Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) for Patients with Severe Sickle Cell Disease (SCD)

Abstract 10

Allo-HSCT remains the only curative approach for patients with SCD, yet a high risk of procedural toxicities and graft-versus-host disease (GvHD) limit this approach in adult patients with end organ damage from SCD. We chose a low-dose radiation approach utilizing sirolimus based upon its unique ability to promote T cell tolerance. Entry criteria include irreversible SCD-related complications (stroke, nephropathy, or tricuspid regurgitant jet velocity >2.5 m/s), or reversible complications not ameliorated by a 6-month course of hydroxyurea (frequent vaso-occlusive crises or acute chest syndrome). Conditioning was achieved with 1mg/kg of alemtuzumab divided over 5 days, a single total body irradiation dose of 300cGy, and oral sirolimus targeting trough levels between 10–15 ng/ml. Donor chimerism was measured by microsatellite PCR among CD3 and CD14/15 positive white cells. Twenty-three patients have been transplanted to date, and their ages ranged from 17 to 64 years (median 28). All are alive at 2 months to 7 years post allo-HSCT. Conditioning was well-tolerated. All received unmanipulated G-CSF mobilized peripheral blood progenitors obtained from 8/8 HLA-matched siblings. CD34+ cell doses ranged from 5.5 to 31 × 10e6/kg (median 14.4), and CD3+ cell doses ranged from 1.6 to 5.4 × 10e8/kg (median 3.4). Three patients engrafted temporarily but lost their grafts between the 2^nd and 3^rd months post transplant and had recurrent SCD. Twenty patients engrafted with mean myeloid chimerism of 97.5% (median 89%) and CD3 chimerism of 42% (median 49%). Improvements in laboratory parameters of engrafted patients are as follows: pre vs post HSCT hemoglobin, 8.7 vs 12.1 g/dL; reticulocyte count, 181 vs 74 k/uL; LDH, 328 vs 202 units/L; total bilirubin, 2.87 vs 1.0 mg/dL. Hemoglobin electrophoresis revealed replacement by donor type hemoglobin in 19 patients by 1 year, with amelioration of the SCD phenotype allowing for therapeutic phlebotomy. In 17 patients at 1 year or more post allo-HSCT, 5 had CD3 chimerism >50% which allowed complete withdrawal of immunosuppression; they have maintained stable mixed chimerism. Two patients received preemptive treatment with ganciclovir or foscarnet for presumed CMV reactivation (blood PCR >300 genome/mL) before day 30. Treatment in both patients was discontinued 1 week later with negative blood PCR and prophylaxis with acyclovir was resumed. There were 2 patients with zoster at 2 and 3 years post allo-HSCT. Finally, no engrafted patient to date has developed any evidence of acute or chronic GVHD. Our results demonstrate that this relatively simple conditioning regimen is well-tolerated across a broad age range of adults with severe SCD, is effective in achieving stable mixed chimerism without the development of GVHD, and is sufficient to induce functional tolerance.