Page 13 - Haematologica Vol. 110 - January 2025

PROS AND CONS EDITORIAL
E. Copelan and R.P. Gale
risk toxicities and potential death from a transplant when the likelihood of long-term survival is low even when the outcome is better compared with the alternatives. Other physicians use re-induction therapy to assess disease sensitivity and likelihood of cure with a transplant. The many people receiv- ing a transplant after failing re-induction therapy suggests many advance to a transplant anyway. Notably, the toxicities of re-induction therapy and of transplants are cumulative or even synergistic. Public reporting of center-specific out- comes also influences physicians’ selection of people with the best predicted transplant outcome like what is reported in cardio-thoracic surgery and kidney transplantation.19-21 The perception that transplanting the best candidates results in better outcomes ignores results of the multi-variable anal- yses used to predict expected outcomes which attempt to account for known adverse risk co-variates. Conversely, some subject- and transplant-related co-variates like frailty, socio- economic status, and MRD are neglected in the analyses.22 These issues have contributed to the incorrect conclusion and recommendation that there is a need for re-induction therapy pretransplant.
The recently published phase III ETAL-3-ASAP trial ad- dresses the efficacy of pretransplant re-induction therapy on transplant outcomes.23 The authors reported no benefit but longer hospitalization and more adverse events in the re-induction cohort.
Most data we reviewed support a transplant as soon as reasonably possible after relapse without attempting pre- transplant re-induction. Co-variates which might identify people likely to achieve a histological complete response after re-induction therapy such as long duration of first remission, favorable cytogenetics, low ECOG performance score, and low blood myeloblast concentration do not help decide which people might benefit from post-relapse therapy because
References
1. Appelbaum FR, Clift RA, Buckner D, et al. Allogenic marrow transplantation for acute nonlymphoblastic leukemia after first relapse. Blood. 1983;61(5):949-953.
2. Appelbaum FR, Pearce SF. Hematopoietic cell transplantation in first complete remission versus early relapse. Best Pract Res Clin Haematol. 2006;19(2):333-339.
3. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogenic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091-2101.
4. Penack O, Peczynski C, Mohty M, et al. How much has allogenic stem cell transplant-related mortality improved since the 1980s? A retrospective analysis from the EBMT. Blood Adv. 2020;4(24):6283-6290.
5. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28(23):3730-3738.
6. Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol.
they also identify patients who are likely to have favorable outcomes when transplanted in relapse.5,14,24 Response to pretransplant re-induction therapy identifies people with more responsive disease. As such, it is a predictive co-variate or biomarker for a better transplant outcome. This is best viewed as an association, not cause-and-effect.
We are not suggesting everyone with AML in first complete remission who relapses goes directly to a transplant. This decision must be made on an individual basis. For people with a brief first histological complete remission or with other adverse risk co-variates, and older people with import- ant co-morbidities, decision-making is complex. However, in many people, advancing to a transplant without further therapy is reasonable. And any decision should consider the proposed transplant conditioning regimen.
In conclusion, we suggest the current practice of giving ev- eryone with AML who relapses pretransplant re-induction therapy is without a strong scientific basis and likely to cause more harm than benefit. Others have also reached similar conclusions.25
Disclosures
EC acknowledges support from the Leon Levine Founda- tion and the Kerry and Simone Vickar Foundation. RPG acknowledges support from the UK National Institute of Health Research (NIHR) Biomedical Research Centre; he is a consultant to Antengene Biotech LLC, a Medical Director for FFF Enterprises Inc., a speaker for Janssen Pharma and Hengrui Pharma, and sits on the Board of Directors of the Russian Foundation for Cancer Research Support and the Scientific Advisory Board of StemRad Ltd.
Contributions
EC and RG wrote the manuscript.
2013;31(10):1293-1301.
7. Weisdorf D, Millard HR, Horowitz MM, et al. Allogenic
transplantation for advanced AML: the value of complete
remission. Cancer. 2017;123(11):2025-2034.
8. Nagler A, Ngoya M, Galimard J-E, et al. Longitudinal outcome
over two decades of unrelated allogenic stem cell transplantation for relapsed/refractory acute myeloid leukemia: an ALWP/EBMT analysis. Clin Cancer Res. 2022;28(19):4258-4266.
9. Yanda M, Yamasaki S, Kondo T, et al. Allogenic hematopoietic cell transplantation for patients with acute myeloid leukemia not in remission. Leukemia. 2024;38(3):513-520.
10. Bolon YT, Atshan R, Allbee-Johnson M, et al. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2022. CIBMTR; Milwaukee, WI, USA. https:// cibmtr.org/CIBMTR/Resources/Summary-Slides-Reports Accessed May 29, 2024
11. Gale RP, Zhang M-J. Statistical analyses of clinical trials in haematopoietic cell transplantation or why there is a strong
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