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Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Summary: Graft‐versus‐host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti‐thymocyte globulin (ATG) and post‐transplant cyclophosphamide (PTCy) are used as lymphocyte‐depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non‐myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II–IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3‐year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non‐relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy‐based regimens resulted in a significantly lower rate of acute GvHD than ATG‐containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies. [ABSTRACT FROM AUTHOR]