Hematopoietic Stem Cell Transplantation (HSCT) as Curative Therapy for Fanconi Anemia (FA) Patients with Acute Leukemia or Advanced Myelodysplasia (MDS).

Historically outcomes have been very poor for FA patients with advanced MDS or leukemia. It remains controversial as to whether HSCT is indicated for such patients and there is no consensus as to the optimal conditioning regimen in this setting. Traditionally, conditioning for FA patients has incorporated total body irradiation (TBI). Here, we report results of a pilot study in which we have substituted busulfan for TBI, designed for FA patients with one or more high risk features, identified following analysis of 42 previous consecutive URD FA transplants: advanced MDS or leukemia, age >18 years, or previous proven fungal or gram negative infection. Between 12/02–08/04 6 patients were enrolled, 5 with acute leukemia. Patient and disease characteristics are presented in Table 1. Conditioning consisted of busulfan (total 3.2mg/kg), cyclophosphamide (total 40mg/kg), fludarabine (total 140 mg/m²) and ATG (total dose 75mg/kg); GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. All patients received prophylactic voriconazole for one month prior to transplant. BM was T cell depleted with CD34 selection by Isolex 300i. Five out of six patients achieved neutrophil engraftment. Median time to an ANC>500 was 16 days (range: 11–20 days). One patient developed Grade I acute GVHD; no patient has developed chronic GVHD. The preparative regimen was well tolerated. Toxicities included Grade IV mucositis (n=1), VOD (n=2), hemorrhagic cystitis (n=1) and CMV pneumonia (n=1). Three patients are alive and in remission with a median follow-up of 575 days.

These results suggest TBI is not required to achieve durable engraftment and leukemia control, busulfan 3.2 mg/kg is tolerable, and advanced MDS or acute leukemia does not preclude HSCT in FA patients.