RATIONALE: Giving chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total body irradiation, before peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer (NK) cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving IL-2 (aldesleukin) after NK cell infusion may stimulate them to kill any remaining cancer cells. PURPOSE: This phase I/II (currently enrolling in phase II) trial is studying how well a donor natural killer cell infusion works in treating patients who are undergoing donor stem cell transplant for acute myeloid leukemia.
OBJECTIVES: Primary * To determine the disease-free survival at 6 months and 1 year in patients with high-risk myeloid malignancies who undergo a reduced-intensity haploidentical hematopoietic stem cell transplantation (HSCT) supplemented with donor natural killer (NK) cells. Secondary * To evaluate the in vivo expansion of a donor CD3- CD19- selected NK cell product administered after a preparative regimen of cyclophosphamide, fludarabine, and total body irradiation (TBI) and HSCT in these patients. * To determine the rate of graft failure defined by absolute neutrophil count (ANC) \< 500/mm³ by day 28. * To determine the incidence of grade III-IV acute graft-versus-host disease (GVHD) at 6 months. * To determine the rate of treatment-related mortality at day 100. * To determine the incidence of chronic GVHD at 12 months. * To determine the incidence of disease relapse at 12 months. * To determine the incidence of post-transplant lymphoproliferative disorder at 12 months. Correlative * To correlate immune reconstitution of the in vivo expanded haploidentical NK cells with clinical outcomes. OUTLINE: This is an open-label study. Patients receive fludarabine intravenous (IV) over 1 hour on days -18 to -14 and cyclophosphamide IV over 2 hours on days -16 and -15. Patients receive cyclosporin A on Day -15 through Day -8. Patients undergo total body irradiation on day -13. Patients then receive an infusion of donor natural killer cells on day -12 and interleukin-2 subcutaneously on alternating days between days -12 to -2. Patients receive thymoglobulin (ATG) and undergo allogeneic peripheral blood stem cell transplantation on day 0. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Administered subcutaneously (SQ) 9 million units every other day beginning Day -12 through -2 (evening of natural killer cell infusion) for a total of 6 doses.
Infusion given on Day -12; The targeted infused cell dose of CD3- CD19- selected NK product is within the range of 2-3 x 10\^7 cells/kg.
Administered intravenously (IV) 50 mg/kg on Day -15
Administered intravenously (IV) 40 mg/m\^2 on Days -18 through -14
On day 0, patients will receive an allogeneic transplant using pool cells from the day -1 and day 0 PBSC which will be CD34+ selected as the donor graft. The graft will be infused over 15-60 minutes.
Administered on Day -13, 200 cGy two times.
intravenous (IV) 3 mg/kg on Day 0 (day of donor CD34 cell infusion)
1.5 mg/kg by mouth or intravenously for target dose range of 150-250; day -15 through day -8.
Administered intravenously (IV) 50 mg/kg on Days -16 and -15
Administered intravenously (IV) 35 mg/m\^2 on Days -18 through -14
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States
Disease-free Survival at 6 Months
Number of patients alive without evidence of disease at 6 months after transplant
Time frame: Month 6
Disease-free Survival at 1 Year
Number of patients alive without evidence of disease at 1 year after transplant
Time frame: 1 Year
In Vivo Expansion of a Donor NK Cells NK Cell Product
Number of patients with in vivo expansion of donor NK cells. In vivo expansion of NK cell is defined as detection of \>100 donor-derived NK cells per microliter of blood.
Time frame: 12 - 14 days after NK cell infusion
Number of Patients With Graft Failure
Number of patients with graft failure defined as \<500 donor neutrophils count by day 28 in the absence of residual or relapsed leukemia
Time frame: Day 28
Incidence of Grade III-IV Acute Graft Versus Host Disease
Grade III-IV acute graft versus host disease is a severe short term complication created by infusion of donor cells into a foreign host
Time frame: Month 6
Number of Patients With Treatment-Related Mortality
Death within the first 100 days related to treatment in patients without relapse or persistent disease.
Time frame: Day 100
Incidence of Chronic Graft Versus Host Disease
Chronic graft versus host disease is a severe long term complication created by infusion of donor cells into a foreign host
Time frame: 1 Year
Number of Patients With Disease Relapse
Disease relapse is the recurrence of leukemia in patients who had cleared their leukemia after treatment. Patients with persistent leukemia are not evaluable for relapse.
Time frame: 1 Year
Incidence of Post-transplant Lymphoproliferative Disorder (PTLD)
Post-transplant lymphoproliferative disorder (PTLD) is a virally-driven cancer of the lymphoid cells caused by immunosuppressive drugs taken after allogeneic stem cell transplantation to prevent or control graft versus host disease.
Time frame: 1 Year
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