Hematopoietic stem cell transplantation for high-risk adult patients with severe aplastic anemia; reduction of graft failure by enhancing stem cell dose.

BACKGROUND AND OBJECTIVES: The main causes of failure after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with severe aplastic anemia (SAA) are graft-versus-host disease (GVHD), infection and graft failure, often exacerbated by large numbers of transfusions and prolonged disease duration before transplant. This study retrospectively analyzes the outcome and factors related to survival or graft failure in high-risk patients with SAA receiving HSCT in our institution. DESIGN AND METHODS: Between January 1995 and December 1999, 40 consecutive adult patients who were multi-transfused (more than 40 units of red blood cells +/- platelets) and/or had a 3 years or longer period prior to transplant were enrolled. Their median age was 27.5 years (range, 16 to 43) and 21 (52.5%) were women. All donors were human leukocyte antigen (HLA)-matched siblings. Before transplant, 29 patients (72.5%) received a course of antithymocyte globulin (ATG) and cyclosporin A (CsA). The median interval from diagnosis to transplant was 59 months (range, 2 to 216). The median number of transfusions was 115 units (range, 10 to 480). All patients received a conditioning regimen of cyclophosphamide, ATG, and procarbazine. Our patients received either bone marrow (BM) alone (n=20) or BM+peripheral blood stem cells (PBSC) (n=20) as a stem cell source. T-cells of PBSC were depleted using the CD34 enrichment method. GVHD prophylaxis consisted of CsA and short-term methotrexate.
RESULTS: In the BM+PBSC group, neutrophil recovery to 0.5 x 10(9)/L and platelet recovery to 20 x 10(9)/L were achieved more rapidly than in the BM group (p=0.005 and 0.039, respectively). The incidences of graft failure, grade II to IV acute GVHD, and chronic GVHD were 22.5%, 12.8% and 23.1%, respectively. Graft failure occurred in 2 of 20 patients (10%) receiving BM+PBSC and in 7 of 20 (35%) receiving BM alone (p=0.069). Seven of 9 patients who had graft failure received a booster treatment and recovered normal marrow function. GVHD incidence was comparable between the BM+PBSC and BM groups. Six patients (15%) died from graft failure (n=2), interstitial pneumonia (n=2), cyclophosphamide-induced heart failure (n=1), and chronic GVHD followed by pneumonia (n=1). The Kaplan-Meier estimate of survival was 83.7% with a median follow-up duration of 40.5 months (range 8-67). In multivariate analysis only chronic GVHD adversely influenced survival (p=0.042). INTERPRETATION AND
CONCLUSIONS: These results suggest that HSCT is an effective treatment for multi-transfused SAA patients with prolonged disease duration. It is highly possible that the infusion of a large number of stem cells leads to a reduction of graft failure and a faster speed of engraftment. Booster treatment is successful in achieving engraftment in patients with graft failure.