Outcome of Allogeneic Peripheral Blood Stem Cell Transplantation In Egyptian Patients with Fanconi Anaemia

Abstract

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital malformations, progressive marrow failure (BMF) and predisposition to hematologic malignancies and solid tumors (Auerbach, 2009). The diagnosis of FA is usually confirmed by increased chromosomal breakage in FA cells following exposure to DNA cross-linking agents such as mitomycin C and diepoxybutane (Auerbach, 1993). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a matched sibling donor (MSD) is the treatment of choice for FA-related BMF (Gluckman & Wagner, 2008). Because of the underlying DNA repair defect in FA, extensive chemotherapy and radiation used in the conditioning can be highly toxic. Reduced intensity conditioning regimens have resulted in acceptable toxicity, high engraftment rates, and improved survival (Bitan et al., 2006). Low-dose cyclophosphamide (CY) is considered the backbone of many conditioning regimens used in FA. To reduce the risk of rejection, CY is usually used in combination with other agents such as antithymocyte globulin (ATG), busulfan and, more recently, fludarabine (Flu) (Ayas et al., 2008). Peripheral blood stem cells (PBSCs) are widely used for allogeneic HSCT. Neither anesthesia nor hospitalization is required for the donor. Besides, there is rapid recovery of neutrophils and platelets which is reflected in shortened hospital stay, less use of antibiotics, and lower transfusion requirements (Bensinger et al., 2001). In this study, we evaluated the outcome of allogeneic PBSCT in 31 patients with FA; transplanted from matched sibling donors using a uniform FLU-based conditioning regimen. The patients were recruited from Bone Marrow Transplantation Unit of Nasser Institute Hospital, in the time period from December 2007 to October 2013. All included patients had evidence of bone marrow aplasia. The median patient age at the time of SCT was 11.7 years. The conditioning consisted of low-dose CY (5 mg/kg x 4 days) and a total dose of FLU of 120/m2. For graft-versus-host disease (GVHD) prophylaxis we used cyclosporine-A at a starting dose of 3mg/kg then tailored according to trough level. ATG was administered in the pre-transplant period to promote engraftment and in the post-transplant period for additional GVHD prophylaxis (30 mg/kg total dose). The mean CD 34+ included was 11.7 x 106/kg recipient weight. Engraftment was attained in 24 (77.4%) patients. Engraftment occurred rapidly (mean, 9.7 days for an absolute neutrophil count > 0.5 x 109/L; mean, 16.1 days for platelet count > 20 x 109/L). Two patients developed secondary graft failure after initial engraftment and one had primary graft failure. Six patients (19.3%) developed acute GVHD (15.6%); 1 patient (3.2%) developed chronic GVHD. Nineteen patients have sustained engraftment and are transfusion-independent. At a median follow up time 1.9 years, the overall survival (OS) was 64.5% and the estimated disease free survival (DFS) was 52.4%. Eleven patients (35.5%) died due to different causes. We conclude that the combination of CY, Flu, and ATG in the doses used in this study was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.