Acute Myeloid Leukemia
Conditions
Keywords
Leukemia, Myeloid, Acute
Brief summary
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.
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.
Interventions
DRUGCyclophosphamide, Fludarabine, Clofarabine, Etoposide, Interleukin-2
See Detailed Description section for additional details of treatment interventions.
PROCEDURENatural Killer Cell Infusion
See Detailed Description section for additional details of treatment interventions.
DEVICECliniMACS System
See Detailed Description section for additional details of treatment interventions.
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | Beginning at on therapy through 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. |
| Proportion of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | Beginning at on therapy through 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Detectable Donor NK Cells at Day 28 | At 28 days | 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. |
| Day That Maximum NK Cell Engraftment Was Reached | Day 0 through Day 28 post NK cell transplantation | The time elapsed after transplantation in days until peak KIR-mismatched donor NK cell expansion was reached in recipients |
| Number of KIR-mismatched NK Cells | Day 2 and day 14 post NK cell transplantation | Number of KIR-mismatched donor NK cells in recipients' blood at day 2 and day 14 post NK cell infusion. |
| Duration of Engraftment of Natural Killer (NK) Cells | Measured at days 2, 7, 14, 21 and 28 after NK cell transplantation, and up to 189 days post transplant as clinically indicated | NK cell engraftment defined as NK cell chimerism in recipients. |
| Relapse-free Survival | Up to 2 years post NK cell transplantation | 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. |
| Overall Survival | Up to 2 years post NK cell transplantation | 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. |
| Number of Participants With Evidence of NK Cells Lysing a Target Cell Line (K562) | Days 2, 7, 14, 21, and 28 after NK cell transplantation | NK cells in recipient achieving ability to lyse target cell line (K562) within normal range established by donor NK cells. |
| Percent of Peak NK Cell Chimerism | Days 2, 7, 14, 21 and 28 after NK cell transplantation | The maximum percent of donor NK cell in recipients during a four-week period after NK cell infusion. |
Countries
United States
Participant flow
Recruitment details
49 participants were recruited between October 2005 and October 2011.
Pre-assignment details
49 participants were enrolled on the study. This report is based on results for 25 patients. 24 were donors and were excluded. All analyses are based on the intent-to-treat principle and therefore include all recipients with data available for the reported endpoint.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine AML in complete remission (stratum 1). AML in complete remission is defined as trilineage hematopoietic recovery with less than 5% blasts in the marrow. Arm 1 participants received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. | 10 |
| Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled prior to Amendment 2.0 received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. | 3 |
| Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled after protocol Amendment 2.0 received a novel conditioning regimen of clofarabine, etoposide and cyclophosphamide prior to NK cell transplantation. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | unacceptable toxicity | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine | Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | Total |
|---|---|---|---|---|
| Age, Continuous | 7.26 years STANDARD_DEVIATION 7.74 | 6.05 years STANDARD_DEVIATION 6.46 | 10.11 years STANDARD_DEVIATION 5.9 | 8.48 years STANDARD_DEVIATION 6.4 |
| Sex: Female, Male Female | 5 Participants | 0 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 10 | 3 / 3 | 11 / 12 |
| serious Total, serious adverse events | 1 / 10 | 0 / 3 | 2 / 12 |
Outcome results
Primary
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.
Time frame: Beginning at on therapy through 100 days post-transplant
Population: Grade 3 and 4 toxicities were assessed using Common Toxicity Criteria V.3.0 The assessment period was from the date on therapy through 100 days post-transplant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Number of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | 2 participants |
| Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine | Number of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | 3 participants |
| Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | Number of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | 11 participants |
Primary
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.
Time frame: Beginning at on therapy through 100 days post-transplant
Population: Grade 3 and 4 toxicities were assessed using Common Toxicity Criteria V.3.0 The assessment period was from the date on therapy through 100 days post-transplant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Proportion of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | 0.20 proportion of patients |
| Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine | Proportion of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | 1.00 proportion of patients |
| Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | Proportion of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | 0.917 proportion of patients |
Secondary
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
Time frame: Day 0 through Day 28 post NK cell transplantation
Population: Nine of the 10 participants in Arm 1 received KIR-mismatched NK donor cells.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Day That Maximum NK Cell Engraftment Was Reached | 14 number of days |
Secondary
Duration of Engraftment of Natural Killer (NK) Cells
NK cell engraftment defined as NK cell chimerism in recipients.
Time frame: Measured at days 2, 7, 14, 21 and 28 after NK cell transplantation, and up to 189 days post transplant as clinically indicated
Population: Arm 2 participants were not analyzed for this outcome as many of these patients proceeded to allogeneic stem cell transplantation following NK cell transplantation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Duration of Engraftment of Natural Killer (NK) Cells | 10 Days |
Secondary
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.
Time frame: Day 2 and day 14 post NK cell transplantation
Population: Nine of the 10 participants in Arm 1 received KIR-mismatched NK donor cells.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Number of KIR-mismatched NK Cells | Day 2 | 210 cells/µl |
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Number of KIR-mismatched NK Cells | Day 14 | 5,800 cells/µl |
Secondary
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.
Time frame: Days 2, 7, 14, 21, and 28 after NK cell transplantation
Population: All 10 participants received NK donor cells; 9 of the 10 participants received KIR-mismatched NK donor cells.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Number of Participants With Evidence of NK Cells Lysing a Target Cell Line (K562) | Lysed within normal range | 10 participants |
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Number of Participants With Evidence of NK Cells Lysing a Target Cell Line (K562) | Did not Lyse within normal range | 0 participants |
Secondary
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.
Time frame: Up to 2 years post NK cell transplantation
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Overall Survival | 100 Percent probability | 95% Confidence Interval 0 |
| Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine | Overall Survival | 0 Percent probability | 95% Confidence Interval 0 |
| Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | Overall Survival | 45.0 Percent probability | 95% Confidence Interval 13.6 |
Secondary
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.
Time frame: At 28 days
Population: Three of 10 participants continued to have detectable donor NK cells at week 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Percent of Detectable Donor NK Cells at Day 28 | 29 percent of donor NK cells |
Secondary
Percent of Peak NK Cell Chimerism
The maximum percent of donor NK cell in recipients during a four-week period after NK cell infusion.
Time frame: Days 2, 7, 14, 21 and 28 after NK cell transplantation
Population: Arm 2 participants were not analyzed for this outcome as many of these patients proceeded to allogeneic stem cell transplantation following NK cell transplantation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Percent of Peak NK Cell Chimerism | 7 percent of NK cells |
Secondary
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.
Time frame: Up to 2 years post NK cell transplantation
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Relapse-free Survival | 100 Percent probability | 95% Confidence Interval 0 |