A Single Dose of Donor Lymphocytes Depleted of Alloreactive T Cells (ATIR101) after Haploidentical HSCT Is Well-Tolerated and Efficacious: Pooled Analysis of Two Phase II Studies

Abstract

Introduction An ex vivo photodepletion method has been developed to produce ATIR101 (Kiadis Pharma), a donor lymphocyte infusion administered after haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) to aid immune reconstitution. ATIR101 is depleted of alloreactive T cells; early administration after T-cell-depleted haplo-HSCT has the potential to reduce serious complications resulting from delayed immune reconstitution. The safety and efficacy of ATIR101 are presented in a pooled analysis of 2 phase II trials: CR-AIR-007, NCT01794299; CR-AIR-008, NCT02500550. Methods A pooled analysis of 2 trials with similar protocols in 37 adult patients (1-year follow-up in n=34; data cut-off June 1, 2018). N=32 patients received a single dose of ATIR101 (2.0 × 106 cells/kg); n=5 discontinued after HSCT and did not receive ATIR101 (death n=2; graft failure n=1; batch rejection n=2). Of the 37 patients, 65% had acute myeloid leukemia, 27% had acute lymphoblastic leukemia, and 8% had myelodysplastic syndromes; patients had intermediate (57%) and high (43%) disease risk index. All underwent myeloablative conditioning followed by a CD34+-selected stem cell graft from a haploidentical family donor. ATIR101, prepared from the same donor, was given at a median of 28 days post HSCT without prophylactic immunosuppression. Outcomes were compared with a historic control group of 35 patients treated with a T-cell-depleted CD34+ selected haplo-HSCT without ATIR101 (CR-AIR-006, NCT02188290). Results Thirty-six patients engrafted, with neutrophil and platelet engraftment at a median (range) of 14 days (8–34) and 12 days (7–35) post HSCT, respectively. Non-relapse mortality (NRM) was 33% and relapse-related mortality was 8% compared with 66% and 15%, respectively, in the control group (Table). The overall survival (OS) was 58% vs 20% in the control group (Fig. A). Total chronic GVHD was 3% vs 11%, chronic severe GVHD was 0% vs 9%, and acute GVHD grade III–IV was 5% (all grade III) vs 6%, respectively. Survival analysis without grade III/IV acute GVHD, chronic GVHD requiring systemic treatment, or relapse (GRFS) showed significant separation for the pooled cohort vs control group (P=0.01; Fig. B); 1-year GRFS rates for both groups were 53% and 20%, respectively. Conclusion OS was ∼3-fold higher in the pooled cohort than in the control group. Disease relapse was limited and NRM in the pooled cohort was half that of the control group. ATIR101 was well tolerated. Results suggest that ATIR101 does not increase GVHD beyond the levels reported with a T-cell-depleted CD34+ selected HSCT alone. GRFS was >2.5-fold higher than in the control group; rates seem higher than reported in studies using post-transplant cyclophosphamide after T-cell-replete HSCT (Solh 2017, McCurdy 2017). A phase III trial of ATIR101 after T-cell-depleted haplo-HSCT vs PTCy after T-cell-replete haplo-HSCT is ongoing.