Page 82 - Haematologica Vol. 110 - January 2025

ARTICLE - HCT in elderly AML
transplant-related complications and the likely potential selection bias in older patients proceeding to HCT have created doubts about the comparative therapeutic value of HCT in older patients. Prospective randomized studies concerning the value of HCT treatment have proved difficult to conduct - particularly in elderly patients.
The present study with RM-LFS as primary endpoint rep- resents the first randomized intention to treat cooperative effort of evaluating HCT in the setting of older patient in CR1 after intensive or low-intensive induction therapy and a matched donor. Our study confirms both the potent anti-leukemic effect as well the NRM with HCT after NMA conditioning as compared with conventional consolidation therapy. Starting after 4 years, RM-LFS is significantly better with HCT compared to non-HCT consolidation outweigh- ing the disadvantage of increased NRM. Previous studies in patients with hematopoietic donors have documented the potent anti-leukemic potential of HCT, but these were non-randomized.12,16,18 By starting registration of the patients at CR1 immediately after induction and by randomization after subsequent first consolidation with a time limit of 5 months from diagnosis to randomization, this trial set out to avoid biases previously considered major issues in the evaluation of HCT in older patients. By choosing a uniform NMA, less toxic conditioning and short aplasia time without outcome differences between ages 60-64, 65-69 and ≥70 years as previously published and confirmed in our study (Online Supplementary Figure S11), the selection of patients ineligible for HCT has been reduced as much as possible.18 RI (91.1% at 5 years) was extremely high in the non-HCT arm of elderly AML despite low, inter-mediate- and high- risk cytogenetic as published previously.2,20 In contrast, RI after HCT was 37.8% in a range similar to the 50% after related, and 16% after unrelated HCT, described previously.15 Furthermore, the study was performed over a period when subpopulation chimerism guided immune suppression, shown to decrease RI early after HCT, was not available to all participating centers.30 Moreover, the NRM of 33.4% at 60 months seems similar to the 29.0% previously observed in phase II trials in this age group.12,14,15 A high proportion of deaths (22.8% of deaths) was caused by bacterial or viral infections in this elderly patient population, which exceeded the proportion of deaths from GVHD (10.5%). Future HCT protocols including better infectious prophylaxis are ex- pected to increase even more the outcome in this elderly patient population with excessively high RI of 91.1% with non-HCT consolidation.
The improved 5-year RM-LFS after HCT in comparison to non-HCT does not translate into a RM-OS benefit during the study period (Online Supplementary Figure S8; Online Supplementary Table 3). The rescue possibility in the non- HCT arm after relapse by HCT impedes RM-OS comparisons. Of note, 19 of the 34 (55.8%) relapsing non-HCT patients were transplanted in CR2.
The results of our study raise some additional points of
D. Niederwieser et al. interest. First, a considerable proportion of CR patients
relapse within a few weeks after CR1 during consolidation and before randomization to HCT or non-HCT underscoring the need to generate more stable or deeper remissions with induction therapy. Unfortunately, we could not determine the MRD status pre- or post-HCT in patients in this study. In the meantime, new treatment strategies and techniques for determining MRD have become available, which allow for more personalized management of additional therapeutic interventions following one or two induction chemothera- pies. In addition, new remission induction approaches e.g., hypomethylating therapy in combination with venetoclax, may induce MRD-negativity prior to transplant with less toxicity. As extensively discussed before, the immuno-ther- apeutic effect of HCT as a consolidation therapy is strong and extends across different sub-types of AML resulting in a reduction of relapse of at least a third of what can be observed in patients consolidated with chemotherapy, as shown again in the present study.27,29 However, especially in older and medically less fit patients, NRM reduces the net effect on LFS and OS, necessitating the selection of patients for whom NRM can be predicted to be acceptable. Several predictive scores have been developed. For instance, the integrated EBMT/HCT-CI score by Versluis et al.28 and the HCT-CI score can be used to tailor the application of HCT and preclude excessive toxicities. However, the predictive value of such scores may be valued differently by physi- cians and patients and did not influence RI or OS (Online Supplementary Figure S4; data not shown) in our trial. For 75.4% of patients in our study, an HLA-identical related or unrelated donor was identified within a few weeks of CR1 and during consolidation, allowing HCT to be scheduled within 5 months from diagnosis of the disease. The best time for a donor search is as early as possible and may already be started at CR1 or even at diagnosis, although depending on local institutional circumstances the time needed to find a donor and the possibility to cancel a do- nor search in patients not undergoing HCT will impact on the choice for an early donor search strategy. Increasing donor availability and shorter diagnosis-HCT time inter- vals are foreseen in the future due to the increased use of haploidentical donors in clinical practice worldwide.31 This trial has a few limitations. During the trial period trans- plant strategies evolved, but none of them have been proven to be superior to low-dose total-body irradiation (TBI) in a prospective trial with unbiased patient inclusion. The use of this minimally toxic, low-dose TBI based, nonmyeloab- lative regimen conditioning with CyA/MMF immunosup- pression has been developed in a dog model,32 translated to clinical phase II studies with long-term outcomes on more than thousand patients13-15,18 and is now studied in a phase III study. While short-term results are available on heterogeneous patients populations with newer transplant strategies, long-term results are missing in elderly patients with post-Cy or newer immunosuppressive therapies.33
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