This is a phase II multi-institutional therapeutic study of NK-cell based nonmyeloablative haploidentical transplantation for the treatment of high-risk acute myeloid diseases. Enrollment will use a two-stage design. Stage 1 will enroll 15 patients unless an early stopping rule is met. If 9 or more of these first 15 patients achieve leukemia free neutrophil engraftment at day +28 accrual will move to stage 2. In stage 2, an additional 28 patients will be enrolled for a total of 43 patients. Patients will be followed for disease response for 2 years.
A reduced intensity conditioning using Fludara, Cytoxan, and irradiation will start on day -22, followed by infusion of donor NK (natural killer) cells on day-17, 6 doses of interleukin-2 (IL-2) to promote NK expansion (day -17 to day -7), 2 doses of ATG for additional immunosuppression to promote engraftment (day -5 to -4), and infusion of a TCR α/β-depleted same donor graft on day 0.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
25
Preparative Regimen: 1\) fludarabine 40 mg/m\^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,
CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.
Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion
Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10\^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.
Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10\^6/kg) on day 0. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.
Emory University
Atlanta, Georgia, United States
University of Minnesota, Masonic Cancer Center
Minneapolis, Minnesota, United States
Washington University
St Louis, Missouri, United States
Ohio State University
Columbus, Ohio, United States
Number of Participants With Donor Neutrophil Engraftment
The rate of donor neutrophil engraftment in the absence of leukemia at day +28 will be determined. Successful neutrophil engraftment is defined as an absolute donor-derived neutrophil count of \>500 cells/μl. Leukemia free is defined as \<5% bone marrow blasts, absence of blasts with Auer rods; absence of extramedullary disease; but cytogenetic or molecular minimal residual disease is allowed.
Time frame: Day 28
Number of Participants With Disease Free Survival
Time frame: At 6 Months
Number of Participants With Treatment Related Mortality (TRM)
Cumulative incidence will be used to estimate TRM.
Time frame: At 6 Months
Number of Participants Who Relapse
Cumulative incidence will be used to estimate relapse.
Time frame: 2 Years
Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells
Successful in vivo donor NK cell expansion will be defined by measuring an absolute circulating donor-derived NK cell count of \>100 cells/μl in patient's peripheral blood 12 days after infusion.
Time frame: Day 12
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