Bone marrow transplantation for Fanconi anemia

Abstract

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Haematopoeitic cell transplantation for Fanconi anaemia – when and how?

“…This early clinical experience prompted in vitro laboratory studies that confirmed the hypersensitivity of FA cells to CY Auerbach et al, 1983) and irradiation (Gluckman et al, 1984). As a result, Gluckman et al proposed the use of lowdose CY (20 mg/kg) and a single fraction of thoraco-abdominal irradiation [(TAI), 500 cGy] conditioning regimen, leading to markedly reduced RRT with enhanced survival after human leucocyte antigen (HLA)-matched sibling donor HCT (Gluckman et al, 1984). Over the last two decades, efforts have focused on ways to improve upon these early experiences with sequential changes to the preparative therapy.…”

“…The conditioning regimens were based upon those administered to patients with acquired aplastic anaemia, most often consisting of cyclophosphamide (CY) 200 mg/kg with or without irradiation and resulted in excessive regimen-related toxicity (RRT), severe acute graft-versus-host disease (GVHD) and poor survival (Gluckman et al, , 1983. This early clinical experience prompted in vitro laboratory studies that confirmed the hypersensitivity of FA cells to CY Auerbach et al, 1983) and irradiation (Gluckman et al, 1984). As a result, Gluckman et al proposed the use of lowdose CY (20 mg/kg) and a single fraction of thoraco-abdominal irradiation [(TAI), 500 cGy] conditioning regimen, leading to markedly reduced RRT with enhanced survival after human leucocyte antigen (HLA)-matched sibling donor HCT (Gluckman et al, 1984).…”

“…In the past decade, in experienced centres, haematopoietic recovery is expected to occur in >85% patients with survival rates >75% (Dufour et al, 2001;Farzin et al, 2007), as shown in Table I. Multivariate analysis has identified age at transplant, pretransplant platelet count, conditioning regimen and GVHD prophylaxis as factors that correlated with survival after HLAidentical sibling donor HCT (Gluckman et al, 1995). More recent results from the International Bone Marrow Transplant Registry (IBMTR) showed that, among 209 patients transplanted between 1994 and 1999 from matched siblings, the 3-year survival was 81% [95% confidence interval (CI) 72-90%] in patients <10 years of age (n = 109) and 69% (95% CI 59-79%) in older patients (n = 100) (IBMTR/ ABMTR, 2002).…”

“…Until recently, HCT for FA using alternate donors has been markedly less successful compared to that after HLA-identical sibling due to high rates of graft failure, RRT, GVHD, and opportunistic infection. Gluckman et al (1995) were the first to report the outcomes of alternative donor HCT in 48 FA patients from multiple institutions, using the database of the IBMTR. Graft failure occurred in 24% patients, and overall survival was 29% at 2 years.…”

Successful second bone marrow transplant for Fanconi's anaemia following escalation of conditioning

“…In view of the increased sensitivity to cyclophosphamide and radiation, and the risk of later malignancy, attention has focused on determining an optimal conditioning regimen for FA. However, because of the rarity and genetic heterogeneity of the syndrome, this problem has proved very difficult (Hows et al, 1989;Flowers et al, 1996;Gluckman, 1996).…”