Acute Myeloid Leukemia, Myelodysplastic Syndromes, Myeloproliferative Disorder, Chronic Lymphocytic Leukemia, B-cell Lymphoma, T-cell Lymphoma, Non Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Myelomonocytic Leukemia
Conditions
Brief summary
The purpose of this study is to evaluate whether addition of a low dose of total body irradiation (TBI) to a standard preparation for transplant \[total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG)\] conditioning will help to augment donor chimerism without reducing tolerability of this regimen or increasing the risk of graft-vs-host disease (GVHD)
Detailed description
Primary Objective: • Determine the proportion of patients with full donor T-cell chimerism at Day 28 following hematopoietic cell transplantation. Secondary Objectives: * Determine the risk of disease progression, overall and event free survival, and non-relapse mortality, following treatment with TLI; ATG; and TBI. * Determine the incidence of acute and chronic GVHD following treatment with TLI; ATG; and TBI. Exploratory Objectives: • Determine the changes in frequency of hematopoietic stem, progenitor, and mature cell subsets and the changes in cytokine milieu and cellular architecture in the bone marrow of patients receiving TLI compared to TLI+TBI.
Interventions
RADIATIONTotal body irradiation (TBI)
Administer Total body irradiation (TBI) 80 cGy on Day 1 of standard TLI ATG conditioning
Given intravenous (IV), Dose 1.5 mg/kg x 5 days
DRUGTacrolimus
Oral, Dose 0.05 mg/kg twice daily, can be given intravenous (IV)
DRUGMycophenolate mofetil (MMF)
Given Oral, 15 mg/k every 2 hours for peripheral blood stem cells (PBSC) from matched related donors; 15 mg/kg every 8 hours for PBSC from unrelated donors (URDs) or mismatched related donors.
RADIATIONTotal lymphoid irradiation (TLI)
9 x 120 cGy over 11 days
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a human leukocyte antigen (HLA)-matched or single allele mismatched adult sibling donor or unrelated donor. * Acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); myeloproliferative disease syndrome (MPD)\]; chronic lymphocytic leukemia (CLL); B- or T-cell non Hodgkin lymphoma (NHL); Hodgkin lymphoma (HL); or chronic myelomonocytic leukemia (CMML), suitable for treatment with allogeneic transplant after TLI and ATG reduced intensity conditioning. * Considered at high-risk for regimen-related toxicity from fully-ablative transplant conditioning (therefore reduced-intensity conditioning is recommended). * Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial.
Exclusion criteria
* Uncontrolled bacterial, viral or fungal infection defined as currently taking medication and progression of clinical symptoms. * Progressive hemato lymphoid malignancy despite conventional therapy. * Chronic myelogenous leukemia (CML). * Active CNS involvement of the underlying malignancy. * HIV positive * Pregnant or lactating * Prior malignancy (EXCEPTION: diagnosed \> 5 years ago without evidence of disease, OR treated ≤ 5 years ago but have a greater than 50% chance of life expectancy of ≥ 5 years for that malignancy). * Have a psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of the primary physician would place the patient at an unacceptable risk from transplant. * Left ventricular ejection fraction (LEVF) \< 30%, or uncontrolled cardiac failure * Diffusing capacity of lung for carbon monoxide (DLCO) \< 40% predicted * Total bilirubin \> 3 mg/dL * Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic-pyruvic transaminase (SGPT) \> 4 x upper limit of normal (ULN) * Creatinine \> 2 mg/dL and an estimated creatinine clearance \< 40 mL/min * Poorly-controlled hypertension despite multiple antihypertensive medications * Karnofsky Performance Status (KPS) \< 60%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Full-dose Donor Chimerism (FDC) at Day 28 Following TLI/ATG/TBI Conditioning. | Day 28 | Subsequent to TLI/ATG/TBI conditioning, the proportion of participants with full dose donor chimerism (FDC) will be determined by Day 28. FDC is defined as achieving ≥ 95% donor type in the CD3+ lineage within 28 days of donor cell infusion, as assessed by short tandem repeat (STR) testing. The outcome will be expressed as the number of participants that achieve FDC by Day 28, a number without dispersion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Progression | 1 year | Transplant recipients will be assessed for disease progression at 1 year after hematopoietic cell transplantation (HCT). The outcome is reported as the number of transplant recipients who experienced disease progression. |
| Overall Survival (OS) | 1 year | Overall survival (OS) is defined as the number of transplant recipients remaining alive at 12 months after transplant. The outcome is expressed as the number of transplant recipients who remained alive at 12 months after treatment, a number without dispersion. |
| Event-free Survival (EFS) at 1 Year | 1 year | Event-free survival (EFS) is defined as the number of transplant recipients remaining alive at 12 months after transplant and who did not experience disease relapse defined as blasts \< 5%. The outcome is expressed as the number of transplant recipients remaining alive at 12 months after transplant without disease relapse, a number without dispersion. |
| Non-relapse Mortality (NRM) | 1 year | Non-relapse mortality (NRM) is defined as death without known disease relapse or recurrence. The outcome is expressed as the number of transplant recipients whose cause of death was not disease relapse or recurrence, a number without dispersion. |
| Graft vs Host Disease (GvHD) | 1 year | Recipients will be monitored for Grade 2 to 4 graft vs host disease (GvHD). The outcome is reported as the number of transplant recipients who experienced acute GvHD grades 2 to 4, the number of transplant recipients who experienced chronic and extensive GvHD. In addition, the number of transplant recipients with chronic and extensive GvHD that was refractory to treatment (persistent) is reported. Per protocol, the result for chronic extensive and persistent GvHD is based on the subset of participants that had chronic and extensive GvHD. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TBI+TLI TBI, single exposure on Day -1, 80 centigray (cGy) in addition to total lymphoid irradiation (TLI, 120 cGy/day for 9 days, weekends excluded) and anti-thymocyte globulin (ATG) 1.5 mg/kg (conditioning regimen)
Total body irradiation (TBI): Administer Total body irradiation (TBI) 80 cGy on Day 1 of standard TLI ATG conditioning
Anti-thymocyte globulin (ATG): Given intravenous (IV), Dose 1.5 mg/kg x 5 days
Tacrolimus: Oral, Dose 0.05 mg/kg twice daily, can be given intravenous (IV)
Mycophenolate mofetil (MMF): Given Oral, 15 mg/k every 2 hours for peripheral blood stem cells (PBSC) from matched related donors; 15 mg/kg every 8 hours for PBSC from unrelated donors (URDs) or mismatched related donors.
Total lymphoid irradiation (TLI): 9 x 120 cGy over 11 days | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | TBI+TLI |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 17 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 67.2 years STANDARD_DEVIATION 10.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 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 | 15 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 22 |
| other Total, other adverse events | 0 / 22 |
| serious Total, serious adverse events | 2 / 22 |
Outcome results
Primary
Full-dose Donor Chimerism (FDC) at Day 28 Following TLI/ATG/TBI Conditioning.
Subsequent to TLI/ATG/TBI conditioning, the proportion of participants with full dose donor chimerism (FDC) will be determined by Day 28. FDC is defined as achieving ≥ 95% donor type in the CD3+ lineage within 28 days of donor cell infusion, as assessed by short tandem repeat (STR) testing. The outcome will be expressed as the number of participants that achieve FDC by Day 28, a number without dispersion.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TBI+TLI | Full-dose Donor Chimerism (FDC) at Day 28 Following TLI/ATG/TBI Conditioning. | 13 Participants |
Secondary
Disease Progression
Transplant recipients will be assessed for disease progression at 1 year after hematopoietic cell transplantation (HCT). The outcome is reported as the number of transplant recipients who experienced disease progression.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TBI+TLI | Disease Progression | 7 Participants |
Secondary
Event-free Survival (EFS) at 1 Year
Event-free survival (EFS) is defined as the number of transplant recipients remaining alive at 12 months after transplant and who did not experience disease relapse defined as blasts \< 5%. The outcome is expressed as the number of transplant recipients remaining alive at 12 months after transplant without disease relapse, a number without dispersion.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TBI+TLI | Event-free Survival (EFS) at 1 Year | 16 Participants |
Secondary
Graft vs Host Disease (GvHD)
Recipients will be monitored for Grade 2 to 4 graft vs host disease (GvHD). The outcome is reported as the number of transplant recipients who experienced acute GvHD grades 2 to 4, the number of transplant recipients who experienced chronic and extensive GvHD. In addition, the number of transplant recipients with chronic and extensive GvHD that was refractory to treatment (persistent) is reported. Per protocol, the result for chronic extensive and persistent GvHD is based on the subset of participants that had chronic and extensive GvHD.
Time frame: 1 year
Population: Per protocol, the outcome for chronic extensive and persistent GvHD is based on the subset of participants that had chronic and extensive GvHD.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TBI+TLI | Graft vs Host Disease (GvHD) | Acute GvHD | 5 Participants |
| TBI+TLI | Graft vs Host Disease (GvHD) | Chronic extensive GvHD | 8 Participants |
| TBI+TLI | Graft vs Host Disease (GvHD) | Chronic extensive and persistent GvHD | 3 Participants |
Secondary
Non-relapse Mortality (NRM)
Non-relapse mortality (NRM) is defined as death without known disease relapse or recurrence. The outcome is expressed as the number of transplant recipients whose cause of death was not disease relapse or recurrence, a number without dispersion.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TBI+TLI | Non-relapse Mortality (NRM) | 2 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the number of transplant recipients remaining alive at 12 months after transplant. The outcome is expressed as the number of transplant recipients who remained alive at 12 months after treatment, a number without dispersion.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TBI+TLI | Overall Survival (OS) | 16 Participants |