Haploidentical hematopoietic cell transplantation (Haplo-HCT) using ex vivo TCR-αβ–Depleted grafts and upfront memory T-cell add-back mitigates the negative impact of pre-transplant measurable residual disease (MRD) in adults with Acute Myeloid Leukemia (AML) and acute lymphoblastic leukemia (ALL) compared to matched related and unrelated donor transplantation

Abstract

Abstract Background Previous studies have shown that in patients receiving allogeneic hematopoietic cell transplantation (HCT) from either a human leukocyte antigen (HLA)-matched sibling donor (MSD) or matched unrelated donor (MUD), the presence of measurable residual disease (MRD) prior to transplant (pre-HCT MRD) is associated with a significantly increased risk of post-transplant relapse and mortality. However, the prognostic impact of pre-HCT MRD in patients undergoing haploidentical HCT using an ex vivo T cell–depleted (TCD) platform remains poorly defined. Methods In this multicenter retrospective study, we analyzed outcomes of 247 adult patients (median age: 18–75 years) with acute myeloid leukemia (AML; n=189) and acute lymphoblastic leukemia (ALL; n=58), all in morphological remission at the time of transplant as determined by multiparameter flow cytometry. All patients underwent allogeneic HCT between January 2017 and May 2025. The cohort included 137 patients who received haploidentical HCT with reduced-intensity conditioning (RIC) using an ex vivo T cell receptor alpha/beta (TCRαβ) and CD45RA-positive–depleted graft platform (Koh et al., Blood 2022;140:4707–8); 63 patients who received MSD HCT; and 47 patients who received MUD HCT, following either myeloablative conditioning (MAC; n=77) or RIC (n=33). Results At a median follow-up of 33 months (range: 3–101 months), the three-year overall survival (OS) rates for the haploidentical-TCD, MSD, and MUD groups were 74%, 73%, and 62%, respectively (p=0.50). Event-free survival (EFS) rates were 69%, 58%, and 47%, respectively (p=0.25). At two years, the cumulative incidence (CI) of relapse was significantly lower in the haploidentical-TCD group (16%) compared to the MSD (32%) and MUD (41%) groups (p=0.03). Transplant-related mortality (TRM) at two years was comparable across cohorts (14% vs. 10% vs. 12%, p=0.63). CI of acute graft-versus-host disease (GVHD) grades II–IV and III–IV by day 180 were not significantly different among groups. However, the CI of chronic GVHD (cGVHD) was markedly lower in the haploidentical-TCD cohort (7%) compared to MSD (49%) and MUD (21%) recipients (p<0.001). These differences translated into significantly superior three-year GVHD/relapse-free survival (GRFS) in favour of the haploidentical-TCD group (63% vs. 22% vs. 36%; p<0.001). Patients without pre-HCT MRD had better three-year outcomes than those with pre-HCT MRD: OS (72% vs. 46%, p=0.08), EFS (73% vs. 51%, p=0.003), and GRFS (53% vs. 39%, p=0.09). Among pre-HCT MRD–positive patients, the two-year relapse incidence was lowest in the haploidentical-TCD group (15%) as compared to MSD (27%) and MUD (55%) (p<0.001). These differences translated into a trend toward improved OS (p=0.44) and significantly better EFS (p=0.05) and GRFS (p=0.005) for haploidentical-TCD recipients as compared to MSD and MUD recipients among MRD-positive patients. In contrast, among MRD-negative patients, relapse incidence did not differ significantly across the three donor groups (p=0.50). In multivariate analysis, haploidentical-TCD HCT was independently associated with superior GRFS (hazard ratio [HR] = 0.68; 95% confidence interval [CI], 0.50–0.90; p=0.016), while pre-HCT MRD positivity remained an independent predictor of relapse (HR = 2.05; 95% CI, 1.18–3.71; p=0.001). Importantly, the adverse prognostic impact of pre-HCT MRD on OS, EFS, and GRFS was effectively mitigated in the haploidentical-TCD group, with comparable outcomes between MRD-positive and MRD-negative recipients: three-year OS (72% vs. 77%; p=0.31), EFS (65% vs. 74%; p=0.26), and GRFS (61% vs. 66%; p=0.50). Conclusion Pre-HCT measurable residual disease does not significantly impact post-transplant outcomes in patients receiving haploidentical HCT using an ex vivo T cell–depleted platform. In patients with pre-HCT MRD, this approach is associated with the lowest risk of relapse and the most favorable overall survival when compared to MSD or MUD transplantation. These results suggest that additional chemotherapy to eradicate MRD prior to transplant may be unnecessary if a haploidentical donor is readily available. This strategy offers an effective and timely alternative for patients lacking HLA-matched donors while avoiding the delay and cost associated with unrelated donor searches.