Outcomes of 544 patients with t(6;9) Acute Myeloid Leukemia undergoing allogeneic stem cell transplantation: An EBMT Study on behalf of the acute leukemia working party (ALWP) and the pediatric diseases working party (PDWP)

Abstract

Abstract Background: The translocation t(6;9)(p23;q34)/DEK::NUP214 defines an adverse-risk subtype of acute myeloid leukemia (AML), for which allogeneic hematopoietic stem cell transplantation (allo-HSCT) is generally recommended. This rare entity, accounting for approximately 1% of AML cases, affects both pediatric and adult patients and is strongly associated with the presence of FLT3-ITD mutation.Methods: Patients with t(6;9) AML undergoing allo-HSCT between 2000 and 2022, were identified in the European Society for Blood and Marrow Transplantation registry and data were retrospectively analyzed. A multivariate analysis focused on patients in first complete remission (CR1) and a matched-pair analysis to assess the impact of FLT3-ITD mutation restricted to CR1 patients were performed.Results: A total of 544 patients, with a mean age of 39.3 years, were included in the analysis. At two years, overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI) and non-relapse mortality (NRM) were 65.7%, 59.1%, 23.0% and 17.9% respectively.The 431 patients transplanted in CR1 showed improved outcomes (OS: 71.7%, LFS: 65.8%, RI: 18.2% and NRM: 16.0%) compared to those transplanted in second or third CR (n= 41, OS: 44.3%, LFS: 40.8%, RI: 30.9% and NRM: 28.3%) and to those transplanted with active disease (n=72, OS: 44.0%, LFS: 31.9%, RI: 45.1% and NRM: 23.0%). Among CR1 patients, multivariate analysis showed better outcomes in pediatric and adolescent/young adult (AYA) and in patients transplanted in more recent years.OS, LFS and NRM progressively worsened starting from 40 years of age. At this threshold, the risk of death nearly doubled (OS: HR 2.29, 95% CI: 1.28–4.07, p=0.005), and similar trends were observed for LFS (HR 1.87, 95% CI: 1.12–3.12, p=0.02) and NRM (HR 2.42, 95% CI: 1.11–5.26, p=0.03).A further age-related deterioration was observed from 53 years of age, with stronger effects on OS (HR 3.13, 95% CI: 1.78–5.51, p<0.001), LFS (HR 2.61, 95% CI: 1.59–4.29, p<0.001), and NRM (HR 3.36, 95% CI: 1.54–7.32, p=0.002).RI also started to increase significantly from 53 years (HR 2.23, 95% CI: 1.16–4.28, p=0.02), and Graft-versus-Host Disease-Free/Relapse-Free Survival declined (HR 1.79, 95% CI: 1.2–2.68, p=0.004).A significant improvement in OS was observed in patients transplanted after 2017 (OS: 0.55, 95% CI: 0.33-0.91, p=0.02), mainly attributable to improvement in NRM without gain in RI. Donor type also influenced relapse risk in patients in CR1, with the use of unrelated donors being associated with significantly lower RI (HR 0.57, 95% CI: 0.34-0.94, p=0.03) compared to matched related donors, without, however, improvement in OS.Among CR1 patients with known FLT3-ITD status (n=242), a matched-pair analysis was performed on 152 patients (76 FLT3-ITD positive and 76 FLT3-ITD negative). The presence of FLT3-ITD mutations was associated with higher RI (HR: 3.12, 95% CI: 1.32–7.34, p=0.009), without impact on OS.Conclusion: To our knowledge, this is the largest analysis ever conducted on patients with t(6;9) AML undergoing allo-HSCT. In this population, outcomes were relatively favorable, especially when allo-HSCT is performed in CR1, with RI considerably lower than what is usually observed in other adverse-risk AML subsets. Among CR1 patients, pediatric and AYA subgroups derived the greatest survival benefit and improved outcomes have been reported in recent years, likely due to advances in supportive care. Unrelated donor use was associated with lower RI, possibly reflecting a stronger graft-versus-leukemia effect. The presence of FLT3-ITD mutation remains a relevant risk factor for relapse, though without impact on OS. The prognostic impact of other factors in t(6;9) AML, such as pre-transplant minimal residual disease and the role of FLT3 inhibitors, warrants further investigation.