Two Non-myeloablative HLA-Matched Related Donor Allogeneic Hematopoietic Cell Transplant Regimens in Patients with Severe Sickle Cell Disease

Document Type

Journal Article

Publication Date

2-24-2025

Journal

Transplantation and cellular therapy

DOI

10.1016/j.jtct.2025.02.021

Keywords

alemtuzumab; allogeneic hematopoietic cell transplant; immune-depletion; mixed myeloid chimerism; non-myeloablative; sickle cell disease; sirolimus

Abstract

BACKGROUND: Non-myeloablative (NMA) conditioning is increasingly being used with success in matched related donor (MRD) and alternative donor allogeneic hematopoietic cell transplant (allo-HCT) in individuals with sickle cell disease (SCD). Advantages include decrease toxicity and applicability in patients otherwise unable to tolerate conditioning regimens due to end organ damage or age. OBJECTIVE(S): We aimed to add to published data outcomes of two similar NMA protocols "Protocol 1" (clinicaltrials.gov ID: NCT00061568) and "Protocol 2" (clinicaltrials.gov ID: NCT02105766)) in mainly adult patients with SCD to evaluate safety, toxicity, and success of these regimens in individuals at high-risk for poor transplant-related outcomes. We also evaluated the tolerability and outcomes of Protocol 2, which included pre-conditioning immuno-depletion, in patients at even higher risk of T-cell mediated rejection or plasma/B-cell mediated anti-donor erythrocyte antibody production-the latter due to ABO incompatibility or recipient red blood cell alloimmunization to a donor antigen. Lastly, we evaluated the incidence and trajectory of mixed donor myeloid chimerism over time following allo-HCT. STUDY DESIGN: In this retrospective analysis of the two prospective phase 2 NMA transplant protocols, 91 individuals with SCD or transfusion-dependent beta thalassemia underwent MRD allo-HCT at the National Heart, Lung, and Blood Institute; regimens contained alemtuzumab, low dose radiation, and sirolimus for graft-versus-host disease (GVHD) prophylaxis with or without preconditioning immuno-depletion with pentostatin and oral cyclophosphamide (Protocol 2). RESULTS: In the total cohort of 91 transplant recipients, outcomes were favorable with timely neutrophil and platelet engraftment (median: 21 days (range, 7-67) and 21 days (10-112), respectively), minimal high-grade acute and no chronic GVHD, overall survival of 90%, sickle-free survival of 85%, and mixed donor myeloid chimerism in 43% at a median follow up of 7.3 years (range, 0.8-20). Most patients with mixed myeloid chimerism at 2-years post-HCT remained stable in their values. In analyzing each protocol separately, outcomes were comparable except for higher cytomegalovirus reactivation requiring treatment in Protocol 2, without associated increase in graft failure. In the combined cohort, graft failure occurred in 11 patients and hematologic malignancy or abnormal cytogenetics on bone marrow evaluation developed in 7 recipients. On a sub-analysis of factors that may implicate transplant outcomes, the number of RBC units transfused post-HCT was significantly higher in recipients with pre-HCT history of alloimmunization to donor red blood cell antigens. There was no difference in RBC units transfused, duration of transfusion, or in red cell engraftment in those with major ABO incompatibility; pre-conditioning immune-depletion and pre-treatment with rituximab were likely helpful. CONCLUSION: Both NMA allo-HCT protocols were successful in achieving adequate engraftment and sickle-free survival with minimal toxicity, including in individuals with mixed donor myeloid chimerism. The addition of pre-conditioning immuno-depletion was well-tolerated and reduced graft failure rate in high-risk recipients.

Department

Pediatrics

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