Allogeneic Stem Cell Transplantation Following Chemotherapy in Patients With Hemoglobinopathies

Multi-Center Study Using Allogeneic Stem Cell Transplantation Following Reduced Intensity Chemotherapy in Patients With Hemoglobinopathies

Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Brigham and Women's Hospital, Emory University, Feist-Weiller Cancer Center at Louisiana State University Health Sciences, Ohio State University

The purpose of this study is to determine if treatment with reduced-dose busulfex, fludarabine and alemtuzumab (CAMPATH) followed by sten cell infusion will allow for donor stem cells to grow in patients with hemoglobinopathies bone marrow and restore circulating blood counts. In addition the incidence and severity of side effects and of graft vs. host disease (GVHD) will be monitored.

In order to undergo transplant procedure, patients will be admitted to the hospital for approximately 10-14 days. To prepare patient's bone marrow to accept donor stem cells, they will receive fludarabine and busulfex. Fludarabine will be given intravenously once daily for 4 days. Busulfex will be given once daily for the same 4 days. One day before patients receive busulfex and fludarabine, they will also be given alemtuzumab intravenously once daily for 5 days. Three days after the end of chemotherapy, patients will receive the infusion of donor stem cells. If patients have thalassemia, they will receive subcutaneous injections of filgrastim starting on day one after the donor stem cell transfusion and will continue receiving filgrastim every day until it appears that the donor stem cells have been accepted. If the patient has sickle cell disease, filgrastim will not be given, Additional drugs will be given to help prevent infection (i.e. antibiotics). After stem cell infusion patients will be examined and have blood tests weekly for 1 month. Bone marrow biopsies, and blood work will also be performed 1 month, 3 months, 6 months and 1 year after stem cell infusion. Patients will be on the study for about 12 months. After study is completed progress will be monitored on an annual basis.

Hemoglobinopathies, Sickle cell anemia, sickle cell-hemoglobin C disease, sickle cell-B-thalassemia, transfusion-dependant thalassemia, allogeneic transplant, nonmyeloablative transplant, Stem cell transfusion, graft vs. host disease

One day before fludarabine and busulfex are started, alemtuzumab will be given once daily for 5 days.

Outcome was measured by ANC >500 for three consecutive days prior to day 30 after PBSC infusion, >25% of hematopoietic cells are donor derived as determined by molecular chimerism assays or cytogenetic methods prior to day 45 after PBSC infusion and >25% of hematopoietic cells are donor derived as determined by molecular chimerism assays or cytogenetic methods after day 180 after PBSC infusion.

Outcome was measured by the assessment of organ toxicity related to Busulfex, fludarabine and alemtuzumab.

Outcome was measured by incidence and severity of acute and chronic GVHD following donor stem cell infusion.

Inclusion Criteria: Patients with sickle cell disease should have one or more of the following: acute chest syndrome requiring hospitalization; nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours; recurrent caso-occlusive pain or recurrent priapism; sickle neuropathy; bilateral proliferative retinopathy and major visual impairment of at least one eye; osteonecrosis of multiple joints; transfusion dependence; vaso-occlusive. Patients with thalassemia should have one or more of the following: transfusion dependence; iron overload; presence of 2 or more alloantibodies against red cell antigens. Exclusion Criteria: Pregnancy Acute hepatitis Cardiac ejection fraction < 30% Severe renal impairment Severe residual functional neurologic impairment Evidence of HIV infection

Armistead PM, Mohseni M, Gerwin R, Walsh EC, Iravani M, Chahardouli B, Rostami S, Zhang W, Neuberg D, Rioux J, Ghavamzadeh A, Ritz J, Antin JH, Wu CJ. Erythroid-lineage-specific engraftment in patients with severe hemoglobinopathy following allogeneic hematopoietic stem cell transplantation. Exp Hematol. 2008 Sep;36(9):1205-15. doi: 10.1016/j.exphem.2008.04.004. Epub 2008 Jun 11.