Graft-Versus-Host-Disease
Conditions
Keywords
GVHD, Allogeneic, Hematopoietic Cell Transplant
Brief summary
IL-2 add-back post allogeneic hematopoietic stem cell transplant (HSCT), combined with Sirolimus (SIR), Tacrolimus (TAC) will optimize Treg reconstitution and prevent graft versus host disease (GVHD).
Detailed description
1\) Determine if a GVHD prophylaxis regimen of IL-2/SIR/TAC enhances in vivo Treg differentiation and growth; 2) Study the safety and effects of IL-2/SIR/TAC on the incidence of acute and chronic GVHD; 3) Evaluate the influence of dual IL-2 supplementation and mammalian target of rapamycin (mTOR) inhibition on T cell-specific signaling pathways and the polarization of emerging T helper cells.
Interventions
DRUGIL-2
A subcutaneous injection will be administered 3 times a week (separated by at least 1 day between injections), from day 0 to +90 (+/- 7 days).
DRUGTacrolimus
Will be administered at 0.01 mg/kg/day (based on ideal body weight) continuous IV infusion or equivalent oral dosing starting on day -3
DRUGSirolimus
Orally on day -1. The dose for loading is 12 mg by mouth (PO)
Sponsors
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have an available 8/8 human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 matched-related or unrelated donor allogeneic hematopoietic peripheral blood stem cell graft. * Acute myeloid leukemia, myelodysplasia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myeloproliferative neoplasms requiring a matched allogeneic HSCT. * Acute Leukemia (AML or ALL) must be in complete remission defined as: \<5% marrow blasts with no morphologic evidence of leukemia, no peripheral blasts, marrow \>20% cellular, and peripheral absolute neutrophil count \>1000/µL (platelet recovery is not required). * Myelodysplasia (MDS) and chronic myeloid leukemia (CML): Must have \<5% marrow blasts. * Myeloproliferative neoplasms (MPN): Must have \<5% peripheral / marrow blasts. * Adequate vital organ function: 1. Left ventricular ejection fraction (LVEF) ≥ 45% by multi gated acquisition (MUGA) scan or ECHO 2. Forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing lung capacity oxygenation (DLCO) ≥ 50% of predicted values on pulmonary function tests 3. Transaminases (AST, ALT) \< 2 times upper limit of normal values 4. Creatinine clearance ≥ 50 cc/min. * Performance status: Karnofsky Performance Status Score ≥ 80% * Donor eligibility: Eligible donors will include healthy sibling, relative or unrelated donors that are matched with the patient at HLA-A, B, C, and DRB1 by high resolution typing.
Exclusion criteria
* Active infection not controlled with appropriate antimicrobial therapy * History of HIV, hepatitis B, or hepatitis C infection * Anti-thymocyte globulin, alemtuzumab, bortezomib, or cyclophosphamide administered within 14 days before or planned to receive with HCT conditioning or as part of GVHD prophylaxis in the 14 days after HCT. * Hypersensitivity to recombinant human IL-2 * Chronic lymphocytic leukemia, Hodgkin lymphoma, and non-hodgkin lymphoma are excluded as these malignancies may express the IL-2 receptor and pose a potential growth signal to any present disease. * Sorror's co-morbidity factors with total score \>4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Regulatory T Cells (Tregs)/Total CD4+ Cells at Day 30 Post-HCT | 30 days post HCT | Percentage of Treg among blood CD4+ T cells at day 30 after hematopoietic cell transplantation (HCT), to compare to SIR/TAC alone data from a previous trial (median of 16%). The study was designed to capture an increase in regulatory T cells from a median of 16.0% at day +30. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival at Day +365 | 365 days post HCT | Overall survival will be defined as the time from transplant date to death from any cause. |
| Cumulative Incidence of Relapse | 1 year post HCT | Incidence of primary disease relapse per standard definitions. |
| Cumulative Incidence of Grade II-IV Acute GVHD by Day +100 | 100 days post HCT | Acute GVHD will be graded per the 1995 consensus guidelines. |
| Cumulative Incidence of Chronic GVHD by Day +365 | 365 days post HCT | Cumulative incidence of chronic GVHD by day +365 per NIH Consensus criteria. |
| Incidence of Non-relapse Death | 365 days post HCT | Incidence of Non-relapse death/Transplant-related mortality. Non-relapse death is defined as death in continuous remission from primary disease requiring transplantation. |
| STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30 | 30 days post HCT | Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +30. |
| STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90 | 90 days post HCT | Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +90. |
| Incidence of Unexpected or Serious Adverse Events (AEs) | Up to days 130 post HCT | Grade 3-5 unexpected or serious adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) v.4.03) were captured up to day +130 or 30 days after the last dose of IL-2. Events listed, with causality in relation to study treatment noted. |
| Proportion of Treg Among Blood CD4+ T Cells at Day +90 After HCT | 90 days post HCT | The proportion of Tregs to non-Treg CD4+ cells to be assessed at day +90. Natural Killer Cells (NKs): Median K/uL NK cells. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Function of Blood Treg After Allogeneic HSCT | 30 days post HCT | Percent of Treg suppression at day +30. Investigators had also planned to test Treg function at day +90, if sufficient Tregs had been available for analysis. |
| Rate of Natural Killer Cell (NK) Reconstitution | 365 days post HCT | Investigators planned to monitor natural killer cell (NK) reconstitution. Standard immune deficiency flow cytometry panels (IDP) was to be drawn on days +90, +180, and +365 to evaluate NK reconstitution. Results of standard lab tests to be compared to compiled data at a later date |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Moffitt Cancer Center, April 2014 through December 2015.
Participants by arm
| Arm | Count |
|---|---|
| GVHD Regimen Graft versus host disease (GVHD) prophylaxis regimen IL-2 with Sirolimus and Tacrolimus after allogeneic hematopoietic cell transplant (HCT). | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | GVHD Regimen |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 49 years |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 20 |
| serious Total, serious adverse events | 11 / 20 |
Outcome results
Primary
Regulatory T Cells (Tregs)/Total CD4+ Cells at Day 30 Post-HCT
Percentage of Treg among blood CD4+ T cells at day 30 after hematopoietic cell transplantation (HCT), to compare to SIR/TAC alone data from a previous trial (median of 16%). The study was designed to capture an increase in regulatory T cells from a median of 16.0% at day +30.
Time frame: 30 days post HCT
Population: All participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GVHD Regimen | Regulatory T Cells (Tregs)/Total CD4+ Cells at Day 30 Post-HCT | 23.8 percentage of CD4+Tregs |
Secondary
Cumulative Incidence of Chronic GVHD by Day +365
Cumulative incidence of chronic GVHD by day +365 per NIH Consensus criteria.
Time frame: 365 days post HCT
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GVHD Regimen | Cumulative Incidence of Chronic GVHD by Day +365 | 61.5 percentage of participants |
Secondary
Cumulative Incidence of Grade II-IV Acute GVHD by Day +100
Acute GVHD will be graded per the 1995 consensus guidelines.
Time frame: 100 days post HCT
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GVHD Regimen | Cumulative Incidence of Grade II-IV Acute GVHD by Day +100 | 40 percentage of participants |
Secondary
Cumulative Incidence of Relapse
Incidence of primary disease relapse per standard definitions.
Time frame: 1 year post HCT
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GVHD Regimen | Cumulative Incidence of Relapse | 35.2 percentage of participants |
Secondary
Incidence of Non-relapse Death
Incidence of Non-relapse death/Transplant-related mortality. Non-relapse death is defined as death in continuous remission from primary disease requiring transplantation.
Time frame: 365 days post HCT
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GVHD Regimen | Incidence of Non-relapse Death | 5.0 percentage of participants |
Secondary
Incidence of Unexpected or Serious Adverse Events (AEs)
Grade 3-5 unexpected or serious adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) v.4.03) were captured up to day +130 or 30 days after the last dose of IL-2. Events listed, with causality in relation to study treatment noted.
Time frame: Up to days 130 post HCT
Population: All participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GVHD Regimen | Incidence of Unexpected or Serious Adverse Events (AEs) | Kidney stone, unrelated | 1 adverse events |
| GVHD Regimen | Incidence of Unexpected or Serious Adverse Events (AEs) | VOD, possibly related | 2 adverse events |
| GVHD Regimen | Incidence of Unexpected or Serious Adverse Events (AEs) | Portal vein thrombosis, possibly related | 1 adverse events |
| GVHD Regimen | Incidence of Unexpected or Serious Adverse Events (AEs) | Sepsis, unlikely to be related | 1 adverse events |
| GVHD Regimen | Incidence of Unexpected or Serious Adverse Events (AEs) | GI bleed, unrelated | 1 adverse events |
| GVHD Regimen | Incidence of Unexpected or Serious Adverse Events (AEs) | Acute kidney injury, unrelated | 3 adverse events |
| GVHD Regimen | Incidence of Unexpected or Serious Adverse Events (AEs) | Intracranial hemorrhage, unrelated | 1 adverse events |
Secondary
Overall Survival at Day +365
Overall survival will be defined as the time from transplant date to death from any cause.
Time frame: 365 days post HCT
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GVHD Regimen | Overall Survival at Day +365 | 77.1 percentage of participants |
Secondary
Proportion of Treg Among Blood CD4+ T Cells at Day +90 After HCT
The proportion of Tregs to non-Treg CD4+ cells to be assessed at day +90. Natural Killer Cells (NKs): Median K/uL NK cells.
Time frame: 90 days post HCT
Population: All participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GVHD Regimen | Proportion of Treg Among Blood CD4+ T Cells at Day +90 After HCT | 0.212 K/uL NK cells |
Secondary
STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30
Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +30.
Time frame: 30 days post HCT
Population: All participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GVHD Regimen | STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30 | pSTAT3 | 34.1 percentage in total CD4s |
| GVHD Regimen | STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30 | pSTAT5 | 97.1 percentage in total CD4s |
| GVHD Regimen | STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30 | pS6 | 19.3 percentage in total CD4s |
Secondary
STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90
Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +90.
Time frame: 90 days post HCT
Population: All participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GVHD Regimen | STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90 | pSTAT3 | 20.2 percentage in total CD4s |
| GVHD Regimen | STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90 | pSTAT5 | 78.6 percentage in total CD4s |
| GVHD Regimen | STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90 | pS6 | 16.3 percentage in total CD4s |
Other Pre-specified
Function of Blood Treg After Allogeneic HSCT
Percent of Treg suppression at day +30. Investigators had also planned to test Treg function at day +90, if sufficient Tregs had been available for analysis.
Time frame: 30 days post HCT
Population: All evaluable participants at day +30.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| GVHD Regimen | Function of Blood Treg After Allogeneic HSCT | 61.0 percentage of suppression | Standard Deviation 11.15 |
Other Pre-specified
Rate of Natural Killer Cell (NK) Reconstitution
Investigators planned to monitor natural killer cell (NK) reconstitution. Standard immune deficiency flow cytometry panels (IDP) was to be drawn on days +90, +180, and +365 to evaluate NK reconstitution. Results of standard lab tests to be compared to compiled data at a later date
Time frame: 365 days post HCT
Population: Lab test results to be compared to compiled data at a later date.