Immune tolerance induction after haploidentical stem cell transplant following organ transplantation in sickle cell disease

Abstract Background: Sickle cell disease (SCD) is debilitating inherited hemoglobinopathy leading to progressive, age-dependent multi-organ damage, SCD related organ dysfunction of vital organs such as liver and kidney dysfunction posing significant challenges to curative treatment leading to significant morbidity and early mortality in young adults. While hematopoietic stem cell transplantation (HCT) remains the most affordable and accessible established modality of cure for SCD, but transplantation-related risks often deter its use, especially in patients with severe comorbidities. Solid organ transplantation (SOT) can address end-organ failure but does not treat the underlying SCD. We report, for the first time, the feasibility, safety, and success of sequential solid organ transplantation followed by non-myeloablative haploidentical HCT (haplo-HCT) from the same living related donor in patients with severe SCD and advanced organ failure. Methods: To the best of our knowledge, this is the first reported series utilizing a combined approach of orthotopic solid organ transplantation (liver or kidney) followed by haplo-HCT in patients with severe SCD and advanced liver or kidney dysfunction. Employing nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide (PTCy). At King Faisal Specialist Hospital and Research Centre. Four patients with homozygous SCD and advanced hepatic (n=3) or renal (n=1) dysfunction underwent planned sequential living donor liver (LDLT) or kidney (LDKT) transplantation followed by haplo-HCT from the same haploidentical related donor. A non-myeloablative conditioning regimen consisting of rabbit anti-thymocyte globulin, thiotepa, fludarabine, cyclophosphamide, and low-dose total body irradiation (200 cGy) was used. Bone marrow was the stem cell source. Graft-versus-host disease (GvHD) prophylaxis included PTCy, Sirolimus, and Mycophenolate mofetil. Immunosuppression tapering began 12 months post-HCT, guided by donor chimerism and graft function. Patients were monitored for donor chimerism, immune reconstitution, graft function, and infectious complications. Results: With a median follow-up of 37.5 months (IQR: 2.25–55.25), all four patients (3 males, 1 female; median age 25 years, IQR: 22.75–27.5) successfully completed sequential transplantation, all patients are alive with stable SOT and HCT graft function. The median interval between SOT and HCT was 5.5 months (IQR: 2.5–9.5). Median donor age 30 yrs (IQR: 28.5-32.25 yrs). Median CD34 graft dose was 5.24 x 10 6 /kg (IQR: 4.25-6.10) and TNC of 7.7 x 10 7 /kg (6.27-9.88). Full donor chimerism (≥95%) in myeloid and lymphoid compartments was achieved by day +30 in all patients; one patient maintained stable mixed chimerism (>90%). Median neutrophils and platelet engraftment was 21 and 33 days, respectively. No cases of acute or chronic GvHD, solid organ rejection, or graft failure were observed. At one-year post-HCT, hemoglobin S (Hb S) was undetectable (0%) in three patients; the remaining patient, who received HCT from a sickle cell trait donor, had Hb S of 24%. Three patients have been successfully weaned off immunosuppressive therapy, and one is tapering. Immune reconstitution was robust, with restoration of CD4+, CD8+, and NK cell subsets. Ferritin levels improved in all patients post-HCT, suggesting reversal of transfusion-related iron overload. Only one patient experienced an asymptomatic CMV reactivation that was successfully treated. Conclusion: To the best of our knowledge, this is the first reported series of patients with severe SCD who successfully underwent sequential solid organ transplantation liver or kidney followed by haplo-HCT, utilizing the same HLA-related donor for both procedures. Our experience demonstrates the feasibility, safety, and curative potential of dual transplantation using the same haploidentical related donor in patients with advanced SCD and related liver or kidney dysfunction. This strategy offers a curative platform durable donor chimerism, organ graft function, and successful immunosuppression withdrawal through the induction of immune tolerance for advance SCD with severe organ dysfunction. With improved transplantation protocols and supportive care, dual sequential haplo-SOT/HCT from the same donor represents a promising and viable curative platform for selected high-risk SCD populations. This strategy approach should be considered a viable option in selected high-risk SCD populations.