Haploidentical Natural Killer Cells to Treat Refractory or Relapsed Acute Myelogenous Leukemia (AML)

Study Overview
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Brief Summary
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This is a phase II therapeutic study of related donor HLA-haploidentical NK-cell based therapy after a high dose of fludarabine/cyclophosphamide with denileukin diftitox preparative regimen for the treatment of poor prognosis acute myelogenous leukemia (AML).

Detailed Description
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Patients achieving a complete remission and neutrophil recovery (ANC > 500) for at least 4 weeks will be considered for allogeneic transplant to prolong remission (independent of this study). All patients, including those who go on to transplant, will be followed to determine disease free survival, treatment related mortality, and time to relapse.

Official Title
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Adoptive Transfer of Haploidentical Natural Killer Cells to Treat Refractory or Relapsed AML MT2010-02

Conditions
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Leukemia, Myelogenous, Acute

Intervention / Treatment
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* Biological: Natural Killer Cells
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Denileukin diftitox
* Procedure: Donor lymphapheresis
* Drug: IL-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 2 years of age Meets one of the following disease criteria: Primary acute myelogenous leukemia (AML) induction failure: no complete remission (CR) after 2 or more induction attempts Relapsed acute myelogenous leukemia (AML): not in CR after 1 or more cycles of standard re-induction therapy. For patients > 60 years of age the 1 cycle of standard chemotherapy is not required if either of the following criteria is met: relapse within 6 months of last chemotherapy blast count < 30% within 10 days of starting protocol therapy Secondary AML from myelodysplastic syndrome (MDS) AML relapsed > 2 months after transplant who do not have the option of donor lymphocyte infusions (e.g. recipients of autologous or umbilical cord blood [UCB] transplants) Patients with prior central nervous system (CNS) involvement are eligible provided that it has been treated and CSF is clear for at least 2 weeks or magnetic resonance imaging (MRI) stable prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment. Available related HLA-haploidentical donor (3-5 of 6 HLA-A, B and C) Karnofsky Performance Status > 50% or Lansky Play score > 50 Adequate organ function defined as: Creatinine: ≤ 2.0 mg/dL (for pediatric patients - ClCr > 50 ml/min or age adjusted Cr) Hepatic: Liver function tests (LFT's) < 5 x upper limit of institutional normal (ULN) Pulmonary Function: oxygen saturation ≥ 90% on room air and pulmonary function >50% corrected Diffusion lung capacity for carbon monoxide (DLCO) and Forced expiratory volume in one second (FEV1) Oxygen saturation [>92%] can be used in child where pulmonary function tests (PFT's) cannot be obtained. (Testing required only if symptomatic or prior known impairment.) Cardiac Function: Ejection fraction (EF) ≥ 40%, no uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to natural killer (NK) cell infusion (excluding denileukin diftitox pre-meds) Women of child bearing potential must have a negative pregnancy test within 14 days prior to study registration and agree to use adequate birth control during study treatment. Voluntary written consent Exclusion Criteria: Bi-phenotypic acute leukemia Transplant < 60 days prior to study enrollment New or progressive pulmonary infiltrates on screening chest x-ray or chest computated tomography (CT) scan that has not been evaluated with bronchoscopy, if feasible. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections). Surgical resection waives any waiting requirements. Uncontrolled bacterial or viral infections - chronic asymptomatic viral hepatitis is allowed Pleural effusion large enough to be detectable on chest x-ray Known hypersensitivity to any of the study agents used Received investigational drugs within the 14 days before enrollment Known active CNS involvement

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treated Patients<br>Patients are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2. | Biological: Natural Killer Cells<br>* Given by infusion on Day 0. The product is T cell-depleted (CD3-) and B cell-depleted (CD19). Target dose for infusion is < or = 8 x 10^7 nucleated cells/kilogram.<br>Drug: Fludarabine<br>* Administered as a 1 hour intravenous infusion once a day for 5 doses beginning on day -6.<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Administered as a 2 hour intravenous infusion with high volume fluid flush and mesna per institutional guidelines on day -5 and -4 one hour after fludarabine infusion. (Day -4 administration may be omitted if patient has had a transplant in the previous 4 months.)<br>* Other names: Cytoxan;Drug: Denileukin diftitox<br>* 12 ug/kg/day will be administered on day -1 and day -2 intravenously.<br>* Other names: Ontak;Procedure: Donor lymphapheresis<br>* Day -1 before planned NK cell infusion, the donor will undergo lymphapheresis (Removal of lymphocytes from donated blood, with the remainder of the blood retransfused into the donor).<br>Drug: IL-2<br>* Administered after NK cell infusion, 10 million units every other day for a total of 6 doses. (Patients weighing less than 45 kilograms will receive a dose of 5 million units/m^2 every other day for 6 doses).<br>* Other names: Interleukin-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients With Successful Expansion of Natural Killer Cells After Infusion | The primary objective of this study was to estimate the incidence of in vivo expansion of natural killer (NK) cells 14 days after infusion of an allogeneic donor product enriched for NK progenitors. Successful in vivo donor NK cell expansion was defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/ul in the patient's peripheral blood 14 days after infusion. | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients With Complete Remission of Disease | Disease response was defined as complete remission (disease response) by morphologic criteria including <5% blasts in a moderately cellular or cellular marrow. Complete remission was also correlated with NK cell expansion in vivo, IL-15 levels and donor/recipient KIR B genotyping, and Treg depletion. | At least 4 weeks after last dose (28 days) | 
| Percent of Patients With Disease Free Survival | Number of patients alive and disease free at 6 months. The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. | Month 6 | 
| Percent of Patients With Incidence of Relapse | Number of patients who have had a relapse(the return of disease after its apparent recovery/cessation) after obtaining a complete remission of their disease. | Month 6 | 
| Number of Patients With Treatment-Related Death | Number of patients who died within the first 100 days of treatment due to toxicity. | Day 100 | 
| Percent of Patients With Natural Killer Cell Expansion Versus KIR Genotype Versus Treg Depletion | Association between in vivo natural killer (NK) cell expansion and complete response without platelet recovery (CRp) with donor killer immunoglobulin-like (KIR) genotype and Treg depletion. In vivo donor NK cell expansion was correlated with regulatory T-cell (Treg) depletion as detected on flow cytometry. | Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myelogenous leukemia, primary acute myelogenous leukemia, secondary acute myelogenous leukemia, relapsed acute myelogenous leukemia