Leukemia, Lymphoma
Conditions
Keywords
Haploidentical donor transplantation, NK cell
Brief summary
In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA) matched related/sibling donor (MSD) or matched unrelated donor (MUD) identified, will receive a haploidentical donor HCT with additional natural killer (NK) cells. The investigators anticipate enrollment of 75 donors and 75 recipients. PRIMARY OBJECTIVE: * To estimate the rate of successful engraftment at day +42 post-transplant in patients who receive haploidentical donor stem cell plus NK cell transplantation with TLI based conditioning regimen for high risk hematologic malignancy. 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.
Detailed description
Donors will undergo G-CSF mobilization of peripheral blood stem cells (PBSC) prior to undergoing two apheresis collections of hematopoietic progenitor cells (HPC,A) and one apheresis collection of therapeutic cell product of purified natural killer cells (TC-NK). The HPC products will be T-cell depleted (TCD) using the investigational CliniMACS device. CD34+ enrichment and CD45RA depletion will be utilized on sequential HPC grafts. Participants will undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, granulocyte colony stimulating factor (G-CSF), thiotepa, and melphalan. This is followed by infusions of donor cells that have been prepared using the CliniMACS system: HPC,A (CD34+ selected), HPC,A (CD45RA depleted), and TC-NK.
Interventions
RADIATIONTotal Lymphoid Irradiation
Participants receive total lymphoid irradiation over four doses.
DRUGFludarabine
Given IV.
DRUGCyclophosphamide
Given IV.
DRUGThiotepa
Given IV.
DRUGMelphalan
Given IV.
BIOLOGICALHPC,A Infusion
Participants received infusions of HPC,A (CD34+ selected) and HPC,A (CD45RA depleted).
BIOLOGICALTC-NK Infusion
Participants receive infusions of TC-NK.
BIOLOGICALG-CSF
Participants receive G-CSF subcutaneously or intravenously. Donors receive G-CSF subcutaneously during cell mobilization.
DRUGMesna
Mesna is generally dosed at approximately 25% of the cyclophosphamide dose. It is generally given intravenously prior to and again at 3, 6 and 9 hours following each dose of cyclophosphamide.
DEVICECliniMACS
The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
DRUGMycophenolate mofetil
Given intravenously or orally.
Sponsors
Assisi Foundation
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
- Transplant Recipients: * Age less than or equal to 21 years. * Does not have a suitable MSD or volunteer MUD available in the necessary time for stem cell donation. * Has a suitable single haplotype matched (≥ 3 of 6) and family member donor. * High risk hematologic malignancy. * If prior CNS leukemia, it must be treated and in CNS CR * Does not have any other active malignancy other than the one for which this HCT is indicated. * No prior allogeneic HCT, and no autologous HCT within the previous 12 months. * Patient must fulfill pre-transplant evaluation Inclusion Criteria - Haploidentical Donor: * At least single haplotype matched (≥ 3 of 6) family member * At least 18 years of age. * HIV negative. * Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female). * Not breast feeding. * Regarding eligibility, is identified as either: (1) Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR (2) 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 |
|---|---|---|
| Number of Transplant Recipients With Successful Engraftment | 42 days post engraftment | Neutrophil engraftment will be determined using the parameters put forth by the Center for International Blood and Marrow Registry. Assessments will be made upon review of daily complete blood count and serial chimerism studies. Successful engraftment for the purposes of this objective will be patients who do not experience graft failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | One year post-transplantation | The one-year event free survival is defined by the patient who has neither experienced relapse nor death within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year event free survival patients and the total number of patients. |
| Overall Survival | one year post-transplantation | The one-year survival is defined by the patient who has not died within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year survival patients and the total number of patients. |
| Number of Transplant Recipients With Acute and/or Chronic Graft Versus Host Disease (GVHD) | 100 days post-transplant for acute GVHD; one year post-transplant for chronic GVHD . | Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The estimate will be the number of recipients who experienced GVHD divided by the total number of patients considered in this group. |
| Number of Transplant Recipients With Malignant Relapse | One-year post-transplantation | Bone marrow studies for disease status evaluation will be performed at 1-year post-transplant. Testing will include a research evaluation for minimal residual disease. |
| Severity of Acute Graft Versus Host Disease (aGVHD) | 100 days post-transplant for acute GVHD. | Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 100 days post transplant. Acute GvHD is graded from 1-4 with 4 being the worst outcome. |
| Severity of Chronic Graft Versus Host Disease (cGVHD) | 1 year post-transplant for chronic GVHD . | Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 1 year post-transplant. Chronic GvHD is graded as mild, moderate or severe with severe being the worst outcome. |
| Number of Transplant Recipients With Transplant-related Mortality (TRM) | In the first 100 days after transplantation | Estimate the proportion of patients died within 100 days after the transplantation who has not experienced a relapse. The estimate will be the number of TRM divides the total number of patients considered in this group. |
Countries
United States
Participant flow
Recruitment details
There are in total 82 transplant recipients enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Transplant Recipients Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded. | 72 |
| Total | 72 |
Baseline characteristics
| Characteristic | Experimental: Transplant Recipients |
|---|---|
| Age, Categorical <=18 years | 63 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 9.5 years STANDARD_DEVIATION 6.23 |
| Donor relationship to patient: Father, Mother, Sibling, Other. Father | 35 Participants |
| Donor relationship to patient: Father, Mother, Sibling, Other. Mother | 31 Participants |
| Donor relationship to patient: Father, Mother, Sibling, Other. Other | 2 Participants |
| Donor relationship to patient: Father, Mother, Sibling, Other. Sibling | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 52 Participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 78 |
| other Total, other adverse events | 78 / 78 |
| serious Total, serious adverse events | 56 / 78 |
Outcome results
Primary
Number of Transplant Recipients With Successful Engraftment
Neutrophil engraftment will be determined using the parameters put forth by the Center for International Blood and Marrow Registry. Assessments will be made upon review of daily complete blood count and serial chimerism studies. Successful engraftment for the purposes of this objective will be patients who do not experience graft failure.
Time frame: 42 days post engraftment
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Transplant Recipients | Number of Transplant Recipients With Successful Engraftment | 70 Participants |
Secondary
Event-free Survival
The one-year event free survival is defined by the patient who has neither experienced relapse nor death within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year event free survival patients and the total number of patients.
Time frame: One year post-transplantation
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Transplant Recipients | Event-free Survival | 49 Participants |
Secondary
Number of Transplant Recipients With Acute and/or Chronic Graft Versus Host Disease (GVHD)
Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The estimate will be the number of recipients who experienced GVHD divided by the total number of patients considered in this group.
Time frame: 100 days post-transplant for acute GVHD; one year post-transplant for chronic GVHD .
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Transplant Recipients | Number of Transplant Recipients With Acute and/or Chronic Graft Versus Host Disease (GVHD) | 24 Participants |
| Number of Transplant Recipients With Chronic Graft Versus Host Disease (cGVHD) | Number of Transplant Recipients With Acute and/or Chronic Graft Versus Host Disease (GVHD) | 16 Participants |
Secondary
Number of Transplant Recipients With Malignant Relapse
Bone marrow studies for disease status evaluation will be performed at 1-year post-transplant. Testing will include a research evaluation for minimal residual disease.
Time frame: One-year post-transplantation
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Transplant Recipients | Number of Transplant Recipients With Malignant Relapse | 18 Participants |
Secondary
Number of Transplant Recipients With Transplant-related Mortality (TRM)
Estimate the proportion of patients died within 100 days after the transplantation who has not experienced a relapse. The estimate will be the number of TRM divides the total number of patients considered in this group.
Time frame: In the first 100 days after transplantation
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Transplant Recipients | Number of Transplant Recipients With Transplant-related Mortality (TRM) | 4 Participants |
Secondary
Overall Survival
The one-year survival is defined by the patient who has not died within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year survival patients and the total number of patients.
Time frame: one year post-transplantation
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Transplant Recipients | Overall Survival | 59 Participants |
Secondary
Severity of Acute Graft Versus Host Disease (aGVHD)
Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 100 days post transplant. Acute GvHD is graded from 1-4 with 4 being the worst outcome.
Time frame: 100 days post-transplant for acute GVHD.
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental: Transplant Recipients | Severity of Acute Graft Versus Host Disease (aGVHD) | No aGVHD within 100 days | 48 Participants |
| Experimental: Transplant Recipients | Severity of Acute Graft Versus Host Disease (aGVHD) | Grade 1 aGVHD within 100 days | 2 Participants |
| Experimental: Transplant Recipients | Severity of Acute Graft Versus Host Disease (aGVHD) | Grade 2 aGVHD within 100 days | 2 Participants |
| Experimental: Transplant Recipients | Severity of Acute Graft Versus Host Disease (aGVHD) | Grade 3 aGVHD within 100 days | 16 Participants |
| Experimental: Transplant Recipients | Severity of Acute Graft Versus Host Disease (aGVHD) | Grade 4 aGVHD within 100 days | 4 Participants |
Secondary
Severity of Chronic Graft Versus Host Disease (cGVHD)
Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 1 year post-transplant. Chronic GvHD is graded as mild, moderate or severe with severe being the worst outcome.
Time frame: 1 year post-transplant for chronic GVHD .
Population: Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental: Transplant Recipients | Severity of Chronic Graft Versus Host Disease (cGVHD) | No cGVHD within 1st year | 56 Participants |
| Experimental: Transplant Recipients | Severity of Chronic Graft Versus Host Disease (cGVHD) | Mild | 6 Participants |
| Experimental: Transplant Recipients | Severity of Chronic Graft Versus Host Disease (cGVHD) | Moderate | 5 Participants |
| Experimental: Transplant Recipients | Severity of Chronic Graft Versus Host Disease (cGVHD) | Severe | 5 Participants |