haploidentical hematopoietic stem cell transplantation

Conditions: Sickle Cell-thalassemia Disease; Thalassemia

Summary: the study is designed as a pilot/phase 1 trial of reduced intensity haploidentical hsct in patients with sickle cell disease and thalassemia. the purpose of the study is to assess the safety and toxicity of reduced intensity conditioning haploidentical hematopoietic stem cell transplantation.

research subjects will undergo reduced intensity conditioning (hydroxyurea, atg, fludarabine, thiotepa, melphalan) followed by infusion of a peripheral blood stem cell graft collected from haploidentical family donors that are cd34+ positively selected using the clinimacs device. sirolimus will be used for gvhd prophylaxis and given for 9 months post-transplant and then tapered off by one year the use of the clinimacs device for cd34 selection will be performed at cnmc through cross-reference of the master file for clinimacs cd34+ reagent by milteyni biotech (bb-mf 8061). clinimacs is an electromechanical device intended to isolate certain cell subsets from mixed cell populations. when used in combination with the clinimacs cd34 reagent, it is possible to prepare extremely pure populations of cd34+ cells with upwards of 5 logs depletion of contaminating t cells within a closed and sterile system. we intend to use this system to select cells from hla haploidentical related donors who have been mobilized with g-csf prior to stem cell collection. since previous investigations of this strategy in adult patients have not translated into enhanced long term survival, we intend to limit this protocol to patients under the age of 22 as they have more rapid immune reconstitution.

Eligibility criteria:
inclusion criteria: * first allogeneic transplant * age up to 22 years * patients with severe sickle cell disease (stroke, elevated tcd velocities, \>2 acute chest syndrome, ongoing chronic red cell transfusion \> 6 months) * patients with transfusion dependent thalassemia and evidence of iron overload * patients must have a related donor that is hla-matched at \>/=4 of 8 but \<8/8 hla-a, -b, -c and -drb1 * cardiac function: shortening fraction \>25%; ejection fraction \>40% * estimated creatinine clearance greater than 50 ml/minute * pulmonary function: dlco ≥40% (adjusted for hemoglobin) and fev1≥50% in patients 7 years and older with normal cognitive function and able to perform the test adequately. if not able to complete the testing a ct chest will be required., oxygen saturation\>91% * liver function: direct (conjugated) bilirubin \< 2x the upper limit of normal and alt/ast \< 2.5x the upper normal limit. * signed informed consent. exclusion criteria: * life expectancy less than 6 months * patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. * pregnant or breastfeeding patients * patients seropositive for the human immunodeficiency virus (hiv) * patient with active hepatitis b or c determined by serology and/or naat * active hepatitis, bridging fibrosis or cirrhosis on liver biopsy (biopsy required for patients on chronic transfusion therapy for \> 1 year and evidence of iron overload with ferritin \>1000 ng/ml) * patients with suitable 8/8 hla matched related and unrelated donors * patients who have an intolerance to or have received alemtuzumab in the prior 6 months will be excluded from enrollment unless alemtuzumab is replaced with rabbit atg in the conditioning regimen