Matched unrelated vs. Haploidentical  donor for allogeneic stem cell transplantation in patients with acute leukemia with identical GvHD prophylaxis – a randomized prospective european trial.

Abstract Haplo-identical allogeneic cell transplantation (haploHCT) using post- transplant cyclophosphamide (PTCy) is increasingly used if no matched related or unrelated donor (MUD) is available. Retrospective studies suggest a stronger GvL effect after haploHCT than MUDHCT. To test the hypothesis that haploHSCT reduces the risk of relapse by 10% we performed an open label, two-arm, multicenter, multinational, randomized phase II trial comparing anti-leukemic activity of HCT for patients with acute leukemia in complete remission (CR) between a 10/10 HLA MUD and a haploidentical donor using identical GvHD prophylaxis consisting of PTCy, Tacrolimus and MMF (NCT04232241). Major inclusion criteria were AML intermediate and adverse risk according ELN or ALL high risk in 1. CR, or AML/ALL in second CR , high risk MDS in CR, age 18-70 years, ECOG ≤2, 10/10 HLA MUD and haplo-identical (≥ 5/10 and ≤8/10 HLA) family donor available. To detect a difference of 10% in relapse incidence at 2 years, 220 patients (pts) per arm are needed. A planned interim and futility analysis was performed after 171 pts were included and 158 pts were randomized to MUD (n=78) or HaploHCT (n= 80). The median age of the pts was 56 years (range 18-70), and 60% were male and 40% female of a mainly Caucasian European population. Disease and patient characteristics were well balanced in both arms regarding disease, AML CR1 (57%) or CR2 (10%) ALL CR1 (21%) and CR2 4% and HR- MDS in CR (6%), median donor age ( 29 vs 31 years) and conditioning intensity: Busulfan (for AML) and TBI (for ALL) based RIC (62%) or MAC (38%). 9/78 in MUD and 9/80 in Haplo discontinued the study due to early progress, withdrawn of consent or others. Due to the unavailability of the donor assigned by randomization, 6/69 pts randomized to MUD received a haplo HSCT and 5/71 pts randomized to HaploHSCT received a MUD; thus, according to Intention to treat (ITT), 78 pts were assigned to MUD while 68 pts received MUD according per protocol (PPP), and in the haploHCT group 80 pts were analyzed acc. ITT and 72 pts according PPP, respectively. The cumulative incidence of relapse at 2 years for MUD and Haplo was 33% (95%CI: 20-46) und 28% (95% CI: 17-42) in the ITT population (p=0.9) and 25% (95%CI:13-39) and 29% (95%CI:17-42) in the PPP population (p=0.4), respectively. The non-relapse mortality (NRM) at 1 year for MUD vs Haplo was 3% (95%CI: 0.5-9) vs 5% (95% CI:2-12) in the ITT population and 5% (95%CI: 1-12) vs 4% (95%CI:1-11) in the PPP (p=0.9), respectively , resulting in an event-free survival (EFS) of 60% vs 64% acc. to ITT- and 65% vs 65% to PPP (p=0.7) and a 2 year overall survival (OS) of 68% vs 77% in the ITT – and 74% vs 75% in the PPP (p=0.77), respectively. The composite endpoint of GvHD/relapse free survival at 2 years acc. to PPP was 61% (95% CI: 48-78) for MUD and 60% (95%CI: 47-75) for haploHCT (p=0.5). Primary graft failure occurred in 3 pts, all iafter haploHCT, and the median time to neutrophile engraftment ANC>1.0x10e9/L and platelets>20x10e9/L was 18 (r.:13-49) and 16 days (r.:1-76) after MUD and 19 (r.:13-36) (p=0.16) and 23 days (r.:6-87) after HaploHCT (p= 0.03). The incidence of any acute GvHD, grade II-IV and severe III/IV GvHD was similar between MUD and Haplo according actual treatment: 35% vs 43%, 17% vs 22% and 4% vs 7%, (p=0.44) respectively. Similar incidence between MUD and Haplo was observed for any cGvHD: 24% vs 15%, mild: 13% vs 7%, moderate: 7% vs 7% and severe: 2% vs 1%, (p=0.31) respectively. Infectious complications were observed in 40% vs 31% (p= 0.34) and AEs grade 3 or higher in 40% vs 36% after MUD and HaploHCT, respectively. Further analysis did not show any benefit for haploHCT or MUD in any investigated subgroup. According to the results, the Data Safety Monitoring Board recommend stopping recruitment because it is unlikely to show a 10% superiority of HaploHCT to MUD regarding relapse incidence with the planned sample size. The planned interims analysis of our prospective randomized multicenter study comparing 10/10 MUD with haploHCT using identical PTCy based GvHD prophylaxis showed comparable toxicity, low GvHD incidence, low NRM and favourable outcome in both arms suggesting that further recruitment will unlikely show superiority regarding endpoint of reducing relapse incidence.