Long-Term Follow-up of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Severe Alpastic Anemia After Cyclophosphamide Plus Antithymocyte Globulin Conditioning Regimen,

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) from an HLA- identical sibling is the treatment of choice for young patients with acquired severe aplastic anemia (SAA). Due to increased rates of secondary solid cancer in patients with SAA who received an irradiation-based conditioning regimen, we decided 2 decades ago to use the association of Cyclophosphamide (CY) and Antithymocyte globulin (ATG). We report here the long-term follow-up of patients who underwent HSCT from an HLA-identical related donor after this conditioning regimen. Patients and Methods: 61 consecutive patients with SAA who received a first transplantation from June 1991 to February 2010 in our center were included. Patients with Fanconi anemia or other congenital bone marrow failure were excluded. The conditioning regimen consisted in CY (200mg/Kg) and ATG (2.5 mg/kg/day × 5 days). The donors were HLA-identical siblings in 60 cases and family HLA-matched in 1 case. Graft-versus -host disease (GvHD) prophylaxis associated cyclosporine and methotrexate (days 1, 3, 6 and 11). Long-term clinical outcome, immune recovery and quality of life were assessed. Results: The median age was 21 years [range: 4–43], 41 being adults. Median duration of the disease before HSCT was 93 days. Most of the patients had idiopathic aplastic anemia (n=49, 80%). Median time from diagnosis to HSCT was 3 months (range, 1 to 140). All but 2 patients received bone marrow as source of stem cells and all but 2 engrafted (primary graft failure= 3.4%) with a neutrophils count > 0.5 G/L and a platelets count >20 G/L after a median of 23 (range, 19 to 43) and 21 days (range, 10 to 177), respectively. In patients who had achieved neutrophil recovery, no secondary graft failure was observed. Cumulative incidence (CI) of acute grade II-IV GvHD was 23% (95%CI, 13 to 34) and 18 patients developed chronic GvHD (CI: 32%, 95% CI, 20 to 46). In multivariate analysis, a higher number of infused CD3 cells was associated with an increased risk of developing chronic GvHD (p=0.017). With a median follow-up of 73 months (8 to 233), the estimated 6-year overall survival was 87% (95%CI, 78 to 97). At 72 months, the CI of secondary malignancies was 9%, 10 patients developed avascular necrosis (21% CI), 12 patients were diagnosed with endocrine dysfunctions (19% CI) and 5 presented cardiovascular complications (CI of 10%). The CI of bacterial, fungal and viral infections were 25% (95% CI, 15 to 36), 8% (95% CI, 3 to 17) and 61% (95% CI, 46 to 73) at 72 months, respectively. At 2 years post HSCT, the immune reconstitution was normal for CD3, CD8 T-cells, B-cell and NK-cell but still incomplete for CD4 T-cells. A FACT-BMT questionnaire of quality of life (QOL) was sent to all survivors (n= 53) of who 26 accepted to respond to the questionnaire. There was no evidence for a change in QOL perception with time after transplantation. Our data were compared with those obtained from HSCT recipients from a Swiss transplant center (n=125 patients), mainly transplanted for hematological malignancies. The perception of QOL in patients who were transplanted for SAA was similar to the group of patients who were transplanted for other reason than SAA. Conclusions: Our results confirm that HSCT from HLA-identical sibling donors after CY-ATG conditioning regimen is a curative treatment for patients with SAA, with an excellent long-term outcome. We found an increased risk of chronic GvHD associated with the number of infused CD3 cells. Furthermore, we also found non negligible late complications as well as a similar quality of life with patients transplanted for hematological malignancies. Improving long-term health conditions must thus be a priority field for research, exploring the use of new conditioning regimen as well as new GvHD prophylaxis to improve the quality of life post HSCT of such patients.

Peffault de Latour:Alexion: Consultancy, Research Funding.