haploidentical allogeneic transplant with post-transplant infusion of regulatory t-cells

Conditions: Leukemia, Acute; Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL); Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL)

Summary: patients with hematologic malignancies will receive myeloablative chemotherapy followed by stem cell rescue with bone marrow or hematopoietic peripheral blood stem cells collected by apheresis from a filgrastim- (g-csf)-mobilized haploidentical related-donor, ie, hematopoietic peripheral blood stem cell transplant (hsct).

this is dose-escalation study intended to evaluate the use of classification determinant 15-positive (cd15+), cd4+, cd127dim, and foxp3+ regulatory t-cells (t-reg cells) supplemented by conventional t-cells (t-con cells), to enhance the efficacy of allogeneic (clinimacs cd34+ selected) hematopoietic stem cell transplantation (allo-hsct), in the setting of leukemia, lymphoma, and myelodysplastic syndrome (mds). this study investigates amelioration of the impaired immune recovery and address the significant relapse incidence in the haploidentical hsct setting. pre-transplant myeloablative conditioning will be melphalan; thiotepa; fludarabine and rabbit antithymocyte globulin (ratg). stem cell rescue will be with cd34+ selected cells. the rescue infusion will be supplemented with infusions of regulatory t-cells (t-reg) and conventional t-cells (t-con) from the same donor collection, on treatment days 14 and 16 respectively. cd34+ cell infusion day is treatment day 0. t-reg cells are those cells enriched by immunomagnetic selection of cd25+ cells, and further purified by flow cytometric cell sorting for the cd15+, cd4+, cd127dim, foxp3+ cell population. these cells are an enriched but naturally-occurring t-cell population. t-con cells are unseparated/unfractionated cells, ie, as collected by the peripheral blood stem cells apheresis procedure. post-transplant follow-up is for 5 years.

Eligibility criteria:
inclusion criteria recipient * histopathologically-confirmed: * acute leukemia (in first remission with poor risk factors and molecular prognosis) * acute myelogenous leukemia (aml) with -5,-7, t (6;9), tri8, -11 * acute lymphoblastic leukemia (all) with ph+ t (9;22), t (4;22), (q34;q11) * acute leukemia with refractory disease or \> complete remission (cr) 1 * chronic myelogenous leukemia (cml) (accelerated, blast or second chronic phase) * myelodysplastic syndrome (in high and high intermediate risk categories) * non-hodgkin's lymphoma (nhl) with poor risk features and not suitable for autologous transplantation * refractory chronic lymphocytic leukemia (cll) * at least 21 days from the end of most recent prior therapy to start of the transplant conditioning regimen * must be \< 60 years old at time of registration. * karnofsky performance status (kps) \> 70% must have related donor who is: * genotypically human leukocyte antigen (hla) -a, b,c and dr beta 1 (drb1), dq loci haploidentical to the recipient (but differing for 2 to 3 hla alleles on the unshared haplotype in the graft-versus-host disease (gvhd) direction) * no hla-matched sibling or matched-unrelated donor is identified. * adequate cardiac and pulmonary function (left ventricular ejection fraction (lvef) \> 45%, diffusing capacity of the lungs for carbon monoxide (dlco) \>50% corrected for hemoglobin) * serum creatinine \ 50 ml/min for those above serum creatinine at least 1.5 mg/dl * serum bilirubin \< 2.0 mg/dl * alanine transaminase (alt) \< 2x upper normal limit (uln) (unless secondary to disease) * no prior myeloablative therapy or hematopoietic cell transplantation donor: * age ≤ 70 years * weight ≥ 25 kg. * medical history and physical examination confirm good health status as defined by institutional standards * seronegative for hiv ag within 30 days of apheresis collection for: * hepatitis b surface antigen (sag) or polymerase chain reaction (pcr) + * hepatitis c ab or pcr+ * genotypically haploidentical as determined by hla typing * female donors (child-bearing potential) must have a negative serum or urine beta-human chorionic gonadotropin (hcg) test within 3 weeks of mobilization * capable of undergoing leukapheresis * has adequate venous access * willing to undergo insertion of a central catheter if leukapheresis via peripheral vein is inadequate * capable of agreeing to second donation of peripheral blood progenitor cell (pbpc) (or a bone marrow harvest) should the patient fail to demonstrate sustained engraftment following the transplant * institutional review board (irb)-approved consent form signed by donor or legal guardian \> 18 years of age donor selection in the priority order: * recipient's biological mother preferred, if available * other available haploidentical donors will be selected based upon the presence of natural killer (nk) alloreactivity between donor and recipient by high-resolution hla typing of the c locus. an nk-alloreactive donor will be preferentially chosen. recipients lacking a killer immunoglobulin-like receptor (kir)-ligand present in the donor along with the corresponding kir defines "nk alloreactivity". * if more than one nk-alloreactive donor is available, preference is to cytomegalovirus (cmv)-seronegative donor exclusion criteria recipient: * suitable candidate for autologous transplantation or allogeneic transplantation with an available matched-related or matched-unrelated donor * seropositive for: * hiv ab * hepatitis b sag or pcr+ * hepatitis c ab or pcr+ * history of invasive aspergillosis * any active, uncontrolled bacterial, viral or fungal infection * uncontrolled central nervous system (cns) disease involvement * lactating female donor: * evidence of active infection or viral hepatitis * factors of increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (g-csf) therapy * lactating female * hiv-positive