National, Retrospective, Multi-Centre Comparison of Alemtuzumab- Versus ATG-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation for Aplastic Anemia: A Study From the British Society for Blood and Marrow Transplantation (BSBMT) (CTCR 09-03)

The ideal conditioning regimen for HSCT in AA is one that achieves engraftment, absence of GVHD and minimal toxicity. Standard conditioning for young patients undergoing matched sibling donor (MSD) HSCT for AA is cyclophosphamide (CY) 200mg/kg and ATG as T-cell depletion (TCD), with ciclosporin (CSA) and methotrexate (MTX) as post graft immunosuppression. For patients who are > 30–40years old receiving MSD HSCT a fludarabine (FLUD)-based regimen with low dose CY (1200mg/m²) and ATG is commonly used. For unrelated donor (UD) HSCT, in Europe, a similar FLUD-based regimen with low dose CY and ATG is commonly used, with addition of low dose TBI (2Gy) for older patients. Long term survival for MSD HSCT is 80–90%, but only 50% for patients aged > 50 years. For UD HSCT, survival is around 75–80%. Chronic GVHD remains a problem, in 30–40% of MSD and up to 50% of UD HSCT. A recent retrospective study of 50 patients transplanted with Alemtuzumab instead of ATG, with CY (1200mg/m2), FLUD, and CSA alone as post graft immunosuppression, showed overall survival at 2 years was 95% for MSD and 83% for UD HCT and only two patients (4%) developed chronic GVHD.

We analyzed data from 159 patients with acquired AA transplanted in the UK, who received either Alemtuzumab or ATG pre-transplant, as part of the conditioning for a first allograft. Patients who received their graft between 1999 and 2009 and had a minimum follow-up of 6months were included in this study. Median age was 20yr (range 1– 67) and M: F ratio was 86: 73. MSD HSCT was performed in 88 (55%) patients, UD HSCT in 65 (41%) including 2 mis-matched, and 6 patients were transplanted from other related donors of which 3 were mis-matched. Source of stem cells was BM in 108 (68%), PB in 39 (25%), BM+PB in 8 (5%) and cord blood in 4 (2%) patients. Conditioning was with Alemtuzumab in 103 (65%) and ATG in 55 (35%), and one patient had received both. CY +/− FLUD was used in 148 and FLUD +/− Melphalan in 11 patients, with addition of TBI in 11 (7%) patients. Median time from diagnosis to HSCT was 6 months (range 0.5–300).

Of 159 patients, 137 (86%) are alive at a median follow up of 3.3yr (range 3 months – 10.4 yr). Twenty two patients have died from the following causes of death (not mutually exclusive): infection (n = 15, 68%), GVHD (n = 6, 27%), multi-organ failure (n = 4), lymphoproliferative disorder (n = 1), relapse of breast cancer (n = 1) and one unknown. For all patients, the 1 yr, 5 yr and 10 yr overall survival (OS) were 89% (95% C.I. = 83–93%), 85% (78–90%) and 85% (78–90%), respectively. There was no difference in the 1 yr OS in relation to the method of TCD (Alemtuzumab 91% (84–95%) versus ATG 84% (71–91%), p = 0.1578). Graft failure was observed in 15 (9%) patients. Median time to neutrophil engraftment, defined as ANC > 0.5 × 10⁹/l on first of 3 consecutive days, was 20 days (range 10–89) and platelet engraftment, defined as platelet count > 20 × 10⁹/l on first of 3 consecutive days and no platelet transfusions 7 days prior, was 21 days (range 0–275). Chimerism was full donor in 70 (46%), mixed in 41 (27%), not performed in 37 (24%) and unknown or not evaluable in 2 patients. Acute GVHD grade I-II occurred in 35 (25%) evaluable patients, grade III-IV in 8 (6%). Chronic GVHD was seen in 23 (16%) evaluable patients, limited in 14, extensive in 6 and unknown in 3.

From this national study, we report excellent outcomes for HSCT in SAA during the last decade. There was a trend, not significant, for better survival with Alemtuzumab instead of ATG in the conditioning regimen. This is the first reported study comparing outcomes after Alemtuzumab versus ATG based conditioning regimens for SAA. Further analyses, comparing graft failure, acute and chronic GVHD, probability of survival and event - free survival, and patient-related, disease-related and treatment related variables, between Alemtuzumab and ATG-based conditioning regimens, are currently in progress.

Marsh:Genzyme: Research Funding. Off Label Use: ATG used as part of conditioning regimen for HSCT in aplastic anaemia. Alemtuzumab used as part of the conditioning regimen for HSCT in aplastic anemia. Pagliuca:Genzyme: Speakers Bureau. Mufti:Celgene: Consultancy, Research Funding.