Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors

Abstract

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...

Late graft failure in FA – case report and review of the literature

“…Similar results have been reported by Chaudury et al. (4) for a cohort of 18 patients transplanted from alternative donors and by other groups (7–10). Another promising approach was described by Huck et al.…”

Combined umbilical cord blood and bone marrow transplantation from a sibling in a patient with Fanconi anemia

“…ATG/OKT-3 has been used in GEFA02 protocol to avoid both Graft versus Host Disease (GvHD) and graft rejection, which might occur after such a reduced intensity conditioning regimen. GEFA02 protocol includes also low-dose busulphan, as added to the conditioning regimen has resulted in a particularly good outcome in pediatric patients with FA [7,10]. In the presented case, hematologic recovery was prompt: absolute neutrophil count > 0.5 × 10 9 /l was reached after 18 days and was similar to that observed in Maschan's study [7].…”

“…GEFA02 protocol includes also low-dose busulphan, as added to the conditioning regimen has resulted in a particularly good outcome in pediatric patients with FA [7,10]. In the presented case, hematologic recovery was prompt: absolute neutrophil count > 0.5 × 10 9 /l was reached after 18 days and was similar to that observed in Maschan's study [7]. The use of ATG may be complicated by infections, as in the described case hemorrhagic cystitis caused by BKV and asymptomatic CMV reactivation were noted.…”

“…It is always necessary to carry out clinical, hematological and cytogenetic tests to exclude FA in related donors [1][2][3]6]. Impaired DNA repair mechanisms in FA result in excessive toxicities after chemotherapy and FA patients must be prepared for transplantation with an appropriate conditioning regimen [7,8]. Fludarabine (FLU), successfully used for the first time in a child with FA in 1997 by Kapelushnik, is considered as a "gold standard" therapy, but it must be combined with other drugs.…”

Matched sibling donor haematopoietic stem cell transplantation in Fanconi anaemia: an update of the Cincinnati Children's experience

“…Among their first 11 patients, the overall survival and event‐free survival at 2 years were 100% and 82%, respectively, with a relatively short median follow‐up of 2·9 years (Tan et al , 2006). In addition, four patients were successfully transplanted using fludarabine (150 mg/m 2 ), busulfan (4 mg/kg) and ATG (90 mg/kg) in a Russian report (Maschan et al , 2004)). These children achieved rapid engraftment of donor cells with minimal short‐term toxic complications, and low levels of GVHD.…”