Backbone of maintenance therapy

Source: Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 21, 2025 · Captured 2026-09-09.

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Context: Treatment of Newly Diagnosed Childhood ALL / Standard Postinduction Treatment Options for Childhood ALL / Maintenance therapy

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. Also, vincristine/steroid pulses during maintenance are used by some groups but not others (see below). It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[99] A protocol conducted by the COG suggested there are significant differences in compliance with oral mercaptopurine regimens among various racial and socioeconomic groups and that level of adherence impacts relapse risk.[99,100]

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In the past, clinical practice generally called for the administration of oral mercaptopurine in the evening, on the basis of evidence from older studies that this practice may improve EFS.[101] However, in a study conducted by the NOPHO group, in which details of oral intake were prospectively captured, timing of mercaptopurine administration (nighttime vs. other times of day) was not of prognostic significance.[102] In a COG study, taking mercaptopurine at varying times of day rather than consistently at nighttime was associated with higher rates of nonadherence. However, among adherent patients (i.e., those who took >95% of prescribed doses), there was no association between timing of mercaptopurine ingestion and relapse risk.[103]

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Some patients may develop severe hematologic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[104,105] These patients are able to tolerate mercaptopurine only in much lower dosages than those conventionally used.[104,105] Patients who are heterozygous for the variant generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[104] Polymorphisms of the NUDT15 gene, observed most frequently in East Asian and Hispanic patients, have also been linked to extreme sensitivity to the myelosuppressive effects of mercaptopurine.[106-108]

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Evidence (maintenance therapy):

A meta-analysis of randomized trials compared thiopurines and found the following:

Thioguanine did not improve the overall EFS, although particular subgroups may benefit from its use.[109]

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A meta-analysis of randomized trials compared thiopurines and found the following:

The use of continuous thioguanine instead of mercaptopurine during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease (sinusoidal obstruction syndrome) and portal hypertension.[110-114]

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A meta-analysis of randomized trials compared thiopurines and found the following:

Because of the increased toxicity of thioguanine, mercaptopurine remains the standard drug of choice.

In the COG AALL0932 (NCT01190930) trial, NCI standard-risk patients with average-risk features were randomly assigned to receive weekly oral methotrexate during maintenance at one of two starting doses: 20 mg/m2 (standard) or 40 mg/m2 (investigational).[115][Level of evidence A1]

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There was no significant difference in 5-year DFS from the start of maintenance therapy between the two treatment arms (5-year DFS rate, 95.1% for patients who received the standard dose vs. 94.2% for patients who received the investigational dose; P = .92), indicating no advantage for the higher dose of oral methotrexate.

An intensified maintenance regimen, consisting of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins along with more standard maintenance agents, has been evaluated in several clinical trials conducted by SJCRH and other groups.[2]

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The intensified maintenance with rotating pairs of agents was associated with more episodes of febrile neutropenia [116] and a higher risk of secondary acute myelogenous leukemia,[117,118] especially when epipodophyllotoxins were included.[116]On the basis of these findings, SJCRH modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine) throughout this treatment phase. Low-risk patients received more standard maintenance (without cyclophosphamide and cytarabine).[59]

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A randomized study from Argentina demonstrated no benefit from this intensified approach compared with a more standard maintenance regimen for patients who receive induction and consolidation phases based on a BFM backbone.[116]

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Studies cited in this source section

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Preserved source evidence · Not medical advice