Addition of low-dose busulfan to cyclophosphamide in aplastic anemia patients prior to allogeneic bone marrow transplantation to reduce rejection

Abstract

Summary:Busulfan was added at the dose of 4 mg/kg to 200 mg/kg cyclophosphamide in 81 patients (3-53 years, median 24) with aplastic anemia to reduce graft rejection. Graftversus-host disease (GVHD) prophylaxis comprised cyclosporine-methotrexate. The number of prior transfusions was 0-276 (median 26), and 48% had received prior immunosuppressive therapy. Two patients experienced primary graft failure, and 10 secondary rejection at 28-1001 days (median 317 days). The cumulative incidence of rejection was 22%; for heavily transfused patients (X50 U) it was 43% compared to 16% for the rest (P ¼ 0.06). Overall survival rate at 8 years was 56%; patients who received p15 and 415 transfusions was 78 and 50%, respectively (P ¼ 0.01), whereas it was 67 and 28% for p50 and 450 transfusions, respectively (P ¼ 0.002). In multivariate analysis, higher number of prior transfusions, shorter period of immunosuppression with cyclosporine and GVHD were associated with inferior survival; moreover, a higher risk of graft rejection were associated with a higher number of prior transfusions and a trend was observed for a shorter cyclosporine administration. Low-dose busulfan is feasible and may be helpful in patients exposed to o50 transfusions. However, rejection remains a significant problem, mainly in heavily transfused patients.

Allografting in patients with severe, refractory aplastic anemia using peripheral blood stem cells and a fludarabine-based conditioning regimen: The Mexican experience

“…In the present study, we coupled these advantages with the use of fludarabine in the conditioning regimen in order to maximize immunosuppression, reduce toxicity, and avoid graft rejection. We found a cumulative rejection incidence of 26% in heavily transfused patients; in contrast, in a recent study from Brazil, a graft rejection of 43% was observed in 48 polytransfused patients conditioned with cyclophosphamide and low-dose busulfan without ATG and grafted with bone marrow-derived cells [16]. On the other hand, GVHD has a significant impact on survival; in fact, it has been considered in some studies as the major cause of morbidity and mortality [11].…”

Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party

“…Graft failure has been of concern for many years in SAA patients undergoing an HLA identical BMT. In some centers, busulfan 16 or low-dose TBI 2 has been added to CY to reduce graft failure; in other centers, ATG has been used successfully to reduce graft rejection. 17 In the present series of alternative donor transplants, we have seen an overall graft failure rate of 18%, with a significant age effect: patients aged 15 years or over showed a graft failure rate of 32%, which is significantly higher when compared to younger patients (5%).…”

Good outcome of haploidentical hematopoietic SCT as a salvage therapy in children and adolescents with acquired severe aplastic anemia

“…The rejection rate was 22% in all 81 patients with acceptable toxicity conditioning with low doses of BU (4 mg/kg)/ CY and the OS was 56% at 8 years in HLA-identical sibling HSCT. 17 To enhance engraftment, BU at the dose of 8 mg/kg was used in our and Xu et al's 4 conditioning regimens. No additional toxicity directly associated with BU was found.…”