Be careful what you wish for?

Following decades of empiric but justifiable escalation of combination chemotherapy to the point of maximum tolerability, many patients with hematologic malignancies, especially children, can expect long-term disease-free survival. However, being “cured” is still inextricably linked with intense, prolonged discomfort, and even the need to face death as a result of the therapy. A big challenge in hemato-oncology is to learn both how and in whom toxicity can be reduced without concomitant reduction in efficacy. In diseases in which the expectation of salvage after relapse is low, the balance between toxicity and efficacy of front-line therapy is particularly precarious. Where the disease in question is relatively uncommon, the opportunity to study this balance in randomized studies requires foresight, hard work, genuine intellectual and practical collaboration, and very careful study monitoring.

Two such collaborative multinational randomized studies of therapy reduction in children and adolescents with mature B-cell non-Hodgkin lymphomas (B-NHLs) are presented in this issue of Blood. Both studies randomized carefully considered—but essentially empiric—treatment reductions against a standard therapy.

Patte and colleagues studied children with intermediate-risk (group B) disease. Using a factorial randomization, 2 reductions—halving the dose of cyclophosphamide in the second induction and omission of the maintenance course (M1)—were assessed. Participants were randomized to either standard therapy, reduced cyclophosphamide in second induction, omission of M1, or both reductions. At 4 years, event-free survival (EFS) was more than 90% in all 4 arms and did not differ among the arms, suggesting that treatment could be safely reduced in intensity and duration. Analysis of the effects of therapy reductions on EFS according to the major prognostic subgroups (for example, Burkitt vs diffuse large B-cell lymphoma [DLBCL]) did not show any significant differences, although it is unlikely that the study was powered to demonstrate subgroup differences.

Cairo and colleagues enrolled high-risk (group C) participants, including those with CNS involvement, in a 2-way randomization between a standard therapy and therapy with both a reduced intensification block and omission of 3 (75%) of the 4 maintenance courses. The study was stopped early when the difference in EFS between the 2 arms met the interim monitoring criterion. At 4 years, intention-to-treat analysis showed EFS for full-intensity therapy of 90% (± 3.1%) versus 80% (± 4.2%) for reduced-intensity therapy, although this difference did not quite reach statistical significance (P = .064). The efficacy diminution here is possibly underestimated, since there was some crossover from the reduced- to the full-intensity arms.

From these studies, we can reasonably conclude that a modest reduction in intensity of therapy is probably safe for children with a better prognosis, and a slightly less modest reduction for those with a worse prognosis is very likely indeed to result in a worse outcome. These conclusions are concordant with the conclusions of a previous trial of therapy reduction in childhood B-NHLs from the BFM group,¹  in which a more favorable balance of toxicity with efficacy was achieved only for patients in the lower-risk groups.

Did either trial convincingly demonstrate worthwhile decreases in toxicity? Toxicity was not an end point of either study and was likely less well documented than the hard end point of EFS. However, both studies show significant diminutions of such toxicities as stomatitis and infection. However, in the study of Patte et al, patients who suffered the most extreme toxicity, that is, death (the number of induction deaths is not specified), all did so exclusively within the initial stages of treatment and were not eligible to be randomized. Hence, the dose reductions did not eradicate early treatment-related mortality. Long-term toxicities are not formally addressed by either of these studies, although these generated some of the stated rationale for the reductions used. Long-term follow-up is vital to assess impact of the randomized dose reductions on fertility, the risk of second malignancies, and other late effects. In summary, “no pain, no gain” may still be true. Entirely novel approaches to therapy coupled with much more precise methods of subclassification are sorely needed.