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

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.

• Natural Killer Cells (Biological): 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.
• Fludarabine (Drug), also known as Fludara: Administered as a 1 hour intravenous infusion once a day for 5 doses beginning on day -6.
• Cyclophosphamide (Drug), also known as Cytoxan: 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.)
• Denileukin diftitox (Drug), also known as Ontak: 12 ug/kg/day will be administered on day -1 and day -2 intravenously.
• Donor lymphapheresis (Procedure): 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).
• IL-2 (Drug), also known as Interleukin-2: 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).

Primary outcomes

• Percent of Patients With Successful Expansion of Natural Killer Cells After Infusion [Day 14]: 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.

Secondary outcomes

• Percent of Patients With Complete Remission of Disease [At least 4 weeks after last dose (28 days)]: 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.
• Percent of Patients With Disease Free Survival [Month 6]: 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.
• Percent of Patients With Incidence of Relapse [Month 6]: 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.
• Number of Patients With Treatment-Related Death [Day 100]: Number of patients who died within the first 100 days of treatment due to toxicity.
• Percent of Patients With Natural Killer Cell Expansion Versus KIR Genotype Versus Treg Depletion [Day 14]: 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.

Sex: All, ages: 2 Years to any

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

Participant flow

Outcome results

• Percent of Patients With Successful Expansion of Natural Killer Cells After Infusion (Primary), Number, Percentage of patients: Evaluable (Treated) Patients 27
• Percent of Patients With Complete Remission of Disease (Secondary), Number, Percentage of patients: Evaluable (Treated) Patients 53
• Percent of Patients With Disease Free Survival (Secondary), Number, Percentage of patients: Evaluable (Treated) Patients 33
• Percent of Patients With Incidence of Relapse (Secondary), Number, Percentage of patients: Evaluable (Treated) Patients 53
• Number of Patients With Treatment-Related Death (Secondary), Number, Percentage of patients: Evaluable (Treated) Patients 13
• Percent of Patients With Natural Killer Cell Expansion Versus KIR Genotype Versus Treg Depletion (Secondary), Number, Percentage of patients: Evaluable (Treated) Patients (Expansion=No) 43; Evaluable (Treated) Patients (Expansion=Yes) 13

Adverse events

Serious adverse events by term

Other adverse events by term

8 more terms not shown.

• Results publication: Bachanova V, Cooley S, Defor TE, Verneris MR, Zhang B, McKenna DH, Curtsinger J, Panoskaltsis-Mortari A, Lewis D, Hippen K, McGlave P, Weisdorf DJ, Blazar BR, Miller JS. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood. 2014 Jun 19;123(25):3855-63. doi: 10.1182/blood-2013-10-532531. Epub 2014 Apr 9. PMID 24719405

• Jeffrey S. Miller, M.D., Principal investigator, Masonic Cancer Center, University of Minnesota