Summary:Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors remains the only modality for the correction of hematological abnormalities in Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT using a novel irradiation and cyclophosphamide-free conditioning regimen. The protocol included fludarabine 150 mg/m 2 , busulfan 4 mg/kg, and antithymocyte globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A, MTX, and daclizumab. The engraftment and occurrence of full stable donor hemopoiesis was rapid in all cases with minimal short-term toxic complications. There were no infections or febrile episodes during the inpatient phase. Three patients developed acute GVHD grade I-II involving gut and skin and one patient progressed to extensive chronic GVHD. The preparative conditioning regimen is safe and associated with low organ toxicity and effective immunosupression for the stable engraftment in FA patients undergoing SCT with matched related donors. Fanconi anemia (FA) is a rare autosomal recessive syndrome of progressive marrow failure, constitutional physical abnormalities of skin, skeleton, kidneys, and cancer susceptibility. 1 FA cells are characterized by chromosomal instability and marked DNA hypersensitivity to crosslinking alkylating agents such as cyclophosphamide or platinum derivatives. 2,3 This hypersensitivity forms the basis for the confirmatory tests for FA with diepoxybutane (DEB), nitrogen-mustard, and others. Bone marrow failure remains the main cause of mortality among the FA patients, followed by complications of stem cell transplantation (SCT) and myeloid and nonmyeloid malignancies. Allogeneic hematopoietic SCT from unaffected sibling donors or suitably matched unrelated donors remains the only curative option for the correction of hematological abnormalities in FA patients. In the past, the use of highdose cyclophosphamide and ionizing radiation in preparative regimens often resulted in excessive organ toxicity and death in the early post transplant period. Low-doses of cyclophosphamide (20-40 mg/kg) combined with a 4-6 Gy of thoraco-abdominal or total body irradiation results in reduced toxicity and substantially improves the outcome for the FA patients transplanted from HLA-matched donors. 4 However, reduced doses of cyclophosphamide may not kill DEB-resistant naturally reverted T-lymphocytes, thereby increasing the risk of rejection in mosaic recipients of unrelated grafts (J Wagner, unpublished). Moreover, longterm follow-up clearly shows that these protocols are still associated with significant regimen-related toxicity and high risk of secondary malignant transformations. 5 More specifically, high incidence and severity of acute and chronic graft-versus-host disease (GVHD) in FA patients, who received cyclosporine alone as the GVHD prophylaxis, significantly contributed to transplantation-related morbidity and mortality, in addition favoring development of late epithelial cancers in irradiated patients. These obs...
Allogeneic stem cell transplantation remains the best option for young patients with SAA. With genetically identical twin as an ideal donor, the majority of SAA patients require appropriate immunosuppression before and after stem cell transplantation to obtain long-term hematopoietic reconstitution. Alkylating agents, used during conditioning, are associated with short- and long-term toxic effects that lead to poor compliance of treatment and could compromise the quality of future life. Three SAA patients, transplanted from genetically identical twins without using alkylating agents during conditioning, showed rapid and sustained hematological reconstitution without any evidence of conditioning-related toxicity.
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