be
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come in clinical trials featuring intensive postremission treatment with cured with only 12 months of treatment. However, which subgroups
glucocorticoids, vincristine, and asparaginase. 144,145 A very high dose of childhood ALL can be cured with abbreviated therapy is unclear. In a
of methotrexate (5 g/m ) appears to improve the treatment outcome of meta-analysis of 42 trials, a third year of continuation therapy reduced
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patients with T-cell ALL. 141,146 This finding is consistent with data indi- the likelihood of relapse during the third year, but no advantage to pro-
cating T-cell blasts accumulate methotrexate polyglutamates (active longing treatment beyond 3 years was observed. Early studies demon-
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metabolites of the parent compound) less avidly than do B-cell pre- strated that the third year of continuation therapy benefits boys but not
cursors; consequently, higher serum levels of the drug are needed for girls. 166,167 Hence, most studies discontinue all therapy for girls after 2 to
an adequate therapeutic effect. 147,148 The conventional dose of metho- 2.5 years of treatment. It is uncertain whether with improved contem-
trexate (1 g/m ) may be too low for many patients with B-cell precur- porary treatment boys still require prolonged continuation treatment.
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sor ALL. Among B-lineage ALL, blasts with either ETV6-RUNX1 or Whether adults with ALL benefit from prolonged continuation therapy
TCF3-PBX1 gene fusion accumulate significantly lower methotrexate is also unclear. In most adult trials, continuation therapy is given for
polyglutamates compared to those with hyperdiploidy or other genetic 2 years from diagnosis.
abnormalities. This finding suggested that patients with ETV6- Methotrexate administered weekly and mercaptopurine adminis-
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RUNX1 or TCF3-PBX1 gene fusion would also benefit from a higher tered daily constitute the usual continuation regimen for ALL. Accu-
dose of methotrexate. mulation of higher intracellular concentrations of the active metabolites
Based on pediatric studies, intensive consolidation therapy has of methotrexate and mercaptopurine and administration of this combi-
become a standard in the treatment of adult ALL even though early stud- nation to the limits of tolerance (as indicated by low leukocyte counts)
ies failed to show the benefit of this phase of treatment. Various drugs have been associated with improved clinical outcome. 168,169 Many inves-
have been used for intensification, including high-dose methotrexate, tigators advocate that drug dosage be adjusted to maintain leukocyte
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high-dose cytarabine, cyclophosphamide, and asparaginase. 67,102,150–153 counts below 3 × 10 /L and neutrophil counts between 0.5 and 1.5 ×
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Increasingly, intensification treatment is risk-adapted and subtype spe- 10 /L to ensure adequate dose intensity during the continuation treat-
cific. In the German 06/93 study, high-dose methotrexate was used for ment in childhood ALL. In one study, the dose intensity of mercap-
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patients with standard-risk B-cell precursor ALL, high-dose metho- topurine was the most important pharmacologic factor influencing
trexate and high-dose cytarabine for high-risk B-cell precursor ALL, treatment outcome. Mercaptopurine is most effective when it is given
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and cyclophosphamide for T-cell ALL. The hyper-CVAD (cyclophos- orally on a daily basis. However, overzealous use of mercaptopurine is
phamide, vincristine, Adriamycin, dexamethasone) regimen of the counterproductive, as such use results in neutropenia and interruption
MD Anderson Cancer Center alternates the combination of cyclophos- of chemotherapy, reducing overall dose intensity. The effect of mer-
phamide, vincristine, doxorubicin (Adriamycin), and dexamethasone, captopurine is better when the drug is administered in the evening.
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with high-dose methotrexate and high-dose cytarabine for four courses Mercaptopurine should not be given with milk or milk products con-
each. More recently, rituximab has been added for patients with CD20 taining xanthine oxidase, which can degrade the drug. Antimetab-
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expression on lymphoblasts. 150,151 In adults, methotrexate dose should olite treatment should not be withheld because of isolated increases of
probably be limited to 1.5 to 2.0 g/m because higher doses may lead to liver enzymes since such liver function abnormalities are tolerable and
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excessive toxicities, delayed subsequent treatment, and reduced compli- reversible. 173
ance. In a Cancer and Leukemia Group B study, a five-drug remission A few patients (one in 300) have an inherited homozygous defi-
induction was followed by early and late intensification courses with ciency of thiopurine S-methyltransferase, the enzyme that catalyzes the
eight drugs. These studies and others suggested the benefit of early S-methylation (inactivation) of mercaptopurine. In these patients, stan-
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intensive consolidation therapy, especially in young adults. In adult dard doses of mercaptopurine have potentially fatal hematologic side
T-cell ALL, benefit is derived from cyclophosphamide and cytara- effects. The drug should be given in much smaller doses (e.g., 10-fold
bine. 67,102 In other adult cases of standard-risk and high-risk ALL, the reduction). Approximately 10 percent of patients are heterozygous
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benefit is derived from high-dose cytarabine. Two German multicen- for the enzyme deficiency and have intermediate levels of thiopurine
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ter trials using high-dose cytarabine, mitoxantrone, and allogeneic methyltransferase. This subgroup can be treated safely with only
hematopoietic stem cell transplantation showed markedly improved moderate reductions in mercaptopurine dosage and appears to have
results in cases bearing the t(4;11), which generally confers an adverse better clinical outcomes than do patients with the homozygous wild-
prognosis. Several ongoing trials are testing the efficacy of aspara- type phenotype. Importantly, patients with this enzyme deficiency are at
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ginase during intensification in young adult ALL because this drug risk for therapy-related myeloid leukemia and radiation-related brain
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clearly improves outcome in childhood ALL and is better tolerated dur- tumors. 176–178 Identification of this autosomal codominant trait has
ing consolidation treatment than during remission induction. been enabled by molecular diagnosis and led to increased emphasis

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