Donor Peripheral Stem Cell Transplant in Treating Patients With Relapsed Acute Myeloid Leukemia

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Giving chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also helps 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. PURPOSE: This clinical trial is studying how well a peripheral stem cell transplant using NK cells from a donor works in treating patients with relapsed acute myeloid leukemia.

Detailed Description
-----------------
OBJECTIVES: Primary Evaluate the in vivo expansion of natural killer (NK) cells 14 days after treatment with allogeneic NK cell-enriched peripheral blood stem cell transplantation in patients with relapsed acute myeloid leukemia. Secondary Determine the response rate, in terms of complete remission, in patients treated with this regimen. Correlate complete remission rate with NK cell expansion, interleukin-15 levels, and donor/recipient killer immunoglobulin receptor (KIR) ligand matching status in patients treated with this regimen. Determine the overall and progression-free survival of patients treated with this regimen. Determine the toxicity of this regimen in these patients. OUTLINE: This is an open-label study. Induction therapy: Patients receive fludarabine IV on days -6 to -2 and cyclophosphamide IV on day -5 or on days -5 and -4. Allogeneic natural killer (NK) cell-enriched peripheral blood stem cell transplantation: Patients receive allogeneic NK cell-enriched peripheral blood stem cells IV over 15-60 minutes on day 0. Patients also receive interleukin-2 subcutaneously beginning on day 0 and continuing 3 times a week for up to 2 weeks. After completion of study treatment, patients are followed periodically for 3 months.

Official Title
-----------------
Allogeneic Natural Killer Cells in Patients With Relapsed Acute Myelogenous Leukemia

Conditions
-----------------
Leukemia

Intervention / Treatment
-----------------
* Biological: aldesleukin
* Biological: therapeutic allogeneic lymphocytes
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Procedure: in vitro treated peripheral blood stem cell transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of acute myeloid leukemia (AML) meeting 1 of the following criteria: Primary refractory disease (no complete response [CR] after ≥ 2 induction therapies) Relapsed disease not in CR after ≥ 1 course of standard reinduction therapy Secondary AML from myelodysplastic syndromes Disease relapsed ≥ 2 months after transplant and no option of donor lymphocyte infusions (e.g., recipients of autologous or umbilical cord blood transplants) Chronic myelogenous leukemia with myeloid blast crisis not in second chronic phase after at least one cycle of standard chemotherapy and imatinib Over 60 years of age with relapse within 6 months after completion of last chemotherapy Over 60 years of age with blast count < 30% within 10 days before study entry Related HLA-haploidentical natural killer cell donor available No severe organ damage (by clinical or laboratory assessment) Performance status 50-100% No evidence of active infection on chest X-ray No active fungal infection Exclusion Criteria: Active central nervous system (CNS) leukemia Pleural effusions large enough to be detectable by chest x-ray Pregnant or nursing (positive pregnancy test) Fertile patients must use effective contraception Less than 60 days since prior transplant Less than 3 days since prior prednisone Less than 3 days since other prior immunosuppressive medication

Ages Eligible for Study
-----------------
Minimum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intent-to-Treat<br>All patients treated with natural killer (NK) cells (at a dose of 1.5-8 x 10^7/kg.) | Biological: aldesleukin<br>* 10 million units three times a week for a total of 6 doses. For any subject less than 45 kilograms the IL-2 will be given at 5 million units per meter squared three times weekly for a total of 6 doses<br>* Other names: IL-2;Biological: therapeutic allogeneic lymphocytes<br>* Cells infused per kg. 1.5-8.0 x 10^7/kg Total cells infused(for 70 kg. adult) 1.05 - 5.6 x 10^9<br>* Other names: lymphocytes;Drug: cyclophosphamide<br>* Days -5 and -4: 60 mg/kg<br>* Other names: Cytoxan;Drug: fludarabine phosphate<br>* Days -5 through -2: 25 mg/m^2<br>* Other names: Fludara;Procedure: in vitro treated peripheral blood stem cell transplantation<br>* Day 0 infuse natural killer cells<br>* Other names: Natural Killer Cells;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Natural Killer (NK) Cell Expansion | Evaluation of expansion of donor allogeneic natural killer (NK) cells at day 14 following infusion (>100 donor-derived NK cells per uL of patient blood detectable at day +14). | Study Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Complete Remission | Clinical response is determined by achievement of a complete remission (CR) as judged by morphological criteria (< 1% blasts in bone marrow with neutrophil recovery). | Day 28-35 | 
| Median Time to Disease Relapse (Months) | Follow-up continued every 3 months after the allogeneic natural killer (NK) cell infusion, unless they were transplanted, relapsed or had progressive disease. Time in months to relapse of disease is calculcated from 1st day of treatment with NK cells. Relapse occurs when leukemia is detected in bone marrow or blood. | From 1st Day of treatment until death or receipt of bone marrow transplant. | 
| Overall Survival Time of Patients With Complete Remission | Median number of months patients were alive after NK cell infusion. | From Day 1 of Treatment until death or patient received bone marrow transplant. | 
| Number of Patients With Complete Remission and Natural Killer Cell Expansion | Includes patients who had both a complete remission of disease and an expansion of natural killer cells. | Day 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
recurrent adult acute myeloid leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22)