Fludarabine-Based Reduced Intensity Regimen for Matched Related Donor Stem Cell Transplantation in Acquired Severe Aplastic Anemia

The outcome of severe acquired aplastic anemia (SAA) has improved dramatically over the past few decades due to advances in allogeneic stem cell transplantation (allo-STC). Different conditioning regimens have been tested in matched related donor (MRD) transplants with variant results. Before 2008, we have encountered poor engraftment in our patients using high dose cyclophosphamide (200 mg/kg) and thymoglobulin (ATG). Fludarabine, low dose cyclophosphamide, ATG and total body irradiation (TBI) was used for alternative donor transplants by Bacigalubo and colleagues (1). Since 2008, we have decided to start using this regimen in our MRD transplants to improve engraftment and ultimately overall survival. To our knowledge, this abstract describes the outcome of the largest cohort of patients who received MRD allo-STC for SAA using this regimen. It represents our single institution experience over a period of 10 years.

Methods: This is a retrospective chart review of all patients diagnosed with acquired SAA who underwent allo-STC between August 2005 and December 2015 at the American University of Beirut Medical Center (AUBMC)

Results: A total of 22 patients underwent transplant with grafts from related HLA-matched donors. Before 2008, three patients received cyclophosphamide 50 mg/kg/day over 4 days and ATG (Fresenius) 30 mg/kg/day over 4 days. Since 2008, nineteen patients received fludarabine 30 mg/m²/day for 4 days (-6, -5, -4 and -3), cyclophosphamide 300 mg/m²/day for 4 days (-6, -5, -4 and -3) and ATG (Genzyme) 3.75 mg/m²/day for 2 days (-4 and -3). TBI at a dose of 2 Gy was added on day -1 for patients more than 15 years of age. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A with either mycophenolate mofetil (50%) or a short course of methotrexate (50%). The median age of patients was 21 years (range: 1.7-64 years). The median duration between diagnosis and transplant was 11 months (range: 1-85 months). Seven patients (31%) had failed immunosuppressive therapy before transplant. The stem cell source was bone marrow (BM) for 14 patients (64%) and peripheral blood (PB) for 8 patients (36%). The median CD34 cell dose infused was 5.4 ×10⁶/kg (range: 1 - 19.5 ×10⁶/kg). The 2-year overall survival rate was 82% with trend toward better survival without statistical significance when using fludarabine-based regimen (84% vs 66%, P: 0.42), if both donor and recipient had the same gender (92% vs 66%, P: 0.11), or if PB was the source of stem cells (87% vs 78%, P: 0.58). Engraftment failure was observed in 2 cases (9%). The median time for neutrophil engraftment was 20.3 days (range: 14-38 days). Neutrophil engraftment was faster when the fludarabine-based conditioning regimen was used (18 vs 38 days, P: 0.04), if PB was used as the source of stem cells (17 vs 20 days, P: 0.03) or if TBI was added to the conditioning regimen (18 vs 20 days, P: 0.07). Chimerism studies were available for 18 out of 20 engrafted patients. Two patients had partial engraftment (89% and 76%) and 16 patients had complete engraftment (>90%). The previous use of IST or the duration between diagnosis and transplant (< or > 1 or 2 years) did not affect survival or engraftment. Acute GvHD (grade I-II) occurred in 2 patients (9%). No cases of chronic GvHD or veno-occlusive disease (VOD) were reported. CMV reactivation occurred in 2 cases while CMV disease was reported in another case. EBV reactivated in one case without LPD. Hemorrhagic cystitis occurred in one case. One patient developed donor cell precursor B-cell acute lymphoblastic leukemia 2 years after transplant.

Conclusions: Fludarabine-based reduced intensity regimen for MRD transplants in SAA has led to improved engraftment with minimal toxicity. This result was not affected by the previous use of IST or the long duration between diagnosis and transplant as was reported in previous studies with different conditioning regimens or donor types. Thus, this regimen may be particulary useful in countries where patients present late to transplant.

References:

1. Bacigalupo A, Locatelli F, Lanino E, et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone marrow transplantation 2005;36:947-50