stem cell transplant for hemoglobinopathy

Conditions: Sickle Cell Disease; Thalassemia; Severe Congenital Neutropenia; Diamond-Blackfan Anemia; Shwachman-Diamond Syndrome

Summary: this study tests the clinical outcomes of one of two preparative regimens (determined by available donor source) in patients with non-malignant hemoglobinopathies. the researchers hypothesize that these regimens will have a positive effect on post transplant engraftment and the incidence of graft-versus-host-disease. regimen a2 has replaced regimen a in this study. two patients were treated on regimen a but did not have evidence of initial engraftment thus triggering the stopping rule for that arm of this study.

prior to transplantation, subjects will receive either: cyclophosphamide, fludarabine, campath, total body irradiation (tbi) or busulfan, cyclophosphamide, antithymocyte globulin (atg), granulocyte colony-stimulating factor (gscf) these drugs (and the radiation) are being given to help the new stem cells take and grow. on the day of transplantation, subjects will receive stem cells transfused via intravenous (iv) catheter. after stem cell transplantation, subjects will be given cyclosporine-a and mycophenolate (mmf)/or methylprednisone/or methotrexate to reduce the risk of graft-versus-host disease, the complication that occurs when the donor's stem cells react against the patient.

Eligibility criteria:
inclusion criteria: * patients with sickle cell disease/thalassemia (scd/thal) 0-50 years of age with an acceptable stem cell donor and disease characteristic defined by the following: * stroke, central nervous system (cns) hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral magnetic resonance imaging (mri) or cerebral arteriogram or mri angiographic study and impaired neuropsychological testing * acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions * recurrent vaso-occlusive pain 3 or more episodes per year for 3 years or more years or recurrent priapism, * impaired neuropsychological function and abnormal cerebral mri scan * stage i or ii sickle lung disease, * sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate \[gfr\] 30-50% of the predicted normal value) * bilateral proliferative retinopathy and major visual impairment in at least one eye * osteonecrosis of multiple joints with documented destructive changes * requirement for chronic transfusions but with red blood cell (rbc) alloimmunization \>2 antibodies during long term transfusion therapy * patients with transfusion dependent alpha- or beta-thalassemia 0-35 years of age with an acceptable stem cell donor as defined in the criteria in section above. * patients with other non-malignant hematologic disorders that are transfusion-dependent or involve other potentially life-threatening cytopenias (including but not limited to severe congenital neutropenia, diamond-blackfan anemia and shwachman-diamond syndrome) who are 0-35 years of age with an acceptable stem cell donor * second transplants * patients with sickle cell disease or thalassemia who have failed to engraft or have autologous recovery after a myeloablative sct regimen or non-myeloablative regimen are eligible for this protocol. * regimen a2 will be utilized for patients with sickle cell disease or thalassemia who do not have an hla-identical sibling donor or for any patient who has pre-existing organ dysfunction making them ineligible for a myeloablative preparative regimen. * regimen b will be utilized for patients with sickle cell disease or thalassemia who have an hla-identical sibling donor. * patients must meet above criteria. * if the patient has received prior radiation therapy, eligibility to receive additional radiation therapy must be determined by dr. dusenbery * if first transplant was a non-myeloablative regimen, the second transplant can occur at any time * if the first transplant was a myeloablative regimen, then the second transplant must be \> 6 months from the first transplant exclusion criteria: * patients with one or more of the following: * karnofsky or lansky performance score \<70 * acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy * stage iii-iv lung disease * gfr\<30% predicted * pregnant or lactating females * active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry. any patient with aids or arc or hiv seropositivity * psychologically incapable of undergoing bone marrow transplant (bmt) with associated strict isolation or documented history of medical non-compliance * patients not able to receive total lymphocytic irradiation (tli) due to prior radiation therapy

Keywords: high risk hemoglobinopathy stem cell transplant donor lymphocyte infusion transfusion dependent stem cell donor cord blood marrow transfusion dependent non-malignant hematologic disorders