Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Myeloid Sarcoma, Chronic Myelogenous Leukemia (CML), Juvenile Myelomonocytic Leukemia (JMML), Myelodysplastic Syndrome (MDS), Non-Hodgkin Lymphoma (NHL)
Conditions
Keywords
Hematological malignancies, Allogeneic hematopoietic cell transplant, Refractory hematologic malignancy, Relapsed hematologic malignancy
Brief summary
This pilot phase II trial studies how well a new reduced intensity conditioning regimen that includes haploidentical donor NK cells followed by the infusion of selectively T-cell depleted progenitor cell grafts work in treating younger patients with hematologic malignancies that have returned after or did not respond to treatment with a prior transplant. Giving chemotherapy and natural killer cells before a donor progenitor cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (progenitor cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's cells. When the healthy progenitor cells from a related donor are infused into the patient they make red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Removing specific T cells from the donor cells before the transplant may prevent this.
Detailed description
PRIMARY OBJECTIVE: * To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical natural killer (NK) cells. SECONDARY OBJECTIVES: * Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation. * Estimate incidence and severity of acute and chronic (GvHD). * Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation. Blood progenitor cells will be collected from adult donors to be used for transplantation. Donor cells will be processed and filtered in a laboratory at St. Jude using a machine called the CliniMACS™ device, and later infused (transplanted) into the participant through his/her veins. Participants undergo a conditioning regimen beginning Day 21 prior to progenitor cell transplantation that includes chemotherapy medications and natural killer cells in preparation for transplantation. They will then receive T-cell depleted HPC transplant followed by CD45RA-depleted HPC transplant the following day.
Interventions
DRUGCyclophosphamide
Given intravenously (IV)
DRUGFludarabine
Given IV
BIOLOGICALG-CSF
Given IV or subcutaneously (SQ)
BIOLOGICALInterleukin-2
Given SQ
DRUGMelphalan
Given IV
DRUGThiotepa
Given IV
DRUGRituximab
Given IV
BIOLOGICALNatural killer cell therapy
Given IV
BIOLOGICALT-cell depleted HPC transplant
T-cell depleted hematopoietic stem cells will be infused on day 0.
BIOLOGICALCD45RA-depleted HPC transplant
CD45RA depleted stem cells will be infused on day 1.
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Age less than or equal to 21 years. * One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic hematopoietic cell transplant (HCT): * ALL, AML, Myeloid Sarcoma, CML, Juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) * Has a suitable single haplotype matched (≥ 3 of 6) family member donor. * Does not have any other active malignancy other than the one for which this transplant is indicated. * If prior central nervous system (CNS) leukemia, it must be treated and in CNS complete remission (CR) * Does not have current uncontrolled bacterial, fungal, or viral infection. * Patient must fulfill pre-transplant evaluation: * Left ventricular ejection fraction \> 40%, or shortening fraction ≥ 25%. * Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2. * Forced vital capacity (FVC) ≥ 40% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing. * Karnofsky or Lansky (age-dependent) performance score ≥ 50 (See Appendix A). * Bilirubin ≤ 3 times the upper limit of normal for age. * Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal for age. * Not pregnant. If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment. * Not breast feeding * DONOR: At least single haplotype matched (≥ 3 of 6) family member * DONOR: At least 18 years of age. * DONOR: HIV negative. * DONOR: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female). * DONOR: Not breast feeding. * DONOR: Regarding donation eligibility, is identified as either: * Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR * Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Engrafted by Day 42 Post-transplant | Day 42 post transplantation | To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical NK cells. Engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm\^3 with evidence of donor cell engraftment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | one year post transplantation | The Kaplan-Meier estimate of event-free survival (EFS) along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given. |
| Overall Survival (OS) | one year post transplantation | The Kaplan-Meier estimate of OS along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of transplant and all participants surviving at the time of analysis without events will be censored. The number of participants surviving to one-year post-transplantation is given. |
| Incidence of Malignant Relapse | one year post transplantation | The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The number of participants with incidence of malignant relapse is given. Relapse was evaluated using standard WHO criteria for each disease. |
| Incidence and Severity of Chronic GvHD | one year post transplantation | The cumulative incidence of chronic GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of chronic GvHD will be described. Chronic GvHD was evaluated using NIH Consensus Global Severity Scoring. The number of participants with incidence by severity is given. |
| Rate of Transplant-related Mortality (TRM) | 100 days post transplantation | The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events. |
| Incidence and Severity of Acute GvHD | 100 days post transplantation | The cumulative incidence of acute GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GvHD. The number of participants with incidence by grade is given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe. |
Countries
United States
Participant flow
Recruitment details
Twelve participants meeting eligibility criteria were enrolled at St. Jude Children's Research Hospital between November 2014 and February 2015.
Pre-assignment details
Six enrolled participants were blood donors and did not undergo transplantation.
Participants by arm
| Arm | Count |
|---|---|
| Participants Participants undergo a conditioning regimen with cyclophosphamide, fludarabine, aldesleukin (interleukin-2), natural killer cell therapy, anti-thymocyte globulin, rituximab, thiotepa, and melphalan prior to transplantation of T-cell depleted HPC transplant on day 0 and CD45RA-depleted HPC transplant on day 1. Beginning Day 6 post-transplant, patients receive G-CSF daily until ANC recovers to normal level.
Cyclophosphamide: Given intravenously (IV)
Fludarabine: Given IV
G-CSF: Given IV or subcutaneously (SQ)
Interleukin-2: Given SQ
Melphalan: Given IV
Thiotepa: Given IV
Rituximab: Given IV
Natural killer cell therapy: Given IV
T-cell depleted HPC transplant: T-cell depleted hematopoietic stem cells will be infused on day 0.
CD45RA-depleted HPC transplant: CD45RA depleted stem cells will be infused on day 1. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 4 |
| Overall Study | Donors | 6 |
Baseline characteristics
| Characteristic | Participants |
|---|---|
| Age, Continuous | 12.6 years STANDARD_DEVIATION 5.5 |
| Age, Customized Age, Median | 12.2 years |
| Primary Diagnosis AML, multilineage dysplasia with prior MDS | 1 participants |
| Primary Diagnosis AML, not otherwise specified | 2 participants |
| Primary Diagnosis AML with 11q23/MLL abnormalities | 2 participants |
| Primary Diagnosis AML, without maturation | 1 participants |
| Race/Ethnicity, Customized Non Spanish speaking, Non Hispanic | 5 participants |
| Race/Ethnicity, Customized Not otherwise specified Spanish, Hispanic, Latino | 1 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 5 / 6 |
Outcome results
Primary
Percentage of Participants Engrafted by Day 42 Post-transplant
To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical NK cells. Engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm\^3 with evidence of donor cell engraftment.
Time frame: Day 42 post transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants | Percentage of Participants Engrafted by Day 42 Post-transplant | 100 percentage of participants |
Secondary
Event-free Survival (EFS)
The Kaplan-Meier estimate of event-free survival (EFS) along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given.
Time frame: one year post transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants | Event-free Survival (EFS) | 2 participants |
Secondary
Incidence and Severity of Acute GvHD
The cumulative incidence of acute GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GvHD. The number of participants with incidence by grade is given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.
Time frame: 100 days post transplantation
Population: Two of six participants did not experience any acute GvHD.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants | Incidence and Severity of Acute GvHD | Grade I | 0 participants |
| Participants | Incidence and Severity of Acute GvHD | Grade II | 0 participants |
| Participants | Incidence and Severity of Acute GvHD | Grade III | 3 participants |
| Participants | Incidence and Severity of Acute GvHD | Grade IV | 1 participants |
Secondary
Incidence and Severity of Chronic GvHD
The cumulative incidence of chronic GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of chronic GvHD will be described. Chronic GvHD was evaluated using NIH Consensus Global Severity Scoring. The number of participants with incidence by severity is given.
Time frame: one year post transplantation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants | Incidence and Severity of Chronic GvHD | Mild | 0 participants |
| Participants | Incidence and Severity of Chronic GvHD | Moderate | 0 participants |
| Participants | Incidence and Severity of Chronic GvHD | Severe | 0 participants |
Secondary
Incidence of Malignant Relapse
The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The number of participants with incidence of malignant relapse is given. Relapse was evaluated using standard WHO criteria for each disease.
Time frame: one year post transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants | Incidence of Malignant Relapse | 2 participants |
Secondary
Overall Survival (OS)
The Kaplan-Meier estimate of OS along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of transplant and all participants surviving at the time of analysis without events will be censored. The number of participants surviving to one-year post-transplantation is given.
Time frame: one year post transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants | Overall Survival (OS) | 2 participants |
Secondary
Rate of Transplant-related Mortality (TRM)
The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events.
Time frame: 100 days post transplantation
Population: All six participants who received the protocol-defined treatment were evaluable for this analysis. One participant died of a non-transplant related cause (leukemia) prior to day 100. Although this participant did not complete the study to Day 100 post-transplantation, they were still evaluable for TRM.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants | Rate of Transplant-related Mortality (TRM) | 0 participants |
Post Hoc
Mean of Days to Absolute Neutrophil Count (ANC) Engraftment
ANC engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm\^3 with evidence of donor cell engraftment.
Time frame: Day 42 post transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants | Mean of Days to Absolute Neutrophil Count (ANC) Engraftment | 10.3 days | Standard Deviation 1.03 |
Post Hoc
Median Days to Absolute Neutrophil Count (ANC) Engraftment
ANC engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm\^3 with evidence of donor cell engraftment.
Time frame: Day 42 post transplantation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants | Median Days to Absolute Neutrophil Count (ANC) Engraftment | 10 days |