Myeloablative Conditioning with Alemtuzumab in Matched Related Donor Hematopoietic Cell Transplant for Sickle Cell Disease Prevents Graft-Versus-Host Disease without Compromising Engraftment.

Introduction Matched related donor (MRD) hematopoietic cell transplant (HCT) is an accepted treatment for sickle cell disease (SCD). Alemtuzumab is a lymphocytic medication that can reduce the risk of GVHD; however, it is associated with mixed donor chimerism (MDC) and graft loss when used with submyeloablative conditioning. We explored the use of myeloablative chemotherapy with alemtuzumab in MRD HCT for SCD to concurrently prevent GVHD and promote durable engraftment. Methods We retrospectively reviewed outcomes for patients that underwent MRD HCT for SCD at Texas Children's Hospital between 2003-2017. All patients received busulfan intravenously every 6 hours for 4 days (target AUC: 800-1200 μM per minute) and cyclophosphamide 50 mg/kg daily for 4 days. GVHD prophylaxis included intravenous alemtuzumab daily for 3-4 doses starting on day -5 (5-15 kg=3 mg, 15-30 kg=5 mg, >30 kg= 10 mg daily), methotrexate and a calcineurin inhibitor. Donor chimerism was evaluated periodically via short tandem repeats or fluorescent-in-situ hybridization of nucleated cells from the peripheral blood. Persistent MDC was defined by the presence of recipient cells on 2 consecutive evaluations without return to full donor chimerism at last follow-up. Results Thirty-eight consecutive patients underwent MRD transplant (3 non-sibling and 35 sibling) with a median age at transplant of 8.6 yrs (range: 2.9-18.4 yr). Stem cell source consisted of bone marrow grafts for all patients. Two patients concurrently received cord blood from the same donor. Neutrophil engraftment was achieved in all patients at a median time of 19 days (range: 13-24 days). Incidence of persistent MDC was 60.5% with a median last chimerism of 94% donor cells (range: 24-100%). Three of 23 patients (13.0%) with persistent MDC had <50% donor cells. The single patient with severe MDC <25% stabilized at 24% at 2 yrs post-HCT with concurrent Hgb S <50% on electrophoresis reflective of sickle cell trait in the donor. Graft rejection and recurrence of SCD related symptoms were not observed in any patient. No additional cell products were given to manage mixed chimerism. Overall incidence of significant acute GVHD (grade II-IV) was 5.3%. One patient developed limited chronic GVHD. Overall survival was 94.7% with a median time to last follow-up of 2.9 yrs (range: 90-4627 days). Two deaths occurred secondary to transplant-related complications including 1 death <100 days from HCT due to disseminated Mycobacterium tuberculosis and 1 secondary to hemophagocytic syndrome on day +318. Conclusions Myeloablative conditioning was well tolerated, and the addition of alemtuzumab minimized occurrence of significant GVHD. Chimerism stabilized at >50% donor cells in most patients and no graft rejection or recurrence of SCD occurred. This regimen may be a promising approach for patients with SCD that can tolerate myeloablative chemotherapy. [ABSTRACT FROM AUTHOR]