In this issue of Blood, Sorror et al1 present data showing no benefit of allogeneic hematopoietic cell transplantation (HCT) in older and medically infirm patients with acute myeloid leukemia (AML). In their large prospective multi-institutional observational study, they not only looked at the influence of age, comorbidities, genetic risk, and remission status on outcome but also paid special attention to frailty, impaired quality of life, depression, and diminished functional status.

There were 692 evaluable patients, with 43% of the patients aged ≥65 years. For the entire cohort, 46% underwent HCT with 4-year survival of 54%, which was better than in the nontransplant arm. However, after adjusting for AML- and patient-specific variables, no benefit of HCT in all, older, and medically infirm patients was seen apart from patients with European LeukemiaNet–adverse risk and those never in first complete remission (CR1). Even more concerning, although fitter patients were selected for HCT, this superior quality of life and fitness were lost after transplantation, thereby questioning the current way of selection for HCT and strongly arguing in favor of randomized trials to identify those patients who benefit most from HCT. The authors conclude that our present approach to offer HCT to older and medically infirm patients with AML is not evidence based and that randomized trials are needed. They propose 3 different types of randomized trials depending on the biology of the disease as well as on comorbidities, quality of life, and functions.

Is this conclusion by Sorror et al in conflict with the most recent treatment recommendations by the international expert panel on behalf of the European LeukemiaNet? Actually not. There, HCT is proposed for patients, with an estimated relapse risk above 35% to 40%, which includes patients with adverse-risk AML and nonadverse risk disease with persistent minimally detectable disease.2 For patients aged ≥60 years, HCT in CR1 is recommended at diagnosis for patients with intermediate- and adverse-risk disease able and willing to undergo remission-inducing therapy. This recommendation is based on large prospective but nonrandomized US and British studies in which patients received conventional induction chemotherapy.3,4 This recommendation is also supported by the only prospective randomized phase 3 trial initiated by the European Blood and Marrow Transplantation Group (EudraCT-Number 2007-003514-34).5 Here, patients older than 60 years with AML in CR1 after conventional induction and early consolidation chemotherapy received either reduced-intensity conditioning with 2 Gy total body irradiation and fludarabine (RIC) HCT or additional consolidation chemotherapy, with a superior leukemia-free survival in the HCT arm.5 Up to now, all these recommendations have been category 2A only owing to the lack of fully published prospective randomized trials.

The present data, therefore, remain not only conflicting but actually do not address the major limitations in the therapy of older patients with AML, as only a minority of patients for whom HCT might be curative can be treated intensively before proceeding to transplantation.6 In most studies, be it the trial by Sorror et al but also those by Ustun et al,3 Russell et al,4 and Niederwieser et al,5 the patients had to be fit for intensive induction chemotherapy, which includes only a minority of older patients with AML. The latest developments with new effective drug combinations, like the use of additional FLT3 inhibitors7 or combinations of hypomethylating agents with venetoclax,8 now standard in the less fit AML patient, have not even been tested yet in conjunction with HCT.

These newer treatment modalities, especially in the less fit patients with AML, might alter the game, since patients unfit at the time of AML diagnosis because of the leukemia burden might become fit for RIC HCT upon entering complete remission with restoration of normal hematopoietic function. As suggested by Sorror et al, it is therefore time now for randomized controlled trials to demonstrate the benefit of HCT compared with other postremission therapies including oral azacitidine.9 The integration of novel drugs will certainly result in new risk stratifications in AML and treatment recommendations that might also include HCT in older patients with AML. Thus, AML therapy for older patients will evolve in a dynamic fashion,10 but this has to be based on the results of well-designed randomized clinical trials.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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