Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αß TCell-Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia.

Depletion of αß T cells from the graft prevents graft-versus-host disease (GVHD) and improves the outcome of hematopoietic stem cell transplantation (HSCT) from haploidentical donors. Delayed recovery of adaptive immunity remains a problem, which can be approached by adoptive T-cell transfer. In a randomized trial, we have assessed the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αß T-cell depletion. Antithymocyte globulin (ATG) is viewed as an essential component of preparative regimen, critical for both prevention of graft failure and GVHD. Variable pharmacokinetics of ATG may significantly affect lymphocyte subpopulations after HSCT. To uncover the potential of mDLI, we replaced rabbit ATG with tocilizumab and abatacept. Here we compare post hoc the immune recovery and the key clinical outcomes, including nonrelapse mortality (NRM), overall- and event-free survival (OS and EFS), between the cohort enrolled in the prospective randomized trial and a historical cohort, comprised of patients grafted with a conventional ATG-based HSCT with αß T cell depletion. A cohort of 149 children was enrolled in the prospective trial and 108 patients were selected as historical controls from a prospectively populated database. Patient population was comprised of children with high-risk hematologic malignancies, with more than 90% represented by acute leukemia. Median age at enrollment was 8.8 years. In the prospective cohort 91% of the donors were haploidentical parents, whereas in the historical cohort 72% of the donors were haploidentical. Conditioning was based on either 12Gy total body irradiation or treosulfan. Thiotepa, fludarabine, bortezomib, and rituximab were used as additional agents. Patients in the historical cohort received rabbit ATG at 5 mg/kg total dose, while prospective cohort patients received tocilizumab at 8 mg /kg on day -1 and abatacept at 10 mg/kg on days 0, 7, 14, and 28. Patients in the prospective trial cohort were randomized 1:1 to receive mDLI starting on day 0, whereas 69% of historical cohort patients received mDLI after engraftment, as part of previous trials. Primary engraftment rate was 99% in the prospective cohort and 98% in the historical cohort. The incidence of grade II-IV aGVHD was 13% in the prospective cohort and 16 % in the control group. Chronic GVHD developed among 13% (historical) and 7% (prospective) cohorts (P = .07). The incidence of cytomegalovirus viremia was 51% in the prospective cohort arm and 54% in the historical control arm (p = ns). Overall, in the prospective cohort 2-year NRM was 2%, incidence of relapse was 25%, EFS was 71%, and OS was 80%, whereas in the historical cohort 2-year NRM was 13%, incidence of relapse was 19%, EFS was 67%, and OS was 76%, difference non-significant for relapse and survival. NRM was significantly improved in the ATG-free cohort (P = .002). Recovery of both αß- and γδ- T cells was significantly improved at days +30 and +60 after HSCT in recipients of ATG-free preparative regimens, as well as recovery of naïve T cells. Among the recipients of αß T-cell-depleted grafts, replacement of ATG with nonlymphodepleting abatacept and tocilizumab immunomodulation did not compromise engraftment and GVHD control and was associated with significantly lower NRM and better immune recovery early after HSCT.

Safety and efficacy of the low-dose memory (CD45RA-depleted) donor lymphocyte infusion in recipients of αß T cell-depleted haploidentical grafts: results of a prospective randomized trial in high-risk childhood leukemia.

Depletion of αß T cells from the graft prevents graft-vs.-host disease (GVHD) and improves outcome of HSCT from haploidentical donors. In a randomized trial, we aimed to evaluate the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αß T-cell depletion. A cohort of 149 children was enrolled, 76 were randomized to receive scheduled mDLI and 73 received standard care. Conditioning was based on either 12 Gy total body irradiation or treosulfan. Rabbit antithymocyte globulin was replaced by tocilizumab and abatacept. Primary end points were the incidence of acute GVHD grades II-IV and the incidence of cytomegalovirus (CMV) viremia. The incidence of grades II-IV aGVHD was 14% in the experimental arm and 12% in the control arm, p-0.8. The incidence of CMV viremia was 45% in the experimental arm and 55% in the control arm, p-0.4. Overall, in the total cohort 2-year NRM was 2%, cumulative incidence of relapse was 25%, event-free survival 71%, and overall survival 80%, without difference between the study arms. Memory DLI was associated with improved recovery of CMV-specific T-cell responses in a subcohort of CMV IgG seropositive recipients.