Application of Alemtuzumab to Myeloablative Conditioning in Transfusion Dependent Beta-Thalassemia to Reduce Graft-Versus-Host Disease (GVHD)

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for transfusion-dependent b-thalassemia (TDT). Application of alternative donor HSCT for TDT is more accepted as rates of graft failure (GF) and GVHD decline. Alemtuzumab is a CD52 monoclonal antibody with potent lymphocytic activity that can reduce GVHD risk, though infectious associations have limited its use. We hypothesize that the addition of alemtuzumab to standard myeloablative conditioning in HSCT for TDT will reduce rates of GVHD without affecting engraftment or transplant-related mortality (TRM). Methods We retrospectively reviewed engraftment, GVHD, and survival for TDT patients (pts) who underwent HSCT at Texas Children's Hospital between 2004-2018. All pts received myeloablative conditioning with IV targeted busulfan (AUC of 800-1200 μM per minute), cyclophosphamide 50 mg/kg daily for 4 days, and IV alemtuzumab (5-15kg= 3mg; 15-30kg=5mg; >30kg=10mg) from d -5 through d -2. Pts receiving MUD/MMUD HSCT additionally received fludarabine 30 mg/m2 for 4 days. GVHD prophylaxis included methotrexate (d +1,3,6,11) and a calcineurin inhibitor. Results Twenty-one consecutive pts underwent MRD (10), MUD (9), or MMUD (2) HSCT with a median age at HSCT of 6.5 yrs (range: 1.5-14.9). Stem cell source consisted of bone marrow (17), peripheral blood (3), MRD umbilical cord and marrow (1). Neutrophil engraftment (ANC>500/ml x 3 d) was achieved in all patients at a median of 19 d (range: 13-29). Median platelet engraftment (platelet > 20,000 × 7 d without transfusion) was 35.5 d (range: 15-123). Median RBC engraftment (Hb >8 g/dL x 7 d without transfusion) was 24 d (range: 10-115). No GF was observed. Poor graft function (PGF) was seen in 2 pts (9.5%) requiring stem cell boost or 2nd HSCT. Overall incidence of acute (grade II-IV) and chronic GVHD (all limited) of 9.5% and 14.2%, respectively. Five-year overall survival was 89.9% with a median follow-up of 3.6 yrs (range: 0-14.4). Two deaths occurred secondary to infections complications in the setting of PGF and GVHD, respectively. Conclusion Myeloablative conditioning with alemtuzumab minimized the incidence of severe GVHD with good overall survival. GF, GVHD, and TRM rates were improved from previous reports in TDT. PGF in our UD cohort was comparable to previous reports of engraftment complications. The addition of Alemtuzumab is a reasonable strategy to reduce GVHD risk in MRD and UD HSCT for TDT, though durability of engraftment after UD HSCT requires further investigation.