Haploidentical hematopoietic stem cell transplant for patients with sickle cell disease using thiotepa, fludarabine, thymoglobulin, low dose cyclophosphamide, 200 cGy tbi and post transplant cyclophosphamide

Background Allogeneic hematopoietic stem cell transplant (HSCT) for sickle cell disease (SCD) is limited by lack of related donors with <20% having an HLA identical sibling. We have previously reported in 2018 the preliminary results (N=4) on the use of a novel myeloablative preparative regimen utilizing thioptepa. (Frangoul et al BMT 53(5):647-650). Methods In 2019 the study was expanded to a 2nd pediatric transplant center. The preparative regimen consisted of antithymocyte globulin 0.5mg/kg on day −9 and 2 mg/kg on days−8 and −7, thiotepa 10 mg/kg on day −7, fludarabine 30 mg/m2 on days −6 to −2, cyclophosphamide 14.5 mg/kg on days −6 and −5, and total body irradiation 200 Gy on day −1. Unmanipulated, T-cell replete hematopoietic stem cells were infused on day 0. GCSF (5-10 μg/kg/d x5 days) primed bone marrow was the preferred donor source (80%) and PBSC (20%) was used if the donor was unable/unwilling to donate bone marrow. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg/dose on days +3 and +4, and sirolimus and mycophenolate mofetil starting day +5. Event is defined as graft rejection or death. Results Between 2015 and 2023 28 consecutive patients with sickle cell disease with severe phenotype were treated at 2 pediatric centers. The median age was 14.4 years (range 5.9-24.8) with 57% male. The majority of the donors were parents (57%) and remainder (43%) were siblings. All patients had SS genotype and 90% of the donors had sickle cell trait. All patients achieved neutrophil and platelet engraftment (>50,000) at a median of 21.5 days (range 15-24) and 26.5 days (range 12-110). Three (11%) developed secondary graft failure in the first 6 months post transplant, and underwent a second transplant. All 3 patients successfully engrafted and are disease free at the latest follow up. The incidence of grades III-IV acute and moderate/severe chronic GVHD were 7.1% (2/28) and 3.5% (1/28) respectively. Of the 25 patients who have more than 1 year follow up, only 1 (4%) remains on tapering immune suppression. One patient (3.5%) died of streptococcus infection more than one-year post transplant. With a median follow up of 2.5 years the EFS and OS are 84% and 95% respectively (Figure 1). Conclusion Our results are encouraging and support the hypothesis that intensifying the preparative regimen with the addition of myeloablative thiotepa can result in rapid and sustained full donor engraftment with acceptable toxicities and GVHD rates.