Transplantation Using Haploidentical Donors Outperforms Matched Sibling Donors in MRD+ ALL

Haploidentical donor transplantation (HIDT) led to stronger anti-leukemia activity compared with matched sibling donor transplantation (MSDT) in transplant-eligible patients with minimal residual disease (MRD)–positive acute lymphoblastic leukemia (ALL), according to results from a study reported during the 2020 European Society for Blood and Marrow Transplantation Annual Meeting.¹

Results showed that the cumulative incidence of MRD positivity following transplant was 26% (95% CI, 19%-33%) with HIDT versus 44% (95% CI, 28%-60%) with MSDT. Additionally, the 3-year cumulative incidence of relapse (CIR) was 2-fold higher in the MSDT cohort compared with the HIDT cohort, at 47% (95% CI, 31%-63%) versus 23% (95% CI, 17%-29%), respectively (P = .006).

Moreover, patients who underwent MSDT also experienced a lower 3-year probability of leukemia-free survival (LFS) compared with those who underwent HIDT, at 65% (95% CI, 58%-72%) versus 43% (95% CI, 27%-59%), respectively (P = .023), thus meeting the primary end point of the study.

By multivariate analysis, HIDT was shown to be significantly associated with low CIR (HR, 0.364; 95% CI, 0.202-0.655; P = .001), improved LFS (HR, 0.414; 95% CI, 0.246-0.695; P = .001), and prolonged overall survival (OS; HR, 0.380; 95% CI, 0.220-0.656; P = .001).

“Haploidentical donors have become an alternative source for allogeneic stem cell transplantation for patients who require [the procedure] but have no related or unrelated donors with matching human leukocyte antigen (HLA),” explained Ying-Jun Chang, MD, professor of Health Sciences at Peking University Institute of Hematology Peking University People’s Hospital, in a presentation during the meeting.

“HLA-identical sibling donors remain the first choice, although several studies have shown that treating patients with ALL using haploidentical donors could achieve comparable outcomes to those who undergo HLA-matched sibling donor transplantation,” added Chang. “On the other hand, using haploidentical transplants, the graft-versus-leukemia effect may be stronger, as mismatches for HLA antigens on leukemic cells would provide allo-immune targets.”

In the prospective, biologically randomized phase 2 trial, Chang and colleagues set out to further evaluate the benefit associated with HIDT versus MSDT. The trial enrolled patients with ALL who achieved a complete remission following chemotherapy but had MRD prior to transplantation. MRD was confirmed by multiparametric flow cytometry in all patients before and after transplantation.

A total of 208 patients with MRD positivity prior to transplantation were included in the analysis; 169 were genetically randomized to HIDT and 39 patients were randomized to MSDT. Prior to transplantation, all patients received the same myeloablative conditioning regimen previously used by the study investigators.² 

The recipients of HIDT and MSDT were comparable in terms of gender, time from diagnosis to HSCT, disease subtype and status, as well as pre-transplantation MRD levels; however, they differed in terms of age. In the HIDT cohort, 63.3% of patients were male with a median age of 24 years; the median level of pre-transplant MRD was 0.07% in this group. The patients in the MSDT arm were older, with a median age of 35 years, and 53.8% were male; the median pre-transplant MRD level in this group was 0.5%.

LFS served as the primary end point of the trial, while key secondary end-points included engraftment rate, the cumulative incidence of MRD following transplantation, relapse, non-relapse mortality (NRM), OS, as well as the incidence of acute graft-versus-host disease (GVHD) grades II-IV and chronic GVHD.

All patients provided bone marrow aspirate samples at the baseline assessment prior to transplant and at approximately 30 to 180 days following transplantation; these samples underwent clinical testing by 8-color MFC.

Additional results from the trial showed that the 100-day cumulative incidence of platelet engraftment in the HIDT group was significantly lower than that in the MSDT group, at 95% (95% CI, 92-98%) versus 100%, respectively (P < .001).

However, the 100-day cumulative incidence of acute GVHD grades II-IV was similar between the cohorts, at 21% (95% CI, 17%-27%) with HIDT versus 23% (95% CI, 10%-36%) with MSDT ( P = .884); this was true for patients with grade III-IV GVHD, as well, at 6% (95% CI, 3%-9%) versus 5% (95% CI, 0%-12%), respectively (P = .838). In addition, the 3-year cumulative incidence of total chronic GVHD was also comparable between the HIDT and MSDT groups, at 44% (95% CI, 36%-52%) and 48% (95% CI, 31% vs 65%), respectively (P = .850); the same held rue for moderate to severe chronic GVHD, at 18% (95% CI, 10%-26%) versus 27% (95% CI, 10%-44%), respectively (P = .192).

Overall survival (OS) also significantly favored HIDT; specifically, the 3-year probability of OS with HIDT was 68% (95% CI, 61%-75%) versus 46% (95% CI, 30%-62%) with MSDT (P = .039).

NRM rates were comparable in both groups at 10% with HIDT versus 11% with MSDT (P = .845).

“The current study paves the way to determine that haploidentical donors are the preferred choice regardless of available matched sibling donors in a subgroup population,” the study authors concluded.

References

1. Chang Y-J, Wang Y, Xu L-P, et al. Haploidentical donor beats matched sibling donor for pre-transplantation MRD positive ALL: a phase 3 genetically randomized study. Presented at: 2020 European Society for Blood and Marrow Transplantation Annual Meeting; August 20-September 2, 2020; Virtual. Abstract O103. https://bit.ly/3m8TING.
2. Wang Y, Liu Q-F, Xu L-P, et al. Haploidentical versus matched-sibling transplant in adults with Philadelphia-negative high-risk acute lymphoblastic leukemia: a biologically phase III randomized study. Clin Cancer Res. 2016;22(14):3467-3476. doi:10.1158/1078-0432.CCR-15-2335