Haploidentical Hematopoietic Cell Transplantation Combined with an Unrelated Cord Blood Unit for Adult Acute Myeloid Leukemia Results in Improved Survival Compared to Haploidentical Hematopoietic Cell Transplantation: Results of a Multicenter, Randomized, Phase III Trial
Authors: Zhou Biqi , Chen Jia , Liu Tianhui , Zhang Yanming , Ye Yishan , Ding Yiyang , Zhu Mingqing , Ma Xiao , Li Xiaoli , Lin Zhihong , Huang He , Xu Yang , Wu Depei 
Published: December 2023

Introduction
Haploidentical hematopoietic cell transplantation (haplo-HCT) is a potent treatment to improve the prognosis of acute myeloid leukemia (AML), but relapse and graft-versus-host disease (GVHD) related to dysregulation of alloreactivity are still the main causes of death posttransplantation. Cord blood graft usually has a promising graft-versus-leukemia effect with a lower cumulative incidence of GVHD. To improve the transplantation strategy, haplo-cord HCT combining haploidentical and unrelated cord blood (UCB) grafts (haplo-cord HCT) has been attempted. Previous studies showed significant improvement in prognosis in B-cell acute lymphoblastic leukemia or refractory acute leukemia patients with haplo-cord HCT compared to haplo-HCT. However, outcomes of haplo-cord HCT for AML patients are not yet clear. This is the first multicentric randomized trial designed specifically for the efficacy and safety of haplo-cord HCT for AML.
Methods
This is a multicenter, randomized, open-label, phase III study conducted in 5 centers in China (NCT03719534). Patients aged 18-60 years, diagnosed with AML (except for acute promyelocytic leukemia) with measurable residual disease, had an available haploidentical donor and were suitable for allotransplantation were enrolled. Patients were randomized 1:1 to receive UCB and haploidentical grafts infusion after Bu/Cy-based regimen or haploidentical graft infusion only after Bu/Cy-based regimen. The UCB unit, which had at least 3/6 matched HLA loci to the recipient and more than 1×10 4 CD34 + cells/kg of recipient weight, was infused immediately after resuscitation and eight hours before the haploidentical graft infusion. The primary endpoint was 3-year overall survival (OS) and secondary endpoints included progression-free survival (PFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM).
Results
From June 1, 2017, to June 30, 2021, 268 patients were enrolled (Table 1). With a median follow-up of 36.00 months, the 3-year OS was 80.5% (95% CI 73.7-87.9) in the haplo-cord HCT group and 67.8% (95% CI 60.0-76.5) in the haplo-HCT group, respectively (p=0.013, figure 1A). Haplo-cord HCT group showed favorable 3-year PFS and CIR than haplo-HCT group (PFS: 70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p=0.012; CIR: 12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p=0.024, figure 1B,C). The 3-year NRM was similar in the two groups (figure 1D).
Within two years posttransplantation, the most common grade 3-4 adverse events (AEs) in the haplo-cord HCT and haplo-HCT groups were infections (33.8% and 29.1%), acute GVHD (20.3% and 12.7%) and chronic GVHD (12.0% and 16.4%). AEs leading to death occurred in 8.3% of haplo-cord HCT and 14.9% haplo HCT patients.
Post- hoc analysis showed similar median levels of haploidentical chimerism in bone marrow (BM) between the two groups. However, UCB microchimerism was detected in the haplo-cord HCT patients by SNP-NGS in +1m posttransplantation (BM: 0.3%, IQR 0.04-1.6; peripheral blood: 0.06%, IQR 0.03-0.4) and its chimerism percentage decreased with time (figure 1E). Compared to haplo-HCT group, haplo-cord HCT group showed a faster cumulative incidence of neutrophil recovery (p=0.026, figure 1F) and a similar cumulative incidence of platelet recovery. Monitor of immune reconstitution showed a more rapidly increasing rate of T cells in the early period after transplantation in the haplo-cord HCT group (figure 1G). Improved recovery of Th2 (p=0.042), Th17 (p=0.047), Treg (p=0.045), and Tc2 (p=0.045) cells was observed in haplo-HCT group.
Conclusions
Coinfusion of a UCB unit in haplo-HCT can improve OS in AML patients without excessive AEs, and affect T-cell reconstitution pattern posttransplantation. Haplo-cord HCT could serve as a suitable therapeutic option for this patient population.