Page 83 - Haematologica Vol. 110 - January 2025

ARTICLE - HCT in elderly AML
D. Niederwieser et al.
While new drugs including venetoclax combinations have become available as consolidation and/or maintenance for non-HCT treatment since study start, most of these have yet to demonstrate improvement of long-term outcome in the broader AML population; e.g., maintenance with CC-486 in comparison to placebo prolonged median relapse-free survival and 2-year survival, but long-term LFS and OS was unaffected.34 Combinations of apoptosis-interacting drugs with HMA and targeted therapy, where possible, have high CR rates and longer median OS, but resistance caused by e.g., loss of p53 function, activating kinase mutations and alternative anti-apoptotic proteins are considered reasons for failing better long-term LFS and OS.35
The preparative regimen described here is currently used less frequently (8.5% of 6289 AML patients >60 years trans- planted from 2020-2022) according to the EBMT registry in comparison to RIC (EBMT personal communication). The latter regimen requires significant expertise and MRD or subpop- ulation chimerism guided immunosuppression. However, it exerts potent anti-leukemic activity.13-15 The NMA regimen has been used intentionally to avoid selection of elderly patients to HCT being associated with an extremely short duration of aplasia and a missing age effect in this elderly patients.18 As a possible sign of selection, only 35% of patients trans- planted in 2020-2022 according to the EBMT registry were older than 60 years of age, despite the highest incidence of the disease in this age group as compared to a younger age group. In our trial, only one patient in CR1 after consolidation was considered unfit for HCT. The extent of selection for HCT using RIC cannot be reliably estimated, but is assumed to be substantial by looking at the HCT activity of elderly patients with AML. It might well be that RIC or even myeloablative conditioning (MAC) may reduce the RI in selected patients in comparison to NMA, but prospective randomized studies in similar patient populations are missing or have similar RI.36 Preemptive or post-HCT MRD driven targeted therapy may improve results further. Unfortunately, no ancillary quality of life studies were performed in this trial.
Furthermore, our study was not intended to answer the question, if HCT in CR2 ultimately leads to similar results as HCT in CR1. As reported previously, patients with he- matological relapse, and especially elderly patients, have a dismal outcome. Only 28.6% of patients >60 years achieve CR2 after relapse and LFS has been described to be only 13.8% at 5 years in this age group.2
Even if induction therapy of AML has changed (and will continuously change), the study provides a solid basis for further trials and an essential backbone for evidence-based AML therapy in elderly aiming at improving long-term LFS from diagnosis. Achievement of molecular CR1 after induc- tion therapy remains the goal to decrease early relapses before consolidation and improve results of HCT consoli- dation. Since none of the available targeted therapies and combinations have shown to be superior in long-term outcome by inducing resistance, consolidation treatment
for long-term LFS is urgently needed. Perceptions of main treatment goals/chances of cure (80%) from patients and of chances of cure (7%) from physicians are clearly discor- dant in elderly patients with AML.37 The only treatment able to improve long-term LFS is HCT as shown in our unbiased randomized ITT study. The current study provides the ratio- nale to increase the use of HCT in elderly patients (currently performed only in a small proportion). Further advances in elderly AML can be reached only by improving the different steps of therapy: decrease relapse after CR1 by increasing molecular remissions and better timing of HCT, decrease relapse incidence after HCT or non-HCT by better main- tenance, decrease NRM after HCT and increase long- (not only short-) term outcome using the results of our study as baseline. The need to analyze the different steps within studies will be the main aim for the next years and the only way to improve long-term outcome of AML in a population of increasing life-expectancy today of >82 years (https:// www.worldometers.info/demographics/life-expectancy/).
Disclosures
YC discloses consulting fees for advisory board from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, Astra-Zeneca and Servier; travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz and Sanofi all via the institution. GG discloses advisory role at Fujimoto Pharmaceutical Corporation, Japan. TH disl- coses advisory board participation at Eurocept; travel grants from Eurocept, Stemline and JAZZ; honoraria from Eurocept and JAZZ. AH discloses research support from Novartis, BMS, Pfizer and Incyte. CS discloses honoraria from AbbVie, Astellas, AstraZeneca, BMS/Celgene, Laboratories Delbert, Jazz Pharmaceuticals, Novartis, Pfizer and Roche; research support (institutional) from Jazz, Boehringer Ingelheim and AngioBiomed. MH dislcoses honoraria from Novartis, SOBI, Gilead Sciences and Falk Foundation; consulting/advisory role at Novartis, BMS/Celgene, Gilead Sciences, Pfizer, In- cyte, Sanofi/Aventis, Roche, Amgen, SOBI and Janssen. BL discloses advisory board participation at Servier, Astellas, Abbvie, Jazz, Kronos Bio and Stemline Pharmaceutics/ Meranini; shareholder/consultancy of CureVac SE. All other authors have no conflicts of interest to disclose.
Contributions
Protocol writing by DN, DH, BL and JC. Data contribution by DN, DH, WB, BJB, HA-A, YC, MvG, CJ, GG, MH, RH, TH, AH, SI, RvMR, NK, JJ, MJ, FB, MM, SM-L, GO, JP ,WP, JS, CS, SS, MS, LFV, VV, BL and JC. Data analysis by DN, DH, BL and JC. Discussion of results by DN, DH, WB, BJB, HA-A, YC, MvG, CJ, GG, MH, RH, TH, AH, SI, RvMR, NK, JJ, MJ, FB, MM, SM-L, GO, JP, WP, JS, CS, SS, MS, LFV, VV, BL and JC. Manuscript writing by DN, DH, BL and JC. Manuscript discussion and approval by DN, DH, WB, BJB, HA-A, YC, MvG, CJ, GG, MH, RH, TH, AH, SI, RvMR, NK, JJ, MJ, FB, MM, SM-L, GO, JP, WP, JS, CS, SS, MS, LFV, VV, BL and JC.
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