Haploidentical hematopoietic stem cell transplantation in adults with severe sickle cell disease: Long-term outcomes using a modified conditioning regimen with peripheral blood stem cells.

Abstract Haploidentical Hematopoietic stem cell transplantation (haplo-HSCT) remains the only curative option for adults with advanced sickle cell disease (SCD) without an HLA-matched sibling donor or access to gene therapy. We analyzed long-term outcomes using a modified Hopkins haplo-HSCT platform with increased total body irradiation dose (TBI, from 2 Gy to 3 Gy) and peripheral blood stem cells (PBSCs) instead of bone marrow. We report on 22 consecutive adults with severe SCD who underwent haplo-HSCT from 9/2015 to 4/2024, all with ≥ 1 year of follow up. Conditioning included: RBC exchange on day -10 (HbS goal < 30%), antithymocyte globulin 2.5mg/kg (days -9 to -7) fludarabine 30mg/m2/day (days -6 to -2), cyclophosphamide 14.5mg/kg/day (days -6 & -5), 3 Gy TBI (day -1), and PTCy 50mg/kg (days +3 & +4). G-CSF mobilized PBSCs were infused. Mycophenolate mofetil (15 mg/kg/day) was given until day + 35 and sirolimus (target trough 5 - 15 ng/mL) for 1 year followed by taper. Median age was 28 years (range, 18-39 years), 14 were female, 13 received grafts from donors with sickle trait. Indications included ≥ 3 vaso-occlusive crisis (VOCs)/year despite hydroxyurea (n = 20), ≥ 2 lifetime episodes of acute chest syndrome (n = 16), and stroke (n = 7). Median CD34+ dose was 9.1x106 cell/kg (range 4.2 - 15.9). G-CSF started on day +5 in neutropenic patients with HbS <30%. Median neutrophil engraftment was 18.5 days (range 15-25). All 22 initially engrafted, 2 (9%) had secondary graft failure, one rescued with CD34+ boost at day +681. At median follow-up of 4.8 years (range 1.1–9.8), 21 of 22 (95%) were alive, 19 (86.4%) were alive and free of graft-versus-host disease (GVHD). 20 (90%) remained VOC-free with stable donor chimerism and Hb improvement from median 8.2 g/dL (range 6.4 – 10.4) pre-HSCT to 14.3 g/dL (range 12 – 16.5) , 13.3 g/dL (range 11.6 - 16.7) and 13.3 g/dL (range 12.3 – 16.6) at 2, 3 and 4 years post-HSCT, respectively. Median CD3 and CD33 chimerism at 2, 3, and 4 years post-HSCT remained 100% in stable engrafters. Immunosuppression was stopped in 20 patients (90%) at median day +467 (range, 300-873). Acute GVHD ≥ grade 2 occurred in 2 patients: one with skin/liver/eye involvement at day+83, another with gut involvement at day +50. Moderate to severe chronic GVHD occurred in 3; 2 improved with ruxolitinib while one with intermittent compliance died from unclear causes at day +407. Long-term toxicities present after Haplo-HSCT included dental complications (5/22), osteopenia (6/22), osteoporosis (1/22), hypogonadism (8/22), hypothyroidism (3/22), cataracts (2/22), and adrenal insufficiency (1/22). No cases of pneumonitis, secondary malignancies, sinusoidal obstruction syndrome, or new cerebrovascular events were seen. Pulmonary function tests were available in 22 at baseline, 13 at 1 year post Haplo-HSCT, and 7 at 2 years. At baseline, 41% had a forced expiratory volume (FEV1) <80%, 36% had FEV1/forced vital capacity (FVC) <0.8 and 41% had a total lung capacity (TLC) <80%. Mean diffusing capacity of lung for carbon monoxide (DLCO), corrected for hemoglobin, was 82.6 (±15.9) and 36.4% patients had a baseline DLCO <80%. There were no significant changes over time in the proportion of patients with FEV1 <80%, FEV1/FVC <0.8, DLCO <80% or TLC <80%. Echocardiographic data (n= 22 baseline, n=14 at 1 year, n= 4 at 3 years) showed one patient with tricuspid regurgitation velocity (TRV) >2.5 m/sec at baseline; none developed elevated TRV post-HSCT. Renal function, assessed by serum creatinine, remained stable in all but one patient who developed atypical hemolytic uremic syndrome (aHUS) at day+488. Urine microalbumin once patients were off sirolimus, was stable to improve from baseline in 8 of 13 patients. These results support Haplo-HSCT with modified conditioning as a safe, effective, and durable curative option for adults with severe SCD, with favorable overall survival, sustained donor chimerism, elimination of VOC-related complications, and preservation of organ function.