Neural Tube Defects, Anemia, Leukemia, Myeloid, Bone Marrow Transplant Failure, Myelodysplastic Syndromes (MDS), Myeloproliferative Disorders
Conditions
Brief summary
Allogeneic stem cell transplantation (transplant of blood cells from another individual) is a treatment option for patients with myelodysplasia or myeloproliferative Disorders. During the course of this study, it will be evaluated whether a particular type of blood cell, called a cytokine-induced killer (CIK) cell, may add benefit to allogeneic stem cell transplantation. CIK cells are present in small quantities in the bloodstream but their numbers can be expanded after a brief period of nurturing in a laboratory.
Detailed description
Primary Objectives: To determine the rate of conversion to FDC following infusion of allogeneic CIK cells among patients with MDS, therapy-related myeloid neoplasms, or MPD who receive non myeloablative preparative regimen of TLI / ATG followed by allogeneic HCT and consolidation with allogeneic CIK cells. Secondary Objectives: * To determine the 2 year overall survival (OS) and event free survival (EFS) * To determine the incidence of acute GVHD following infusion of allogeneic CIK cells * To assess the pre-transplant expression of NKG2D ligands in patients' bone marrow aspirates.
Interventions
DRUGCIK cells
Standard of care
DRUGCyclosporine
5 mg/kg, po
DRUGMycophenolate Mofetil
15 mg/kg, oral
DRUGThymoglobulin
7.5 mg/kg, IV
RADIATIONTotal Lymphoid Irradiation (TLI)
Sponsors
Everett Meyer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
, RECIPIENT WITH MYELODYSPLASTIC SYNDROME (MDS) * Diagnosis of MDS classifiable by the World Health Organization (WHO) on the basis of: * Refractory anemia * Refractory anemia with excess blasts-1 * Refractory anemia with excess blasts-2 * Refractory cytopenia with multi-lineage dysplasia * Refractory cytopenia with multi-lineage dysplasia and ringed sideroblasts * Chronic myelomonocytic leukemia (CMML) * MDS transformed to acute leukemia * MDS-unclassified * Participants with advanced MDS must have \< 10% marrow blasts prior to receiving conditioning with TLI/ATG, documented by marrow examination within 1 month prior. * Participants with evolution to acute leukemia (AML) must be in a morphologic leukemia free-state (MLFS) with blasts \< 5% INCLUSION CRITERIA, RECIPIENT WITH MYELOPROLIFERATIVE DISORDER (MPD) * Diagnosis of MPD on the basis of: * Idiopathic myelofibrosis * Polycythemia vera * Essential thrombocythemia * Chronic myelomonocytic leukemia (CML) * CML, Philadelphia chromosome-negative * Chronic neutrophilic leukemia * Chronic eosinophilic leukemia * Hypereosinophilic cyndrome * Systemic mastocytosis * \< 10% marrow blasts prior to receiving conditioning with TLI/ATG, documented by marrow examination within 1 month prior. * Participants with evolution to acute leukemia (AML) must be in a morphologic leukemia free-state (MLFS) with blasts \< 5%. Presence of residual dysplastic features following cytoreductive therapy is acceptable. INCLUSION CRITERIA, RECIPIENT WITH THERAPY-RELATED MYELOID NEOPLASM (t MDS) * \< 10% marrow blasts prior to receiving conditioning with TLI/ATG, documented by marrow examination within 1 month prior. * Morphologic leukemia free-state with blasts \< 5 %. * Age \> 50 years, or \< 50 years of age but at high-risk for regimen-related toxicity associated with conventional myeloablative transplants due to pre-existing medical conditions or prior therapy * Availability of a fully HLA-matched or single antigen/allele mismatched sibling or unrelated donor * Prior malignancy diagnosed \> 5 years ago without evidence of disease, or \< 5 years ago with life expectancy of \> 5 years are eligible (prior malignancy is not a requirement) INCLUSION CRITERIA, DONOR * Donors must be HLA-matched or one allele mismatched. * Donor age \< 75 (EXCEPTION by Principal Investigator discretion) * Must consent to PBSC mobilization with G-CSF; apheresis; and collection and donation of plasma * Donor must consent to placement of a central venous catheter in the event that peripheral venous access is limited.
Exclusion criteria
, RECIPIENT Any of the following: * Uncontrolled CNS involvement with disease * Pregnant * Cardiac function: ejection fraction (EF) \< 35% or uncontrolled cardiac failure * Diffusing capacity of the lungs for carbon monoxide (DLCO) \< 40% predicted * Bilirubin \> 3 mg/dL * Aspartate aminotransferase (AST) \> 3x the upper limit of normal (ULN) * Alanine aminotransferase (ALT) \> 3x ULN * Estimated creatinine clearance \< 50 mL/min * Karnofsky performance score (KPS) \< 70% * Documented fungal disease that is progressive despite treatment * HIV-positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Full Donor Chimerism (FDC) | 90 days | Proportion of patients achieving full donor T-cell chimerism (FDC) by on or before Day 90 post non-myeloablative allogeneic transplant with allogeneic cytokine-induced killer (CIK) cells will be determined. FDC is defined as the attainment of \>95% donor type CD3+ cells. The outcome will be reported as number of participants who achieved full donor chimerism, a number without dispersion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 2 years | Overall survival (OS) is an expression of the number of participants that remain alive 2 years after cytokine-induced killer (CIK) infusion. The outcome will be reported as the number of participants alive 2 years after CIK infusion, a number without dispersion. |
| Event-free Survival (EFS) Rate | 2 years | Event-free Survival (EFS) rate will be assessed on all enrolled participants and is defined as the duration of time after cytokine-induced killer (CIK) cell infusion that the participants remain alive with experiencing relapse, Grade 3 to 4 acute graft vs host disease (aGVHD), or death. The outcome will be reported as the number of participants, stratified by receipt of CIK cells, that did not experience a specified event, a number without dispersion. |
| Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | 1 year | Acute graft vs host disease (aGvHD) Grade 2 to 4 was staged & graded using modified Keystone criteria, as below. The outcome is reported as the number of participants that experience Grade 2 to 4 aGvHD within 100 days and 1 year. * Stage 1: Skin: rash \< 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea 500 to 1000 mL/day or persistent nausea with positive biopsy for GvHD * Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea 1000 to 1500 mL/day. * Stage 3: Skin: rash \> 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea \> 1500 mL/day. * Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin \> 15 mg/dL. Gut: severe abdominal pain with or without ileus Grade of aGvHD was determined as follows. * Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage * Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut * Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut * Grade 4: Stage 4 Skin + or Stage 2 |
| Pre-transplant Expression of Natural-killer Group 2, Member D (NKG2D) Ligands | Pre-transplant | Pre-transplant expression of natural-killer group 2, member D (NKG2D) ligands MIC A, MIC B, and the UL16 binding proteins (ULBPs) will be assessed in participants' bone marrow aspirates. The outcomes is expressed as the number of participants whose expression level for each ligand was elevated compared to background, represented by the known levels for individual without cancer. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Allogeneic Cytokine Induced Killer Cells (CIK) Target dose of ≥ 5 x 106 CD34+ cells/kg of recipient body weight plus an additional 2 x109 mononuclear cells.
CIK cells: Standard of care
Cyclosporine: 5 mg/kg, po
Mycophenolate Mofetil: 15 mg/kg, oral
Thymoglobulin: 7.5 mg/kg, IV | 44 |
| Total | 44 |
Baseline characteristics
| Characteristic | Allogeneic Cytokine Induced Killer Cells (CIK) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 22 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 6.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 39 Participants |
| Region of Enrollment United States | 44 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 24 / 44 |
| other Total, other adverse events | 44 / 44 |
| serious Total, serious adverse events | 27 / 44 |
Outcome results
Primary
Full Donor Chimerism (FDC)
Proportion of patients achieving full donor T-cell chimerism (FDC) by on or before Day 90 post non-myeloablative allogeneic transplant with allogeneic cytokine-induced killer (CIK) cells will be determined. FDC is defined as the attainment of \>95% donor type CD3+ cells. The outcome will be reported as number of participants who achieved full donor chimerism, a number without dispersion.
Time frame: 90 days
Population: Cytokine-induced killer (CIK) cells were infused in a subset of participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allogeneic Cytokine Induced Killer Cells (CIK) | Full Donor Chimerism (FDC) | 6 Participants |
Secondary
Event-free Survival (EFS) Rate
Event-free Survival (EFS) rate will be assessed on all enrolled participants and is defined as the duration of time after cytokine-induced killer (CIK) cell infusion that the participants remain alive with experiencing relapse, Grade 3 to 4 acute graft vs host disease (aGVHD), or death. The outcome will be reported as the number of participants, stratified by receipt of CIK cells, that did not experience a specified event, a number without dispersion.
Time frame: 2 years
Population: All participants are reported. Cytokine-induced killer (CIK) cells were infused in a subset of participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Allogeneic Cytokine Induced Killer Cells (CIK) | Event-free Survival (EFS) Rate | Non-CIK-infused participants | 4 Participants |
| Allogeneic Cytokine Induced Killer Cells (CIK) | Event-free Survival (EFS) Rate | CIK-infused participants | 14 Participants |
Secondary
Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year
Acute graft vs host disease (aGvHD) Grade 2 to 4 was staged & graded using modified Keystone criteria, as below. The outcome is reported as the number of participants that experience Grade 2 to 4 aGvHD within 100 days and 1 year. * Stage 1: Skin: rash \< 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea 500 to 1000 mL/day or persistent nausea with positive biopsy for GvHD * Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea 1000 to 1500 mL/day. * Stage 3: Skin: rash \> 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea \> 1500 mL/day. * Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin \> 15 mg/dL. Gut: severe abdominal pain with or without ileus Grade of aGvHD was determined as follows. * Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage * Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut * Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut * Grade 4: Stage 4 Skin + or Stage 2
Time frame: 1 year
Population: Cytokine-induced killer (CIK) cells were infused in a subset of participants. Results are reported for both subsets and collectively, at 2 time points.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Allogeneic Cytokine Induced Killer Cells (CIK) | Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | All participants within 100 days | 9 Participants |
| Allogeneic Cytokine Induced Killer Cells (CIK) | Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | All participants within 1 year | 11 Participants |
| Allogeneic Cytokine Induced Killer Cells (CIK) | Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | CIK-infused participants within 100 days | 3 Participants |
| Allogeneic Cytokine Induced Killer Cells (CIK) | Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | CIK-infused participants within 1 year | 5 Participants |
| Allogeneic Cytokine Induced Killer Cells (CIK) | Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | Non-CIK-infused participants within 100 days | 6 Participants |
| Allogeneic Cytokine Induced Killer Cells (CIK) | Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | Non-CIK-infused participants within 1 year | 6 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS) is an expression of the number of participants that remain alive 2 years after cytokine-induced killer (CIK) infusion. The outcome will be reported as the number of participants alive 2 years after CIK infusion, a number without dispersion.
Time frame: 2 years
Population: Cytokine-induced killer (CIK) cells were infused in a subset of participants. Participants that did not receive CIK cells were not included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allogeneic Cytokine Induced Killer Cells (CIK) | Overall Survival (OS) | 16 Participants |
Secondary
Pre-transplant Expression of Natural-killer Group 2, Member D (NKG2D) Ligands
Pre-transplant expression of natural-killer group 2, member D (NKG2D) ligands MIC A, MIC B, and the UL16 binding proteins (ULBPs) will be assessed in participants' bone marrow aspirates. The outcomes is expressed as the number of participants whose expression level for each ligand was elevated compared to background, represented by the known levels for individual without cancer.
Time frame: Pre-transplant
Population: Insufficient tumor sample materials from the pre-transplant diagnostic bone marrow aspirate was available for the research analysis. No analysis was conducted.