Page 77 - Haematologica Vol. 110 - January 2025

ARTICLE - HCT in elderly AML D. Niederwieser et al.
years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible pa- tients were excluded, and 125 randomized to HCT (N=83) or non-HCT (N=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95% confidence interval [CI]: 18.9-30.1) in the HCT and 15.6 months (95% CI: 10.4-20.8) in the non-HCT arm (P=0.022) due to a decrease in cumulative relapse incidence from 91.1% (95% CI: 80.7-100.0) after non-HCT to 37.8% (95% CI: 27.2-48.4) after HCT (P<0.0001). The secondary endpoints RM-OS up to 5 years was 27.8 months (95% CI:22.3-33.2) in the HCT as compared to 28.6 months (95% CI: 22.2-35.0) in the non-HCT arm; non-relapse mortality at 5 years was 33.4% (95% CI: 23.0-43.9) with HCT and 0% without. In older patients with AML in CR1 5-year RM-LFS is better with HCT than with non-HCT consolidation treatment. The long-term RM-LFS benefit did not translate into a better RM-OS during the study period.
Introduction
Acute myeloid leukemia (AML) has a dismal prognosis in the continuously growing population of patients of greater age. Advances in supportive therapy have im- proved the proportion of patients who might benefit from a potentially curative treatment.1-4 However, attempts to improve leukemia-free survival (LFS) by increasing therapy intensity have largely been unsuccessful, mostly because of very high relapse rates (>80%), resulting in average long-term survival rates of 20% or less.2,5 For the time being long-term outcome perspectives have not been significantly improved by more recent treatment approaches.6-11
Hematopoietic cell transplantation (HCT) has been shown to be the treatment modality with a high anti-leukemic potential, combining immunological anti-leukemia effects with preparative regimens of variable intensities.12 For decades, HCT was restricted to younger and fit patients up to the age of 60 years. Since the beginning of the century, the use of HCT has been extended to adults of greater age (generally up to the age of 75 years) by em- ploying reduced-intensity conditioning (RIC) or non-my- eloablative (NMA) preparative regimens.13-16 Retrospective analyses and prospective studies in elderly patients have confirmed the potential of HCT to induce durable long term remissions.16-19 On the basis of these clinical trials, the application of HCT at older age patients has risen substantially. Randomized studies have yet to be done so a critical assessment of the comparative therapeutic value of HCT has not yet become available. This is relevant especially in patients of greater age since various selec- tion factors (e.g., leukemia prognostic risk, comorbidities) in the older age segment may significantly influence the access to HCT. As a consequence, the selection of more favorable risk patients for HCT may profoundly impact on therapeutic outcome.
Here, we report the results of a prospective randomized study in patients with AML aged 60-75 years eligible for an intensive and low-intensity induction treatment approach that were enrolled directly after achievement of first CR (CR1). The design enabled the assessment of the dropout rate of patients on consolidation and prior to HCT, the
chance of identifying a matched donor, the logistics of performing HCT within a predetermined maximal interval from diagnosis, and the kinetics of relapse.
Methods
Trial design
This is an international, prospective, open, randomized, controlled trial to compare allogeneic HCT versus conven- tional consolidation therapy in elderly patients with AML in CR1. The study design is detailed in the Online Supple- mentary Figure S1.
Patients, 60-75 years of age, with newly diagnosed AML were treated with one or two induction therapies (Online Supplementary Table S4A). After reaching CR1, patients were registered and subsequently HLA typed. A related/unrelated donor search was initiated and consolidation therapy started. After consolidation, patients were evaluated for comorbidity and hematological response. Eligible patients (see Online Supplementary Table S1) with an HLA-identical related or 10/10 matched unrelated donor were randomized (2:1 ratio) to receive HCT within 4 weeks or non-HCT consolidation according to institutional treatment protocols (Online Sup- plementary Table S4B) within 2 weeks after randomization. No additional chemotherapy was applied between random- ization and HCT or non-HCT treatment. Randomization used Pocock minimization with center, type of donor (unrelated vs. HLA-identical sibling donors) and risk group at diagnosis (high-risk vs. intermediate- to low-risk according to Grim- walde et al.20) as strata. Patients randomized to non-HCT treatment maintained the fallback option of using their stem cell donor in the event of relapse. The trial was approved by the ethics committees of the participating institutions, registered (EudraCT number: 2007-003514-34) and informed consent obtained from each participant.
Trial procedures
HCT was performed after conditioning with fludarabine/200 cGy total body irradiation and cyclosporine /mycophenolate mofetil immunosuppression as previously described.14,15 No ATG was used. Non-HCT consolidation was administered according to local protocols.
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