Hodgkin Lymphoma, Non-hodgkin Lymphoma
Conditions
Keywords
allogeneic stem cell transplant, reduced intensity conditioning, graft versus host disease, GVHD, RIC transplantation
Brief summary
This trial is comparing whether using a drug called sirolimus for graft versus host disease (GVHD) prevention can decrease the chance of the participant's lymphoma relapsing after transplantation, compared to using a standard GVHD prevention regimen without sirolimus. Since mTOR inhibitors have anti-lymphoma activity, their use after transplantation may lead to a decreased risk of relapse and hence better transplantation outcome.
Detailed description
* Because no one knows which of the study options is best, participants will be randomized into one of the two possible groups for GVHD prophylaxis: 1) a sirolimus-containing regimen (tacrolimus, sirolimus and methotrexate) or 2) a sirolimus-free regimen (tacrolimus and methotrexate or cyclosporine and mycophenolate mofetil). * Participants will receive a reduced intensity conditioning regimen. This is done to prepare the body for transplantation. This will consist of a combination of drugs (either fludarabine and busulfan or fludarabine, cyclophosphamide and low-dose total body irradiation). The purpose of these drugs is to weaken the immune system and lower the chance of the body rejecting the donated stem cells. * Participants will also receive the GVHD prophylaxis regimen that they have been randomized to. These drugs will lower the chance of rejecting the donor cells and lower the chance of developing GVHD.
Interventions
DRUGSirolimus
Taken orally for at least 12 months
DRUGMethotrexate
Given intravenously on the first, third and sixth day after transplant
DRUGTacrolimus
Taken orally or given intravenously for at least 6 months
DRUGCyclosporine
Taken orally or given intravenously for at least 6 months
DRUGMMF
Taken orally for about 2 months
Sponsors
Brigham and Women's Hospital
Massachusetts General Hospital
National Cancer Institute (NCI)
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 72 Years
Healthy volunteers
No
Inclusion criteria
* Patients will be eligible if their primary indication for transplantation is among the following: Indolent B-cell non-Hodgkin lymphoma (NHL); Aggressive B-Cell NHL; T-cell NHL; or Hodgkin Lymphoma. * Patients must have one of the following combinations of disease status and disease histology at the time of enrollment: 1) Patients may be transplanted as part of first-line therapy if they have one of the following histologies: CLL with adverse cytogenetics, MCL or, T-cell NHL. 2) Patients may be transplanted as part of treatment for relapsed or refractory disease without a prior autologous transplantation of they have one of the following histologies: Indolent NHL (including CLL/SLL), MCL or T-cell NHL. 3) Patients may be transplanted as part of treatment for disease that has relapsed or progressed after autologous transplantation if they have any of the histologies listed above. Patients may also be enrolled without a prior autologous transplantation if they have a contraindication to autologous transplantation, in the opinion of the treating clinician. 4) There is no minimal or maximal time interval from the patient's last anti-lymphoma therapy and the time of transplantation. * 18-72 years of age * Matched related or matched unrelated donor * Donor willing to donate peripheral blood stem cells and meeting institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to individual transplant center criteria.
Exclusion criteria
* Patients with Burkitt lymphoma or DLBCL with a c-myc rearrangement * Karnofsky performance status of less than 70% at the time of registration * Prior allogeneic stem cell transplantation (note that prior autologous stem cell transplantation is allowed) * Uncontrolled infection * Serum creatinine 2.0mg/dl or greater * Total bilirubin 2.0mg/dl or greater (unless related to hemolysis or Gilbert's syndrome) * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times or greater than the institutional upper limit of normal * Left ventricular ejection fraction \< 30% * Cholesterol \> 500mg/dl or triglycerides \> 500 mg/dl despite appropriate treatment * Seropositivity for HIV * Pregnancy or breast-feeding (effective contraception must be used during therapy and for at least 6 months after the end of immunosuppressive agents) * Prior history of allergy to sirolimus, tacrolimus, cyclosporine, methotrexate or MMF * Concomitant treatment with another investigational drug (unless cleared by study chair)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To Compare 2-year Overall Survival of Patients With Lymphoma Undergoing RIC SCT Between Those Receiving Tacrolimus/Sirolimus/Methotrexate and Those Receiving Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil | 2 years |
Secondary
| Measure | Time frame |
|---|---|
| To Compare 2-year Progression-free Survival Between the Two Treatment Arms | 2 years |
| To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms | 2 years |
| To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms | 6 months |
| To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms. | 2 years |
| To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | 2 years |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus-Containing Regimen The Sirolimus containing arm will consist of the following drugs:
Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate
Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3.
Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2.
Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6.
Sirolimus: Taken orally for at least 12 months
Methotrexate: Given intravenously on the first, third and sixth day after transplant
Tacrolimus: Taken orally or given intravenously for at least 6 months | 66 |
| Sirolimus-Free Regimen There are two choices for the Sirolimus free arm:
Control Arm 1: tacrolimus + methotrexate
Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3.
Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11.
Control Arm 2: cyclosporine + MMF
Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3.
MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3.
Methotrexate: Given intravenously on the first, third and sixth day after transplant
Tacrolimus: Taken orally or given intravenously for at least 6 months
Cyclosporine: Taken orally or given intravenously for at least 6 months
MMF: Taken orally for about 2 months | 73 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Sirolimus-Containing Regimen | Sirolimus-Free Regimen | Total |
|---|---|---|---|
| Age, Continuous | 58 years | 57 years | 57 years |
| Region of Enrollment United States | 66 participants | 73 participants | 139 participants |
| Sex: Female, Male Female | 24 Participants | 29 Participants | 53 Participants |
| Sex: Female, Male Male | 42 Participants | 44 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 41 / 66 | 54 / 73 |
| serious Total, serious adverse events | 15 / 66 | 15 / 73 |
Outcome results
Primary
To Compare 2-year Overall Survival of Patients With Lymphoma Undergoing RIC SCT Between Those Receiving Tacrolimus/Sirolimus/Methotrexate and Those Receiving Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus-Containing Regimen | To Compare 2-year Overall Survival of Patients With Lymphoma Undergoing RIC SCT Between Those Receiving Tacrolimus/Sirolimus/Methotrexate and Those Receiving Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil | 70 percentage of participants |
| Sirolimus-Free Regimen | To Compare 2-year Overall Survival of Patients With Lymphoma Undergoing RIC SCT Between Those Receiving Tacrolimus/Sirolimus/Methotrexate and Those Receiving Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil | 68 percentage of participants |
Secondary
To Compare 2-year Progression-free Survival Between the Two Treatment Arms
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus-Containing Regimen | To Compare 2-year Progression-free Survival Between the Two Treatment Arms | 61 percentage of participants |
| Sirolimus-Free Regimen | To Compare 2-year Progression-free Survival Between the Two Treatment Arms | 58 percentage of participants |
Secondary
To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus-Containing Regimen | To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms | Grade II-IV aGVHD | 9 percentage of participants |
| Sirolimus-Containing Regimen | To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms | Grade III-IV aGVHD | 3 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms | Grade II-IV aGVHD | 25 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms | Grade III-IV aGVHD | 4 percentage of participants |
Secondary
To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus-Containing Regimen | To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms. | 59 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms. | 63 percentage of participants |
Secondary
To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus-Containing Regimen | To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms | Cumulative incidence of relapse/progression | 26 percentage of participants |
| Sirolimus-Containing Regimen | To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms | Non-relapse mortality | 14 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms | Cumulative incidence of relapse/progression | 30 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms | Non-relapse mortality | 12 percentage of participants |
Secondary
To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied.
Time frame: 2 years
Population: Given the small number of patients within each group, we considered indolent histologies (indolent B-cell NHL, CLL and HL) together in one group (indolent group), and aggressive histologies (aggressive B-cell NHL, MCL, and T-cell NHL) in another (aggressive group).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Non-relapse mortality | 8 percentage of participants |
| Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Progression Free Survival | 71 percentage of participants |
| Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Overall Survival | 82 percentage of participants |
| Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Cumulative Incidence of Progression | 21 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Progression Free Survival | 53 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Cumulative Incidence of Progression | 33 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Overall Survival | 63 percentage of participants |
| Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Non-relapse mortality | 15 percentage of participants |
| Aggressive Group: Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Overall Survival | 54 percentage of participants |
| Aggressive Group: Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Progression Free Survival | 46 percentage of participants |
| Aggressive Group: Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Cumulative Incidence of Progression | 32 percentage of participants |
| Aggressive Group: Sirolimus-Containing Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Non-relapse mortality | 21 percentage of participants |
| Aggressive Group: Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Progression Free Survival | 64 percentage of participants |
| Aggressive Group: Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Overall Survival | 76 percentage of participants |
| Aggressive Group: Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Non-relapse mortality | 9 percentage of participants |
| Aggressive Group: Sirolimus-Free Regimen | To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. | Cumulative Incidence of Progression | 27 percentage of participants |