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Chapter 65 Clinical Manifestations and Treatment of Childhood Acute Lymphoblastic Leukemia 1025

Minimal Residual Disease Consolidation Therapy
The rapidity of response to induction therapy is an important inde- The importance of a consolidation phase following remission induction
pendent predictor of outcome. There is strong concordance between is undisputed, but the treatment regimen and duration varies in the
the assessment of MRD by flow cytometry and by PCR methods. We different childhood ALL studies. Commonly used strategies include
monitor MRD primarily using the flow cytometry method because it is high-dose methotrexate plus mercaptopurine, frequent pulses of
simple and rapid, and we reserve the PCR method for the few patients vincristine and corticosteroid plus high-dose asparaginase for 20 to
(less than 5%) whose leukemic cells lack a suitable immunophenotype. 30 weeks, and re-induction treatment with the same agents given
−4
About half of all patients show a disease reduction to 10 or lower during initial remission induction. Re-induction treatment has become
after only 2 weeks of remission induction, and these patients appear an integral component of contemporary protocols. In one random-
to have an exceptionally good treatment outcome. Persistence of MRD ized study, double re-induction further improved treatment outcome
−4
of 10 or more at 4 months from diagnosis is associated with an in patients with intermediate-risk ALL, while additional pulses of
especially dismal outcome. The adverse prognosis of high-risk slow vincristine and prednisone after a single re-induction course was not
early responders can be improved with intensification of induction beneficial, suggesting that the increased dose intensity of other drugs,
and consolidation. Low-risk cases may be spared the increased risk such as asparaginase, was responsible for the observed improvement.
of early morbidity and mortality from intensive induction provided that An “augmented” regimen including additional doses of vincristine and
they receive postinduction intensification therapy. Novel approaches at asparaginase during periods of myelosuppression, improved outcome
measuring MRD using deep sequencing are being evaluated. of patients with a slow early response to therapy.

analyses with SNP array and especially NGS have discovered many the extent that neutropenia necessitates chemotherapy interruption,
nonrandom genetic abnormalities, several of which have already been reduces overall dose intensity and is counterproductive. The optimal
found to have prognostic and therapeutic implications. duration of therapy remains unknown. Attempts to shorten therapy
duration from 24 months to 12 or 18 months have resulted in a
significant increase in relapses. Several studies showed no advantage
THERAPY, INCLUDING STEM CELL TRANSPLANTATION to prolonging treatment beyond 3 years. A small number of patients
with particularly poor prognostic features may undergo allogeneic
In contrast to Burkitt leukemia, which is treated with short-term hematopoietic cell transplantation during first remission.
intensive chemotherapy, therapy for B-ALL or T-ALL is administered Radiation therapy was the first modality successfully used to
over 2 to 3 years. Treatment starts with a 4- to 6-week remission- prevent CNS relapse. The effectiveness of cranial radiation as preven-
induction phase aiming at eradicating the initial leukemic cell burden tive therapy was offset by substantial late effects in long-term survivors,
and restoring normal hematopoiesis. The induction phase typically including learning disabilities, multiple endocrinopathies, and an
includes the administration of a glucocorticoid (prednisone or dexa- increased risk of second malignancies. Subsequent trials demonstrated
methasone), vincristine, and at least a third drug (asparaginase or that, in the context of optimal systemic and intrathecal therapy,
anthracycline, or both). A three-drug induction regimen appears cranial irradiation can be omitted in all patients but reserved for a
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sufficient for most low-risk cases, provided they receive intensified few patients who developed subsequent CNS relapse. A recent
postremission therapy. The benefit in long-term survival of using four collaborative group study showed that prophylactic cranial irradiation
or more drugs during induction is widely accepted in higher risk failed to improve outcome of any high-risk subgroups and in fact was
patients but less clear in lower risk patients. With this approach, 98% associated with poor survival in several subgroups. Patients with
to 99% of patients can attain remission, as defined by <5% blasts in high-risk genetic features, T-lineage ALL, and leukemic cells in the
the marrow and a return of neutrophil and platelet counts to near cerebrospinal fluid (CSF) even from iatrogenic introduction from a
normal levels. Intrathecal chemotherapy is usually initiated at the traumatic lumbar puncture at diagnosis, require more intensive CNS-
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start of treatment but may be delayed in selected patients, as men- directed therapy to reduce CNS relapse. Studies have successfully
tioned earlier. used early triple intrathecal therapy with methotrexate, hydrocorti-
Following remission induction, consolidation (or intensification) sone, and cytarabine or intrathecal methotrexate alone. Systematically
is given to eradicate drug-resistant residual leukemic cells. Therapy is administered agents including high-dose methotrexate, dexametha-
tailored to the leukemia subtype and risk group. All patients benefit sone, and asparaginase also contribute to prevention of extramedul-
from a delayed intensification (or delayed re-induction), consisting of lary relapse.
using drugs similar to those used in remission induction therapy after Based on reports of more potent in-vitro antileukemic activity and
a 3-month period of a less intensive, interim maintenance chemo- better CNS penetration, dexamethasone has replaced prednisone in
therapy. Double-delayed intensification with a second re-induction many continuation regimens. Prednisone remains the preferred glu-
at week 32 of treatment improves outcome in patients with cocorticoid during induction because of the relative increased toxicity
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intermediate-risk leukemia but does not benefit patients with rapid associated with dexamethasone use. Polyethylene glycol–conjugated
early response. An augmented intensification regimen consisting of asparaginase, a long-acting and less allergenic form, is progressively
the administration of additional doses of vincristine and asparaginase replacing the native Escherichia coli asparaginase, and is being increas-
during the myelosuppression period following delayed intensifica- ingly administered intravenously instead of intramuscularly. Aspara-
tion has improved the outcome of intermediate- and high-risk ginase derived from Erwinia chrysanthemi has a short half-life and its
patients. use is currently limited to patients who are allergic to the E. coli
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After completion of induction and consolidation, patients receive formulations. The dose schedule for asparaginase should take into
a 2- to 2.5-year continuation (or maintenance) phase consisting of low account the variability in the pharmacokinetic profile and potency
intensity metronomic chemotherapy designed to eradicate any residual among the different preparations. Intensifying asparaginase therapy
leukemic cell burden. Weekly low-dose methotrexate and daily oral during the early phase of treatment benefits high-risk patients, par-
mercaptopurine form the backbone of most continuation regimens. ticularly those with T-cell disease. Significant improvement was also
Many groups add regular pulses of vincristine and corticosteroids to reported in the outcome of patients receiving early intensification
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this regimen, although the benefit of these pulses and their optimal consisting of intermediate- or high-dose antimetabolite therapy.
duration and frequency of administration in the context of contem- The optimal dose of methotrexate depends on the leukemic cell
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porary therapy have not been established. Adjusting chemotherapy genotype and phenotype, as well as host pharmacogenetic and
2
9
doses to maintain white cell count between 2 and 3 × 10 /L and pharmacokinetic parameters. Methotrexate at 2.5 g/m is adequate
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neutrophil counts between 0.5 and 1.5 × 10 /L has been associated for most patients with standard-risk B-ALL, but a higher dose (5 g/
2
with a better clinical outcome. Overzealous use of mercaptopurine, to m ) may benefit those with T-cell or high-risk B-ALL. This