Comparative Study for Haplo, MSD and MUD Allo-Hcts for AML Patients with KMT2A Rearrangement: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background

Acute myeloid leukemia (AML) patients with KMT2A rearrangement (KMT2Ar, except for t(9;11)(p21.3;q23.3)/MLLT3::KMT2A) are classified as adverse risk in the 2022 European LeukemiaNet (ELN) classification. There is uncertainty on their outcome following allogeneic cell transplantation (allo-HCT). We compared, in an European Society for Blood and Marrow Transplantation (EBMT) global multi-center registry-based analysis, outcomes following an allogeneic stem cell transplantation (allo-HCT) with either a matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAPLO).

Methods

Data from 586 AML patients with KMT2Ar receiving a first allo-HCT in 183 EBMT centers from 2010-2022 were analyzed. All patients achieved first complete remission (CR1) before transplantation. Patients with t(9;11), without details on translocation, receiving mismatched UD (<10/10), umbilical cord blood, or grafts with ex-vivo manipulation were excluded. Univariant analysis and Cox regression models were used.

Results

KMT2A rearranged AML patients received allo-HCT from 201 MSD, 256 10/10 MUD, and 129 HAPLOs. For KMT2Ar type, t(6;11), t(11;19), t(10;11) or other translocations account for 27.8%, 37.5%, 23.9% and 10.8%, respectively. Peripheral blood was the major graft source (83.2%), and myeloablative conditioning accounted for the majority (60.2%) of all allo-HCTs. Engraftment rates were comparable in the three cohorts (MSD 99.5%, MUD 98.4% and HAPLO 96.9% p=0.17). AML relapse was the major cause of death in each donor cohort.

On univariate analysis, HAPLO was associated with a lower 2-year relapse incidence (RI) (MSD 41.1%, MUD 37.2%, HAPLO 20%) but a higher 2-year non-relapse mortality (NRM) (MSD 6.1%, MUD 19.3%, HAPLO 21.3%) compared with MSD and MUD. The 180-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was lower in MSD (18.8%) than in MUD (31.3%) or HAPLO groups (26.5%), respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were comparable among the three cohorts. Lower RI was observed in patients with t(11;19) compared with t(6;11) or t(10;11). Complex karyotype (CK) (at least 3 abnormalities) or monosomal karyotype (MK) were both associated with higher RI compared with those without. In addition, in-vivo T cell depletion was related to lower intensive chronic GVHD (cGVHD) incidence.

On multivariate analysis, HAPLO HCT was associated with lower RI (hazard ratio [HR=0.46], 95% CI 0.28-0.77; p<0.01) but higher incidence of NRM (HR=2.36, 95% CI 1.17-4.78; p<0.01) compared with MSD, while HAPLO had no significant impact on LFS, OS and GRFS. MUD HCT was associated with higher incidence of grade II-IV aGVHD (HR=1.82, 95% CI 1.19-2,78; p<0.01), NRM (HR=2.73, 95% CI 1.51-4.94; p<0.01), and lower LFS (HR=1.37, 95% CI 1.03-1.83; p<0.05) compared with MSD (reference). Concerning translocation type, t(11;19) was associated with a lower RI (HR=0.64, 95% CI 0.43-0.94; p=0.022), a better LFS (HR=0.66, 95% CI 0.48-0.91; p=0.012), OS (HR=0.63, 95% CI 0.45-0.89; p=0.008) and GRFS (HR=0.75, 95% CI 0.57-1; p=0.049) compared with t(6;11)(reference). Translocations other than t(6;11), t(11;19) or t(10;11) were related to a lower RI (HR=0.45, 95% CI 0.24-0.87) and better OS (HR=0.57, 95% CI 0.34-0.95) compared to t(6;11). MK was associated with higher RI (HR=1.59, 95% CI 1.04-2.45; p<0.05) and lower LFS (HR=1.47, 95% CI 1.01-2.14; p<0.05).

Conclusions

For AML patients with KMT2Ar, HAPLO HCT was associated with a lower RI but higher NRM, leading to similar LFS, OS and GRFS compared with MUD and MSD HCTs. In the setting of allo-HCT, t(11;19) seems to be associated with favorable outcomes compared with other KMT2Ar.