Alemtuzumab Used with Fludarabine and Cyclophosphamide (FCC) for Stem Cell Transplantation in Acquired Aplastic Anemia Is Associated with a Low Risk of Graft Versus Host Disease and Viral Infections and with Sustained Engraftment.
Authors: Marsh Judith C W , Gupta Vikas , Lim ZiYi , Marks David , Gordon-Smith Edward C. , Mufti Ghulam J 
Published: October 2019

Abstract
Abstract 1084
Poster Board I-106
Graft rejection and chronic GVHD remain major obstacles to successful outcome after stem cell transplantation (SCT) for aplastic anemia (AA). Using cyclophosphamide (CY) 200mg/kg with ATG, rejection occurs in 5-10% and chronic GVHD in 30-40% of patients transplanted from HLA matched sibling donors (MSD). For unrelated donor (UD) SCT using Fludarabine with CY and ATG, rejection occurs in 18% (30% for patients > 14 years of age) and chronic GVHD in 27%. We have pioneered the use of Alemtuzumab with CY in AA SCT and shown a reduction in GVHD although graft rejection was high at 24%. More recently, Fludarabine has been added to the conditioning to reduce graft rejection. In this retrospective, multi-center study, we report outcomes after SCT for acquired AA in 37 patients using Alemtuzumab, Fludarabine and CY (FCC) conditioning regimen. Alemtuzumab dose was 0.2mg/kg x5 days (n=20), 60mgx1 (n=12), 25mgx4 (n=4) and 40mgx1+30mgx2 (n=1). All patients received Fludarabine 30mg/m2x4 and CY 300mg/m2 x4 (FCC). Patients were transplanted from 1999 to 2009. Median follow up of survivors was 641days (range 72-3547). Disease severity was ‘very severe’ in10, ‘severe’ in 20 and ‘non-severe’ in 7 patients. SCT was performed using MSD in 15 patients (40%) and UD in 22 (60%), of whom all but one were matched for 8/8 or 10/10 alleles. Median age was 35 years (range 8-55). Stem cell source was bone marrow (BM) in 21 (57%), peripheral blood stem cells (PBSC) in 7 (19%), BM+PBSC in 5 (13%) and G-mobilised BM in 4 (11%). Time from diagnosis to SCT was < 12 months in 57% of patients and > 12 months in 41%. 8/15 (53%) of sibling transplants and 18/22 (82%) of UD transplants received immunosuppressive therapy prior to SCT. There were 5 cases of graft failure, early rejection in 2 UD SCT and late graft rejection in 3 (one UD and two MSD). Of the 5 patients with graft rejection, BM was used as the stem cell source in 3, G-mobilised BM in one and PBSC in one. Cumulative incidence of graft failure at 1 year was 15% ± 4% (14% for MSD and 15% for UD SCT). For patients transplanted > 12 months from diagnosis, graft failure was 25% compared with 10% for patients transplanted within 12 months (p= 0.191). Acute GVHD occurred in 13.5% patients, grade I-II in all cases. Chronic GVHD occurred in only one patient (2.7%, extensive). Data for CMV and adenovirus infections was available in 21 patients, and in 20 patients for EBV. CMV reactivation occurred in 2/21 (9.5%) patients, with one case of CMV disease. EBV infection occurred in 2/20 patients (10%): one responded to Rituximab and one patient died from progressive EBV PTLD. There were no cases of adenovirus infection. Overall survival (OS) at 3 years was 89% (93% for MSD and 85% for UD SCT, p= 0.658). For all patients, OS was 95% when time from diagnosis to SCT was < 12 months and 80% for > 12 months (p= 0.273). For patients > 40 years of age, there was no significant difference in OS compared with patients < 40 years old (93% vs 82%). There were 3 deaths, one from chronic GVHD and CMV at day + 427, one from graft failure at day +134 and one due to EBV PTLD at day +180. We conclude that the use of Alemtuzumab with Fludarabine and CY (FCC) for MSD and UD SCT for acquired AA is associated with excellent survival, a low incidence of acute and chronic GVHD and a low incidence of viral infections.

Disclosures
Marsh: Genzyme: Consultancy, Honoraria. Off Label Use: Alemtuzumab used for conditioning for stem cell transplantation for aplastic anemia. Gupta:Genzyme: Honoraria, Research Funding.