Fludarabine, Antithymocyte Globulin and Low Dose Cyclophosphamide As Conditioning Regimen for Allogeneic Stem Cell Transplantation in Children with Severe Aplastic Anemia

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There is no standard conditioning regimen for children with severe aplastic anemia (SAA) and short telomeres. Here, we summarize our experience in ten patients with SAA and short (n=6) or undetermined telomeres (n=4) who have been transplanted with HLA-matched related hematopoietic donor cells. All patients were transplanted using the following conditioning that included fludarabine (35mg/m2) on day -6 to -2, cyclophosphamide (40mg/kg) on day -6 and -5, and rabbit antithymocyte globulin (thymoglobulin) (2.5mg/kg) on day -5 to -2. GVHD prophylaxis was mycophenolate mofetil and cyclosporine. All ten patients (6 females and 4 males) with an average age of 7 (range 0.8-13.3 years) had bone marrow failure as a predominate feature and except for one patient who had short stature, mental retardation and a brain MRI with bilateral encephalomalacia there were no abnormal physical findings, specifically no classical features of DC i.e. nail dystrophy, leukoplakia, and skin pigmentation. All donors had normal physical examination and normal CBC. History of consanguinity was reported in all patients except one. Patients had normal chromosomal fragility test. All ten patients engrafted successfully, median time to neutrophil engraftment was 20 (range, 11-29 days) and platelet engraftment 22 (range, 13-42 days). Median infused nucleated cell dose was 3.2 (range, 1.6-4.4 X108/kg) and CD34 cell dose was 6.6 (range, 1.1-13.1 X106/kg). Median donor chimerism was 94% for myeloid cells and 63% for T cells around 90 days post HSCT. None of our patients had acute GVHD and one patient had mild classic chronic GVHD of the skin that was controlled with topical therapy. Two patients had late graft failure. The first patient had pancytopenia one year post transplant with loss of donor chimerism and underwent successful second transplant using fludarabine, ATG, and melphalan. The second patient had progressive pancytopenia starting six months post transplant despite having full donor chimerism. All patients are alive with median follow-up duration of 917 days (range, 40-1413 days). In conclusion, fludarabine-based conditioning using reduced dose cyclophosphamide (80mg/kg) seems safe and feasible in our SAA patients with shorter telomeres. Larger study is needed to confirm our results and to determine the optimal dose of cyclophosphamide.

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