Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Postinduction Treatment for Childhood ALL
Backbone of maintenance therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical trials generally call for the administration of oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. 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. Nonadherence to treatment with 6-mercaptopurine (6-MP) in the maintenance phase is associated with a significant increase in the risk of relapse.
Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[36,37] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[36,37] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematopoietic toxicity than do patients who are homozygous for the normal allele.
Evidence (maintenance therapy):
- In a meta-analysis of randomized trials that compared thiopurines, 6-thioguanine (6-TG) did not improve the overall EFS, although particular subgroups may benefit from its use. The use of continuous 6-TG instead of 6-MP during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[39,40,41,42,43] Because of the increased toxicity of 6-TG, 6-MP remains the standard drug of choice.
- Another approach is an intensified maintenance phase that consists of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins, along with more standard maintenance agents.
- The intensified maintenance with rotating pairs of agents has been associated with more episodes of febrile neutropenia  and a higher risk of secondary acute myelogenous leukemia, especially when epipodophyllotoxins are included.
SJCRH has 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).
- 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.