Bone marrow transplantation for patients with Fanconi anemia: reduced doses of cyclophosphamide without irradiation as conditioning

Abstract

Summary:Fanconi anemia (FA), a rare autosomal recessive disease, frequently evolves to bone marrow failure and acute myeloid leukemia, and BMT is the treatment of choice for patients with FA. However, their exquisite hypersensitivity to DNA cross-linking agents is associated with severe complications and several investigators have been looking for the ideal preparatory regimen. We have been involved in a program of progressively decreasing doses of cyclophosphamide (CY) as conditioning therapy, in an attempt to identify the lowest dose of CY capable of maintaining the graft with minimum complications. Here, we describe our experience of allogeneic BMT offered to 16 patients with FA and an HLA-compatible sibling donor, conditioned with 100 mg/kg of CY. The actuarial survival is 88% at approximately 37 months. Mucositis у grade II was the most common complication (94%), followed by bacteremias (38%). Veno-occlusive disease and hemorrhagic cystitis did not occur. Sustained engraftment was obtained in 94% of patients, and acute and chronic GVHD was diagnosed in 13% and 7%, respectively. The lowest dose of CY for transplant in FA patients is yet to be determined, but further reductions seem possible.

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

“…[15][16][17][18] In FA, continuous improvements to the approach to BMT over the last 20 years have resulted in reduced regimen-related toxicity, superior engraftment and less GVHD, leading to improved survival. [19][20][21] However, in contrast to BMT with HLA-identical siblings, using alternate donors has been markedly less successful, due to the high rates of graft failure, regimen-related toxicity, GVHD and opportunistic infection. 20 For this purpose a more intensive conditioning with additional lowdose irradiation (IR) has been demonstrated to exert the immunosuppressive effect that enables durable engraftment.…”

Unrelated cord blood transplantion in a Fanconi anemia patient using fludarabine-based conditioning

“…7 In our experience, decreasing the doses of CFA without irradiation has resulted in lower rates of toxicity and acute and chronic GVHD, with good engraftment. [8][9][10] However, we have been limited to the setting of related transplantation.…”

Results of allogeneic BMT in 16 patients with Fanconi's anemia

“…The frequencies of the traits can be as high as 3-9% for ␤ 0 thalassemia, and up to 54% or higher for Hb E. 1 Patients with ␤-thalassemia/Hb E can be as severely affected as those with homozygous ␤-thalassemia or Cooley's anemia. At present, allogeneic hematopoietic stem cell transplantation is the only curative therapy for thalassemia.…”

“…Medeiros et al 1 recently reported their results of allogeneic BMT in 16 patients with Fanconi's anemia (FA) using cyclophosphamide (CY) only as conditioning with a total dose of 100 mg/kg. One striking observation in this study is that no patient developed hemorrhagic cystitis.…”