Successful Allogeneic Alternative Donor Hematopoietic Stem Cell Transplantation in High-Risk Patients with Severe Sickle Cell Disease
Authors: Klahr Miriam , Assal Amer , Reshef Ran , Pan Samuel S. , Bhatia Monica , George Diane , Mapara Markus Y 
Published: December 2024

Introduction:
While gene therapy approaches appear promising and have recently received FDA approval, allogeneic hematopoietic stem cell transplant (HSCT) is currently considered to be the only curative treatment option for patients with severe sickle cell disease (SCD). Here, we present our institutional experience using alternative donors (AD) in comparison to patients with matched related donors (MRD).
Methods:
Eligibility for HSCT included frequent vaso-occlusive crises and evidence of end-organ damage. Non-myeloablative conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) was used for MRD HSCT (n=12). AD consisted of three donor types, matched unrelated (n=4), mismatched unrelated (n = 5), or haploidentical donors (n = 1). Patients undergoing AD transplants (n=10) were treated with either an in-house IRB-approved research protocol using CD34 selection (Alemtuzumab [54 mg/m2], fludarabine [180 mg/m2], and melphalan [140 mg/m2]) conditioning (n=7) or a standardized protocol with Alemtuzumab, TBI, and post-transplant Cyclophosphamide (PTCy) (n=3). All patients received G-CSF mobilized peripheral blood. All patients underwent RBC exchange to achieve Hgb S &lt;30% before the start of conditioning. Data is reported using n (%) or median (range).
Results:
Median age at time of transplant in years was 29 (21-42) for MRD recipients and 26 (18-44) for AD recipients. All patients were homozygous for hemoglobin S except one with hemoglobin Sβo-thalassemia in the MRD group and another heterozygous for hemoglobin S and C in the non-MRD group. The cohorts included 12 patients with sickle cell nephropathy (defined as a GFR &lt;60 or evidence of proteinuria). Of these patients, five had end-stage-renal-disease (ESRD) (MRD n=2 v. PTCy = 3, p = 0.004). Notably, the MRD group included one patient with a renal allograft from the same donor. Two of the five patients with ESRD underwent a successful cadaveric donor kidney transplant following HSCT. Median follow-up was 50.3 months (9.2-107.7) for MRD recipients and 57.1 months (4.7 - 85.1) for AD.
All patients engrafted with no cases of graft failure and with recipients of CD34-selected grafts having a quicker ANC engraftment. Furthermore, donor T cell chimerism at 1-year post-transplant was also significantly higher in the CD34 group (p = 0.037). Overall survival was 100% in MRD vs 90% (9/10) in AD patients (p = 0.455). One patient on the CD34-selected protocol died at 554 days due to sepsis. GVHD occurred in 4/12 MRD patients and 4/10 AD patients (p = 0.716). All GVHD cases were steroid-responsive and resolved. One patient in the MRD group and four patients in the non-MRD group developed Posterior Reversible Encephalopathy Syndrome (PRES. p = .163). The median length of stay for transplant admission was not different between MRD (35 days [27 - 71]) and AD recipients (42 days [36 -70]) (p = 0.127). The number of hospital readmissions per patient within the first year of transplant showed marked variation in both groups, with a median of 2 (0-5) readmissions per patient in the MRD group and 3 (1-9) for AD (p = 0.299). Post-transplant markers of hemolysis (LDH, haptoglobin, absolute reticulocyte count, and indirect bilirubin) were studied as surrogate markers for clinical efficacy. We observed a decrease in all hemolysis markers at six months and one-year post-transplant.
Conclusion:
AD HSCT is feasible in high risk SCD patients even with ESRD, but is associated with higher, though not statistically significant, rates of transplant-related complications (e.g., PRES, hospital readmissions) compared to MRD. Given these encouraging results in patients with nephropathy, development of sequential or combined kidney HSCT procedures should be pursued for patients with SCD to allow better access to kidney graft allocation.