Page 15 - Haematologica Vol. 110 - January 2025

PROS AND CONS EDITORIAL
Hematopoietic cell transplantation soon after first relapse in acute myeloid leukemia – the CONS
Yishai Ofran1 and Jacob M. Rowe1,2,3
11Hematology and Stem Cell Transplantation Department and the Eisenberg R&D Authority, Shaare Zedek Medical Center, Hebrew University Jerusalem, Jerusalem; 2Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa and 3The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
“Happy families are all alike; every unhappy family is unhappy in its own way” – Leo Tolstoy
Adapting the opening line of Tolstoy’s “Anna Karenina”, we could say: “Patients with acute myeloid leukemia (AML) achieving long-lasting remission are all alike; but each patient with relapsed / refractory disease progresses in their own unique way”. In the past, given the devastating outcome and the limited therapeutic options available, clin- ical trials were designed to focus on relapsed or refractory disease, leaving little space to consider the heterogeneity in molecular profile, timing of relapse, and intensity and type of therapy that yielded first remission. For relapsed or refractory patients transplanted while not in remission, historic survival data from 30 years ago were devastat- ing, with only 25% overall survival.1,2 These results led to a longstanding standard approach that mandates attempts to achieve a second remission, or maximal response, prior to a transplant.
This paradigm was challenged by a recent randomized study.3 In the German ETAL-3-ASAP trial, patients were random- ized to receive reinduction (salvage) chemotherapy (based on high-dose cytarabine) prior to personalized conditioning regimen versus immediate allogeneic hematopoietic stem cell transplant (alloHSCT) using a FLAMSA-RIC sequential regimen consisting of intensive chemotherapy (including cytarabine) followed by a reduced-intensity conditioning.4,5 Although the predefined cutoff for non-inferiority of imme- diate transplantation had not been achieved in this trial, the almost identical outcome of the two arms leaves room for adopting an immediate transplantation approach.
Copelan and Gale argue for implementing immediate trans- plantation as a new standard.6 They correctly note that current practice is not evidence-based, if one adheres to the requirement for large prospective randomized studies. It is, however, based on a sound scientific rationale and substantial supporting observational and retrospective data. Such a course is not without risks, not least for increasing toxicities of the transplant, particularly if a significant re-
sponse was not achieved. It seems that the data from the ASAP trial do not dismiss this risk. Furthermore, the high rates of actual transplants in both arms (96% in the disease control group vs. 93% in the remission induction group) are quite exceptional in an intention-to-treat trial, suggesting patient selection for either an immediately available donor (unlikely, since only 15% had matched sibling donors) or an indolent disease biology that allowed waiting for a transplant. The reported data from the ASAP trial reflect recent im- provements in transplantation and the development of sequential protocols. Moreover, current treatment options for a patient with AML at relapse are not binary, being a choice between intensive chemotherapy alone or immedi- ate transplantation. The intensive salvage approach used in the ASAP trial, with mitoxantrone and cytarabine (HAM), has been used for more than 30 years. Disappointingly, the rate of reported remissions after the HAM regimen has only marginally increased from 44-53% during the 1990s7-9 to the current 51-58%.10,11
One cannot discount the importance of reaching minimal re- sidual disease (MRD) prior to an alloHSCT,12-15 which has been reported in multiple studies and consensus reports.16-21 This is not surprising and is in line with the concept applicable to all immunotherapies. The FLAMSA-RIC regimen used in the ASAP trial includes remission-inducing chemotherapy prior to the conditioning (RIC) such that it is likely that the aim of reaching MRD was also achieved in a substantial number of patients, although this was not documented. In similar regimens, a reduction in the post-alloHSCT relapse rate was shown to be associated with peripheral blast clearance after induction.22
For the entire population of induction failure or relapsed AML, a cogent argument must be made for a more per- sonalized approach. Twenty years ago, Sing and Lipton23 suggested that, in select patients, alloHSCT may be offered to relapsed patients, even if not in remission, based on
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Correspondence: Y. Ofran yofran@szmc.org.il
Received: October 10, 2024. Accepted: October 10, 2024.
https://doi.org/10.3324/haematol.2024.286780
©2025 Ferrata Storti Foundation Published under a CC BY-NC license