hematopoietic stem cell transplantation in high risk patients with fanconi anemia

Conditions: Fanconi Anemia

Summary: rationale: a bone marrow or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. giving combination chemotherapy before a donor stem cell transplant may make the transplant more likely to work. this may be an effective treatment for patients with high risk fanconi's anemia. purpose: this clinical trial is studying how well combination chemotherapy works in treating high risk patients who are undergoing a donor stem cell transplant for fanconi's anemia.

objectives: primary * determine whether the incidence of neutrophil engraftment is acceptable in high-risk patients with fanconi's anemia treated with busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin followed by allogeneic hematopoietic stem cell transplantation. secondary * determine the tolerability of mycophenolate mofetil in these patients. * determine the incidence of acute and chronic graft-vs-host disease in patients treated with this regimen. * determine the incidence of major infections in patients with a history of major infections treated with this regimen. * determine the incidence of relapse in patients with refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia treated with this regimen * determine the probability of 1-year survival of patients treated with this regimen. outline: patients are stratified according to donor/recipient hla type (identical vs other). * cytoreductive combination chemotherapy: patients receive busulfan intravenously (iv) over 2 hours twice daily on days -7 and -6 and cyclophosphamide iv over 2 hours and fludarabine iv over 30 minutes once daily on days -5 to -2. * graft failure prophylaxis: patients receive methylprednisolone iv twice daily on days -5 to 30 and anti-thymocyte globulin iv over 4-6 hours twice daily on days -5 to -1. * graft-vs-host disease prophylaxis: patients receive cyclosporine iv over 2 hours twice daily on days -3 to 100 (if patient has a matched sibling donor) or days -3 to 180 (if patient has another donor type). patients also receive mycophenolate mofetil orally or iv twice daily on days -3 to 45. * allogeneic hematopoietic stem cell transplantation (hsct): patients undergo allogeneic hsct (using bone marrow or umbilical cord blood) on day 0. patients receive filgrastim (g-csf) subcutaneously beginning on day 1 and continuing until blood counts recover. after completion of study treatment, patients are followed periodically for 3 years.

Eligibility criteria:
inclusion criteria: * patients must be \<45 years of age with a diagnosis of fanconi anemia with: * biallelic brca2 mutations, or * aplastic anemia, or advanced myelodysplastic syndrome (mds) (mds with ≥5% blasts), or acute leukemia who are ineligible for total body irradiation. aplastic anemia is defined as having at least one of the following (with or without cytogenetic abnormalities): platelet count \<20 \* 10\^9, - absolute neutrophil count (anc) \<5 \* 10\^8/l, - hgb \<8 g/dl * patients must have an hla-a, b, drb1 identical or 1 antigen mismatched related or unrelated bm donor or have an hla-a, b, drb1 identical, 1 antigen or 2 antigen mismatched related or unrelated umbilical cord blood (ucb) donor. patients and donors will be typed for hla-a and b using serological level typing and for drb1 using high resolution molecular typing. * adequate major organ function including: * cardiac: ejection fraction \>45% * hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites, no cirrhosis) * karnofsky performance status \>70% or lansky \>50% * women of child bearing potential must be using adequate birth control and have a negative pregnancy test. exclusion criteria: * active cns leukemia at time of hsct. * active uncontrolled infection within one week of hematopoietic stem cell transplant (hsct). * pregnant or lactating female. donor inclusion criteria: * donor must be in good health based on review of systems and results of physical examination. * donor must have a normal hemoglobin, white count, platelet count and partial thromboplastin time (ptt), and a negative diepoxybutane (deb) test. * hiv-nat negative, htlv-1, htlv-2 negative, hepatitis b and c negative. * female donors of childbearing potential must have a negative pregnancy test. * unrelated donors must agree to peripheral blood stem cell (pbsc) donation donor exclusion criteria: * donor is a lactating female.

Keywords: fanconi anemia