This trial represents a single institution phase I/II pilot study with the primary objective of establishing the safety and feasibility of generating and infusing ML NK cells after TCRαβ haplo-HCT.
Complete remission (CR) defined by < 5% marrow blasts by morphology in the context of hematological recovery (ANC ≥ 0.5× 10^9/L, platelet count ≥ 50 × 10^9/L).
Morphological leukemia free state (MLFS) defined by the absence of hematological recovery and < 5% marrow blasts by morphology
MRD ≥ 1% after first induction course
MRD ≥ 0.1% after second induction course
Both Cohorts
Active GvHD. If patient had prior GvHD, patient must be off immunosuppression for at least 3 months prior to starting study treatment.
Active non-hematologic malignancy. History of other malignancy is acceptable as long as therapy has been completed and there is no current evidence of disease.
Currently receiving any other investigational agents at the time of transplant.
Parallel
Rabbit Anti thymocyte globulin
DrugrATG is administered intravenously over 6-18 hours for a total of 2 to 3 doses. The daily dose is based on body weight and lymphocyte count.
Busulfan
DrugBusulfan is administered intravenously either Q6H or Q24H, with a recommended target Busulfan AUC of 70-90 mg\*h/L.
Fludarabine
DrugFludarabine is administered intravenously at a dose of 40 mg/m\^2/dose once daily for 4 days.
Thiotepa
DrugThiotepa is administered intravenously at a dose of 5 mg/kg/dose Q12H for 2 doses.
Melphalan
DrugMelphalan is administered intravenously at a dose of 70 mg/m\^2/dose once daily for 2 days.
TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft
Biological/VaccineThe HPC product obtained from a haploidentical donor will undergo ex vivo TCR alpha beta and CD19+ depletion, and will be infused fresh on Day 0. There is no maximum limit for CD34+ dose. A maximum dose of 1 x 10\^5/kg recipient weight of TCRαβ cells should not be exceeded in the final HPC product.
memory-like natural killer cells
Biological/VaccineThe ML NK cells (dose: max capped at 20 x 10\^6/kg recipient weight, minimum dose allowed is 0.5 x 10\^6/kg recipient weight) will be infused on Day +7.
IL-2
Biological/VaccineIL-2 is administered subcutaneously at a dose of 1 million units/m\^2 on Days +7, +9, +11, +13, +15, +17, and +19 (7 doses total).
Plerixafor
DrugIf suboptimal collection of stem cells is predicted, plerixafor may be administered at a dose of 0.24 mg/kg subcutaneous injection once (maximum 40mg/dose). For patients with renal impairment, plerixafor will be administered at a dose of 0.16 mg/kg subcutaneous injection (maximum 27 mg/day).
Granulocyte Colony-Stimulating Factor
Biological/VaccineG-CSF will be administered at a dose of 10 mcg/kg/day for 5 days, or 6 days if two days of collection are needed.
CliniMACS
DeviceAfter stem cells are collected by leukapheresis, in order to create the HPC product, the stem cells will be washed to remove platelets and the cell concentration will be adjusted per laboratory and CliniMACS technology recommendations. The cells are then labeled using the CliniMACS TCRαβ Biotin Kit and CD19+ immunomagnetic microbeads. After labeling, the cells are washed to remove unbound microbeads. The partially processed product is loaded on the CliniMACS device where labeled cells are depleted and the negative fraction is eluted off the device. The negative fraction is centrifuged and volume reconstituted to obtain the final product.
Safety of patients being administered donor-derived ML NK cells following TCR alpha beta depleted haploidentical cell transplant
Safety will be determined by events occurring following transplant. Non-relapse mortality, engraftment failure, and development of severe GvHD will be considered events.
Feasibility of manufacturing and administering donor-derived ML NK cells following TCR alpha beta depleted haploidentical cell transplant
Feasibility is defined by product manufacture failure, i.e., the inability to infuse ML NK cells due to product contamination or insufficient cell dose (\<0.5x10\^6 / kg recipient weight).
Relapse Free Survival (RFS)
Defined as the time between the date of transplant and date of last follow up, relapse, or death due to any cause.
Overall Survival (OS)
Defined as death from any cause following transplant.
Development of acute graft versus host disease (aGvHD)
Incidence of grade II, III, or IV acute GvHD as graded according to the NIH consensus criteria. Severe aGvHD (Grades III-IV) is considered an event.
Development of chronic graft versus host disease (cGvHD)
Incidence of chronic GvHD as graded according to the NIH consensus criteria. Severe cGvHD is considered an event.
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Washington University School of Medicine
Lead sponsor
The Leukemia and Lymphoma Society
Collaborator
Rising Tide Foundation
Collaborator
St. Louis Children's Hospital Foundation
Collaborator
Children's Discovery Institute
Collaborator
Hyundai Hope On Wheels
Collaborator
