Acute Graft Versus Host Disease
Conditions
Keywords
Acute Graft Versus Host Disease (aGVHD), GVHD, graft-versus-host disease, tacrolimus, sirolimus, methotrexate, combination therapy, GVHD prophylaxis
Brief summary
The purpose of this research is to compare the effectiveness of Tacrolimus and Rapamycin to Tacrolimus and Methotrexate in the prevention of severe graft-versus-host-disease. Graft-versus-host-disease (GVHD) is a risk associated with allogeneic hematopoietic cell transplants (HCT). An allogeneic hematopoietic cell transplant is a transplant using bone marrow and blood cells that come from someone other than the patient (a donor).
Detailed description
All drugs used in this study have been used in the prevention of graft-versus-host-disease after allogeneic hematopoietic cell transplant. Tacrolimus and Methotrexate used in combination are currently used as standard of care in the prevention of graft-versus-host-disease after allogeneic hematopoietic cell transplant. Tacrolimus and Rapamycin is a newer combination we are testing to see if it would be better than Tacrolimus and Methotrexate.
Interventions
DRUGTacrolimus (TAC)
Tacrolimus: administered at 0.02 mg/kg/day (based on ideal body weight) continuous IV infusion or equivalent oral dosing starting on day -3.
DRUGMethotrexate (MTX)
Methotrexate: administered on day 1 at dose of 15 mg/m\^2, and a dose of 10 mg/m\^2 on days 3, 6, and 11. Dose can be adjusted for reduced creatinine clearance.
DRUGRapamycin (RAPA)
Rapamycin: initially as 9 mg oral loading dose on day -1. Thereafter, administered as an oral regimen of 4 mg daily.
Sponsors
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 16 and ≤ 70 * Signed informed consent * Adequate vital organ function * No active infection, or asymptomatic infection well controlled by antibiotic HIV negative by ELISA or RT-PCR \[if ELISA is positive and RT-PCR is negative, the ELISA is considered false positive\] * Hepatitis B and C negative by serology or RT-PCR * Performance status: Karnofsky Performance Status Score ≥ 60%.
Exclusion criteria
* Those with any Sorror's co-morbidity factors with score \> 3 * 2 or more Sorror's factors with composite score of ≥ 3
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Evidence of Acute Graft Versus Host Disease (aGVHD), Post Transplant | 100 Days Post Transplant | Incidence of acute graft versus host disease grades 2-3 according to the Common Toxicity Criteria (CTC) version 3. Graft-versus-host-disease (GVHD) is a risk associated with allogeneic hematopoietic cell transplants (HCT). Clinical evidence of acute GVHD was recorded per standard grading scheme. Acute GVHD classified as the following: 1. classic acute GVHD - onset within 100 days after transplant 2. persistent - acute GVHD with onset prior to day 100 and without resolution beyond day 100 3. recurrent - acute GVHD recurrent after prior episode of acute GVHD 4. late acute GVHD - syndrome consistent with acute GVHD, without features of chronic GVHD, with onset occurring beyond 100 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Increased Absolute Numbers of Regulatory T Cells (Treg) | 30 days and 90 days | Absolute numbers of Treg at designated time points according to study arm. MTX = methotrexate/tacrolimus-treated patients; SIR = sirolimus/tacrolimus-treated patients; Treg absolute number units = number of cells/microL. A two-sided Wilcoxon's rank-sum test was employed to test differences in percent Treg (% Treg/total CD4+ cells). |
| 2 Year Post Transplant Overall Survival (OS) Rate | 2 years | Defined as time from transplantation (day 0 as day of stem cell infusion per standard nomenclature) to death from any cause . |
Countries
United States
Participant flow
Recruitment details
Patients recruited between 09/10/2008 through 05/13/2011 from the Blood and Marrow Transplant Program patient population.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus / Rapamycin Tacrolimus / Rapamycin
Tacrolimus / Rapamycin: Tacrolimus - 0.02 mg/kg/day (based on ideal body weight) continuous IV infusion or equivalent oral dosing starting on day -3.
Rapamycin - initially as 9 mg oral loading dose on day -1. Thereafter, administered as an oral regimen of 4 mg daily. | 37 |
| Tacrolimus / Methotrexate Tacrolimus / Methotrexate
Tacrolimus / Methotrexate: Tacrolimus administered at 0.02 mg/kg/day (based on ideal body weight) continuous IV infusion or equivalent oral dosing starting on day -3
Methotrexate: administered on day 1 at dose of 15 mg/m\^2, and a dose of 10 mg/m\^2 on days 3, 6, and 11. Dose can be adjusted for reduced creatinine clearance. | 37 |
| Total | 74 |
Baseline characteristics
| Characteristic | Tacrolimus / Rapamycin | Tacrolimus / Methotrexate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 34 Participants | 68 Participants |
| Age, Continuous | 49 years | 48 years | 49 years |
| Region of Enrollment United States | 37 participants | 37 participants | 74 participants |
| Sex: Female, Male Female | 9 Participants | 14 Participants | 23 Participants |
| Sex: Female, Male Male | 28 Participants | 23 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 37 | 0 / 37 |
| serious Total, serious adverse events | 3 / 37 | 2 / 37 |
Outcome results
Primary
Percentage of Participants With Evidence of Acute Graft Versus Host Disease (aGVHD), Post Transplant
Incidence of acute graft versus host disease grades 2-3 according to the Common Toxicity Criteria (CTC) version 3. Graft-versus-host-disease (GVHD) is a risk associated with allogeneic hematopoietic cell transplants (HCT). Clinical evidence of acute GVHD was recorded per standard grading scheme. Acute GVHD classified as the following: 1. classic acute GVHD - onset within 100 days after transplant 2. persistent - acute GVHD with onset prior to day 100 and without resolution beyond day 100 3. recurrent - acute GVHD recurrent after prior episode of acute GVHD 4. late acute GVHD - syndrome consistent with acute GVHD, without features of chronic GVHD, with onset occurring beyond 100 days
Time frame: 100 Days Post Transplant
Population: All participants who received treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Tacrolimus / Rapamycin | Percentage of Participants With Evidence of Acute Graft Versus Host Disease (aGVHD), Post Transplant | 43 percentage of participants |
| 2 Tacrolimus / Methotrexate | Percentage of Participants With Evidence of Acute Graft Versus Host Disease (aGVHD), Post Transplant | 89 percentage of participants |
Secondary
2 Year Post Transplant Overall Survival (OS) Rate
Defined as time from transplantation (day 0 as day of stem cell infusion per standard nomenclature) to death from any cause .
Time frame: 2 years
Population: All participants who received treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Tacrolimus / Rapamycin | 2 Year Post Transplant Overall Survival (OS) Rate | 61 percentage of participants |
| 2 Tacrolimus / Methotrexate | 2 Year Post Transplant Overall Survival (OS) Rate | 69 percentage of participants |
Secondary
Incidence of Increased Absolute Numbers of Regulatory T Cells (Treg)
Absolute numbers of Treg at designated time points according to study arm. MTX = methotrexate/tacrolimus-treated patients; SIR = sirolimus/tacrolimus-treated patients; Treg absolute number units = number of cells/microL. A two-sided Wilcoxon's rank-sum test was employed to test differences in percent Treg (% Treg/total CD4+ cells).
Time frame: 30 days and 90 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 1 Tacrolimus / Rapamycin | Incidence of Increased Absolute Numbers of Regulatory T Cells (Treg) | 30 Day Measure | 16.27 Cells/MicroL |
| 1 Tacrolimus / Rapamycin | Incidence of Increased Absolute Numbers of Regulatory T Cells (Treg) | 90 Day Measure | 14.6 Cells/MicroL |
| 2 Tacrolimus / Methotrexate | Incidence of Increased Absolute Numbers of Regulatory T Cells (Treg) | 30 Day Measure | 9.87 Cells/MicroL |
| 2 Tacrolimus / Methotrexate | Incidence of Increased Absolute Numbers of Regulatory T Cells (Treg) | 90 Day Measure | 9.67 Cells/MicroL |