alpha/beta t-cell depleted blood-forming stem cell transplant from related or unrelated donors for blood diseases in children and young adults

Conditions: Blood Disease

Summary: this single institution, phase i clinical trial will determine the safety and feasibility of employing t-cell receptor (tcr) αβ+ and cd19+ (cluster of differentiation ) depleted hematopoietic stem cell transplantation (hsct) using peripheral blood stem cells (pbmc) from closely matched unrelated donors or haploidentical donors to treat non-malignant hematologic diseases in children and young adults. allogeneic hematopoietic stem cell transplantation has become a curative option for children and adolescents with a variety of otherwise fatal conditions. to reduce the incidence and severity of graft-versus-host disease (gvhd) associated with allogeneic hematopoietic stem cell transplantation, donor grafts are depleted of t cells, either using cd34+ selection or cd3+/cd19+ depletion of grafts. however, these selection processes also deplete the graft of protective cell subsets, such as γδ t cells, natural killer(nk) cells, monocytes and dendritic cells, which play important roles in the immune response to infectious agents. moreover, the presence of nk cells and γδ t in donor grafts is associated with more rapid immune reconstitution after hsct transplantation. in order to retain these protective immune cell subsets, this trial will use a novel, highly selective graft engineering process using the miltenyi clinimacs system that selectively depletes αβ-t cells and b cells which are responsible for gvhd and epstein barr virus (ebv)-related post-transplantation lymphoproliferative disorder, respectively. prior to transplantation, patients will be treated with a conditioning regimen, specific for the original disorder. the primary objective of this study is evaluation of the safety and feasibility of hsct using tcrαβ+/cd19+ depleted hematopoietic stem cells to treat non-malignant hematologic diseases. this will be assessed by evaluating the incidence of graft failure, grade iii-iv acute gvhd and chronic gvhd and trm. secondary objectives include the evaluation of immune reconstitution and incidence of post-transplant infections, adverse events, serious adverse events, overall and disease-free survival and the efficiency of graft processing by the clinimacs system.


Eligibility criteria:
inclusion criteria: * no human leukocyte antigen (hla) identical sibling available and * no hla matched unrelated donor available or urgent need of hsct precludes time necessary to search for suitable hla matched unrelated donor and * haploidentical donor or closely matched unrelated donor available and willing to undergo mobilization and apheresis * if subject has genetically confirmed inherited bone marrow failure, related donor must be evaluated for this disorder and testing must be negative. * if subject has sickle cell disease, donor may have only sickle cell trait * patient must be diagnosed with one of the following diseases or disorders: hemoglobinopathies * sickle cell disease for patients ≤ 21 years of age for whom hydroxyurea has been trialed for at least six months, and failed * thalassemia major for patients ≤ 21 years of age acquired bone marrow failure syndromes * paroxysmal nocturnal hemoglobinuria with bone marrow failure * myelodysplastic syndromes (lower risk) inherited bone marrow failure syndromes * fanconi anemia * diamond blackfan anemia * dyskeratosis congenita and related telomere disorders * congenital thrombocytopenia syndromes * severe congenital neutropenia * shwachman-diamond syndrome * age ≤ 40 years (except patients with hemoglobinopathies) * life expectancy ≥ 3 months * karnofsky (patients \> 16 years)/lansky (patients ≤ 16 years) index ≥ 60 * organ function requirements renal function * creatinine clearance or radioisotope glomerular filtration rate (gfr) greater than or equal to 60 ml/min/1.73m\^2 liver function * total bilirubin \< 3 mg/dl * alanine aminotransferase (alt)/ serum glutamic-pyruvic transaminase; synonymous with alt (scpt) ≤ 3 x upper limit of normal(uln) for age cardiac function * ejection fraction of \> 40% by multiple gated acquisition scan (muga) or echocardiogram pulmonary function * no evidence of dyspnea at rest * no supplemental oxygen requirement * if measured, carbon monoxide diffusion capacity (dlco) \> 50% * willing to use effective birth control method if patient is of reproductive potential * informed consent obtained (patient or legal representative) exclusion criteria: * pregnant * hiv infection * uncontrolled, serious active infection at screening * significant serious intercurrent illnesses * enrollment in any other treatment study that would interfere with the endpoints of this study according to judgement of principal investigator(or pi designee).