Lower relapse incidence with HAPLO versus MSD or MUD HCTs for AML patients with KMT2A rearrangement: a study from the Global Committee and the ALWP of the EBMT
Authors: Yishan Ye, Myriam Labopin, Jia Chen, Depei Wu, Tobias Gedde-Dahl, Didier Blaise, Gérard Socie, Edouard Forcade, Urpu Salmenniemi, Sébastien Maury, Jurjen Versluis, Ali Bazarbachi, Arnon Nagler, Eolia Brissot, Lin Li, Yi Luo, Jimin Shi, Fabio Ciceri, He Huang, Mohamad Mohty, Norbert Claude Gorin
Journal: Blood Cancer Journal (2024)

To the Editor, KMT2A-rearranged (KMT2Ar) AML has been categorized as adverse-risk with the exception of t(9;11)(p21.3;q23.3)/KMT2A-MLLT3considered as intermediate-risk in the 2022 European LeukemiaNet (ELN) classification [1].Pigneux et al. reported on 159 adult patients with KMT2Ar AML allografted in remission first (CR1) or second (CR2) between 2000 and 2010.The 2-year overall survival (OS) and leukemia-free survival (LFS) were 56 ± 4% and 51 ± 4%, respectively, indicating the potential role of allo-HCT in significantly improving the prognosis for adult patients with KMT2Ar AML [2].Different KMT2A fusion partners have been observed to predict survival in pediatric KMT2Ar AML [3,4], but their prognostic value in the transplant setting remains unclear.Since haploidentical donor HCTs (Haplo-HCT) might exert superior graft-versus-leukemia effects than Matched Sibling and Matched Unrelated Donor (MSD/MUD) transplants, especially in high-risk AML [5,6], we sought to discover if Haplo-HCT could bring benefit to AML patients with adverse-risk KMT2Ar (t(9;11) excluded) through relapse prevention.We also wished to investigate the prognostic value of different KMT2A fusion partners.We therefore conducted a retrospective international multicenter study using the EBMT (European Society for Blood and Marrow Transplantation) registry.The study protocol was approved by the EBMT and the institutional review board of each site.All patients had provided informed consent for data collection before transplantation.The study was conducted as per the Declaration of Helsinki and Good Clinical Practice guidelines.The eligibility criteria were as follows: ( 1) adult patients ≥18 years old; (2) first allo-HCT between January 2010 and December 2022; (3) eligible diagnosis: KMT2Ar AML in CR1 with available data on translocation involving 11q23 in the registry; (4) allo-HCTs from either a matched sibling (MSD), a 10/10 MUD or a T cell replete Haplo-HCT.The exclusion criteria were as follows: (1) allo-HCTs from mismatched UD (<10/10), umbilical cord blood, grafts with ex-vivo manipulation, or previous allo-HCT; (2) KMT2Ar AML with t(9;11); (3) patients without details on 11q23 chromosomal involvement.The conditioning regimens were defined as myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) according to the established definitions [7].Neutrophil and platelet engraftment was defined as absolute neutrophil count exceeding 0.5 × 10 9 /L and platelet count exceeding 20 × 10 9 /L for 3 consecutive days without transfusion, respectively.The primary study endpoint was LFS.Secondary endpoints were engraftment, OS, RI, non-relapse mortality (NRM), grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) (aGVHD), chronic GVHD (cGVHD) and extensive cGVHD, and GVHD-free, relapse-free survival (GRFS).All endpoints were measured from the date of transplantation.The follow-up time was calculated using the reverse Kaplan-Meier method.OS was defined as the time from transplant to death from any cause.LFS was defined as survival with no evidence of relapse or progression.GRFS events were defined as the first event among grade III-IV aGVHD, extensive cGVHD, relapse, and death from any cause.Acute and cGVHD were diagnosed and graded using the revised Glucksberg [8] and the NIH criteria [9], respectively.Patients' characteristics were compared between the different donor types using the Kruskal-Wallis test for continuous variables and the chi-squared or Fisher's exact test for categorical variables.The probabilities of OS, LFS, and GRFS were calculated using the Kaplan-Meier estimate.The probabilities of RI, NRM, aGVHD, and cGVHD were estimated using cumulative incidence curves.Both relapse and death were competing risks for GVHD.Univariate analyses were performed using the log-rank test for LFS, OS, and GRFS, and Gray's test for cumulative incidence estimates.Multivariate analysis was performed using a Cox proportional-hazards regression model, which included factors differing in distribution between the groups (with a p value less than 0.10), factors known to be associated with outcomes, plus a center frailty effect to take into account the heterogeneity across centers.GVHD prevention was not included in the Cox regression as it was related to donor type.Results were expressed as the hazard ratio (HR) with a 95% confidence interval (95% CI).All tests were two-sided with a type 1 error rate fixed at 0.05.Statistical analyses were performed with SPSS 25.0 (IBM Corp., Armonk, NY, USA) and R 4.0.2(R Core Team (2020.R: A language and environment for statistical computing.R Foundation for Statistical Computing, Vienna, Austria.URL https://www.R-project.org/).Data from 586 adult AML patients with adverse-risk KMT2A rearrangement receiving a first allo-HCT in CR1 in 183 EBMT centers between January 2010 and December 2022 were analyzed.Patients received an allo-HCT from 201 MSD, 256 MUD, and 129 Haplo, respectively.Translocation subsets t(6;11), t(11;19), t(10;11), or 'other' translocations (listed in Supplementary Table S1) accounted for 27.8%, 37.5%, 23.9%, and 10.8%, respectively.Table 1 describes the patient, disease, and transplant characteristics of the three cohorts.Details of conditioning regimens are summarized in Supplementary Table S2, and regimens for GVHD prevention are summarized in Supplementary Table S3.Post-transplant cyclophosphamide (PTCy) was more frequently used in Haplo-HCT (57.8%) than in MSD (8%) or MUD (7.1%) to prevent GVHD.In vivo T-cell depletion was more commonly used in MUD (81.2%), followed by MSD (46.3%) and Haplo-HCT (39.8%).Engraftment rates were comparable among the three cohorts (MSD 99.5%, MUD 98.4%, and Haplo 96.9%).