Natural Killer (NK) Cell Transplantation for AML

Pilot Study Of Haplo-Identical Natural Killer Cell Transplantation For Acute Myeloid Leukemia

The purpose of this study is to assess the safety and efficacy of infusing natural killer cells from a donor as treatment for patients with acute myeloid leukemia in remission or who have experienced relapse.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Cyclophosphamide, Fludarabine, Clofarabine, Etoposide, Interleukin-2; Procedure: Natural Killer Cell Infusion; Device: CliniMACS System

Detailed Description

Natural killer (NK) cells extracted from a [parental] donor are infused intravenously. Most patients are given a multi-agent chemotherapeutic conditioning regimen prior to the infusion. The conditioning regimen may be omitted for patients who have previously received traditional stem cell transplant.

Details of Treatment Plan:

Stratum 1 (AML in complete remission)

Cyclophosphamide 60 mg/kg IV Day -7 Fludarabine 25 mg/m2/day IV Days -6 through -2 Donor pheresis Day -1 Start IL-2 on Day -1, then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0

Stratum 2 (AML that is refractory or relapsed or AML with increasing minimal residual disease)

Clofarabine 40 mg/m2 IV, days -6 through -2 Etoposide 100 mg/m2 IV, days -6 through -2 Cyclophosphamide 400 mg/m2 IV, days -6 through 02 Donor pheresis Day -1 Start IL-2 Day -1, and then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0.

For patients who have received prior SCT, the conditioning regimen may be omitted if the NK cells are obtained from the original SCT donor.

Cytokine regimen (stratum 1 and 2): 1 million units/m2 of IL-2 given subcutaneously three times per week for two weeks (6 doses) starting on the evening of day -1.

NK Cell Transplantation (stratum 1 and 2): NK cells from haplo-identical family donor will be infused on day 0.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants with AML that is in complete remission, is relapsed or refractory, or with increasing minimal residual disease.
• Participants in complete remission must have recovered from toxicity of previous therapy and have evidence of bone marrow recovery
• Participants who had prior stem cell transplant (SCT) must have no evidence of GVHD and 60 or more days have elapsed since the SCT.

Exclusion Criteria:

• Participants who are pregnant
• Participants with inadequate renal, liver, or pulmonary functions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stratum 1; Stratum 1 (AML in complete remission) Cyclophosphamide 60 mg/kg IV Day -7 Fludarabine 25 mg/m2/day IV Days -6 through -2 Donor pheresis Day -1 Start IL-2 on Day -1, then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0	Drug: Cyclophosphamide, Fludarabine, Clofarabine, Etoposide, Interleukin-2; See Detailed Description section for additional details of treatment interventions.; Procedure: Natural Killer Cell Infusion; See Detailed Description section for additional details of treatment interventions.; Device: CliniMACS System; See Detailed Description section for additional details of treatment interventions.
Experimental: Stratum 2; Stratum 2 (AML that is refractory or relapsed or AML with increasing minimal residual disease) Clofarabine 40 mg/m2 IV, days -6 through -2 Etoposide 100 mg/m2 IV, days -6 through -2 Cyclophosphamide 400 mg/m2 IV, days -6 through 02 Donor pheresis Day -1 Start IL-2 Day -1, and then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0.	Drug: Cyclophosphamide, Fludarabine, Clofarabine, Etoposide, Interleukin-2; See Detailed Description section for additional details of treatment interventions.; Procedure: Natural Killer Cell Infusion; See Detailed Description section for additional details of treatment interventions.; Device: CliniMACS System; See Detailed Description section for additional details of treatment interventions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant	Document the number of patients experiencing grade 3 or 4 toxicities during conditioning and up to 100 days post-transplant. Toxicities were identified using Common Toxicity Criteria V 3.0 criteria.	Beginning at on therapy through 100 days post-transplant
Proportion of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant	Document the proportion of patients experiencing grade 3 or 4 toxicities during conditioning and up to 100 days post-transplant. Toxicities were identified using Common Toxicity Criteria V 3.0 criteria.	Beginning at on therapy through 100 days post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Engraftment of Natural Killer (NK) Cells	NK cell engraftment defined as NK cell chimerism in recipients.	Measured at days 2, 7, 14, 21 and 28 after NK cell transplantation, and up to 189 days post transplant as clinically indicated
Percent of Peak NK Cell Chimerism	The maximum percent of donor NK cell in recipients during a four-week period after NK cell infusion.	Days 2, 7, 14, 21 and 28 after NK cell transplantation
Percent of Detectable Donor NK Cells at Day 28	The percent of detectable donor NK cells in recipients at 28 days after NK cell infusion. Three of 10 participants had detectable donor cells at week 4. The results report the percent of detectable cells in the 3 participants.	At 28 days
Day That Maximum NK Cell Engraftment Was Reached	The time elapsed after transplantation in days until peak KIR-mismatched donor NK cell expansion was reached in recipients	Day 0 through Day 28 post NK cell transplantation
Number of KIR-mismatched NK Cells	Number of KIR-mismatched donor NK cells in recipients' blood at day 2 and day 14 post NK cell infusion.	Day 2 and day 14 post NK cell transplantation
Number of Participants With Evidence of NK Cells Lysing a Target Cell Line (K562)	NK cells in recipient achieving ability to lyse target cell line (K562) within normal range established by donor NK cells.	Days 2, 7, 14, 21, and 28 after NK cell transplantation
Relapse-free Survival	For Arm 1, the efficacy of NK cell transplantation will be reported as the proportion of participants who achieve complete or partial remission. Kaplan-Meier estimates of relapse-free survival and confidence interval was determined by binomial distribution because no events were observed. The binomial interval is based on the number of patients at risk.	Up to 2 years post NK cell transplantation
Overall Survival	Overall survival is defined as the time relapse from on study date to death with those alive at last follow up date censored. The Kaplan-Meier method was used to compute survival probability estimates and confidence interval was determined by binomial distribution (for no events or all events) or by log hazard method. The binomial interval is based on the number of patients at risk. The confidence intervals for Arm 1 and Arm 2a were determined by binomial distribution. The confidence interval for Arm 2b was determined by log hazard method.	Up to 2 years post NK cell transplantation

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Investigators: Principal Investigator: Jeffrey E. Rubnitz, M.D., St. Jude Children's Research Hospital

Publications and helpful links

General Publications

• Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B, Bell T, Pui CH, Leung W. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol. 2010 Feb 20;28(6):955-9. doi: 10.1200/JCO.2009.24.4590. Epub 2010 Jan 19.

Helpful Links

• St. Jude Children's Research Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Estimate): June 19, 2014
• Last Update Submitted That Met QC Criteria: June 18, 2014
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Leukemia; Acute; Myeloid
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Etoposide; Clofarabine; Fludarabine; Interleukin-2
• Other Study ID Numbers: NKAML