Tacrolimus/Sirolimus/Methotrexate vs Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00928018
• Collaborator: Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), National Cancer Institute (NCI) (NIH)
• Enrollment: 139
• Locations: 5
• Arms: 2
• Duration (Months): 65
• Patients Per Site: 27.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-hodgkin Lymphoma; Hodgkin Lymphoma	Drug: Sirolimus; Drug: Methotrexate; Drug: Tacrolimus; Drug: Cyclosporine; Drug: MMF	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 139 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Multicenter, Randomized Trial Comparing Tacrolimus/Sirolimus/Methotrexate Versus Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Sirolimus; Taken orally for at least 12 months; Other Names: Rapamycin ; Drug: Methotrexate; Given intravenously on the first, third and sixth day after transplant; Other Names: Abbreviated MTX Trade name:Trexall ; Drug: Tacrolimus; Taken orally or given intravenously for at least 6 months; Other Names: Prograf
Active Comparator: Sirolimus-Free regimen There are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at a 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 a dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at a 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 on day 3.	Drug: Methotrexate; Given intravenously on the first, third and sixth day after transplant; Other Names: Abbreviated MTX Trade name:Trexall ; Drug: Tacrolimus; Taken orally or given intravenously for at least 6 months; Other Names: Prograf ; Drug: Cyclosporine; Taken orally or given intravenously for at least 6 months; Other Names: Brand names: •Gengraf •Neoral •Sandimmune •Sangcya ; Drug: MMF; Taken orally for about 2 months; Other Names: Mycophenolate mofetil (MMF) Brand Names: CellCept Myfortic

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. To Compare 2-year Progression-free Survival Between the Two Treatment Arms [2 years]

2. To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms [2 years]

3. To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms [6 months]

4. To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms. [2 years]

5. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 72 Years
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital	Atlanta	Georgia	United States	30322
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
4	University of Minnesota	Minneapolis	Minnesota	United States	55454
5	Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• Massachusetts General Hospital
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Philippe Armand, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Philippe Armand, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00928018
• Other Study ID Numbers: 09-073; CA142106
• First Posted: Jun 25, 2009
• Last Update Posted: Feb 1, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Philippe Armand, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute: allogeneic stem cell transplant; reduced intensity conditioning; graft versus host disease; GVHD; RIC transplantation
• Additional relevant MeSH terms: Lymphoma; Cyclosporine; Sirolimus; Mycophenolic Acid; Methotrexate; Tacrolimus; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	Sirolimus-Containing Regimen	Sirolimus-Free Regimen
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	66	73
COMPLETED	65	73
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Sirolimus-Containing Regimen	Sirolimus-Free Regimen	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	66	73	139
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58	57	57
Sex: Female, Male (Count of Participants)
Female	24 36.4%	29 39.7%	53 38.1%
Male	42 63.6%	44 60.3%	86 61.9%
Region of Enrollment (participants) [Number]
United States	66 100%	73 100%	139 100%

Outcome Measures

1. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus-Containing Regimen	Sirolimus-Free Regimen
Arm/Group Description	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	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
Measure Participants	66	73
Number (95% Confidence Interval) [percentage of participants]	70 106.1%	68 93.2%

2. Secondary Outcome

Title	To Compare 2-year Progression-free Survival Between the Two Treatment Arms
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus-Containing Regimen	Sirolimus-Free Regimen
Arm/Group Description	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	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
Measure Participants	66	73
Number (95% Confidence Interval) [percentage of participants]	61 92.4%	58 79.5%

3. Secondary Outcome

Title	To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus-Containing Regimen	Sirolimus-Free Regimen
Arm/Group Description	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	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
Measure Participants	66	73
Cumulative incidence of relapse/progression	26 39.4%	30 41.1%
Non-relapse mortality	14 21.2%	12 16.4%

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus-Containing Regimen	Sirolimus-Free Regimen
Arm/Group Description	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	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
Measure Participants	66	73
Grade II-IV aGVHD	9 13.6%	25 34.2%
Grade III-IV aGVHD	3 4.5%	4 5.5%

5. Secondary Outcome

Title	To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus-Containing Regimen	Sirolimus-Free Regimen
Arm/Group Description	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	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
Measure Participants	66	73
Number [percentage of participants]	59 89.4%	63 86.3%

6. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Indolent Group: Sirolimus-Containing Regimen	Indolent Group: Sirolimus-Free Regimen	Aggressive Group: Sirolimus-Containing Regimen	Aggressive Group: Sirolimus-Free Regimen
Arm/Group Description	Indolent group:indolent B-cell NHL, CLL and HL histologies 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.Taken orally or given intravenously for at least 6 months 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.Taken orally for at least 12 months Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6.Given intravenously on the first, third and sixth day after transplant	Indolent group: indolent B-cell NHL, CLL and HL histologies 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. Taken orally or given intravenously for at least 6 months 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. Taken orally or given intravenously for at least 6 months 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. Taken orally for about 2 months.	Aggressive group: aggressive B-cell NHL, MCL, and T-cell NHL histologies 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.Taken orally or given intravenously for at least 6 months 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.Taken orally for at least 12 months Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6.Given intravenously on the first, third and sixth day after transplant	Aggressive group: aggressive B-cell NHL, MCL, and T-cell NHL histologies 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. Taken orally or given intravenously for at least 6 months 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. Taken orally or given intravenously for at least 6 months 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. Taken orally for about 2 months.
Measure Participants	38	40	28	33
Overall Survival	82 124.2%	63 86.3%	54 38.8%	76 NaN
Progression Free Survival	71 107.6%	53 72.6%	46 33.1%	64 NaN
Cumulative Incidence of Progression	21 31.8%	33 45.2%	32 23%	27 NaN
Non-relapse mortality	8 12.1%	15 20.5%	21 15.1%	9 NaN

Adverse Events

Time Frame	Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points during the study. The study defined follow up period is 2 years.
Adverse Event Reporting Description	All AEs grades 3-5 and SAEs whether reported by participant, discovered during questioning, directly observed, or detected by physical examination, laboratory test, etc, will be recorded in participant's medical record and appropriate study-specific forms Only events reported in >1 patient on at least one of the arms are listed in Other AE table
Arm/Group Title	Sirolimus-Containing Regimen		Sirolimus-Free Regimen
Arm/Group Description	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		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
All Cause Mortality
	Sirolimus-Containing Regimen		Sirolimus-Free Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sirolimus-Containing Regimen		Sirolimus-Free Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/66 (22.7%)		15/73 (20.5%)
Blood and lymphatic system disorders
Hemolysis	0/66 (0%)	0	1/73 (1.4%)	1
Thrombotic Microangiopathy	0/66 (0%)	0	1/73 (1.4%)	1
Cardiac disorders
Pericardial Effusion	0/66 (0%)	0	1/73 (1.4%)	1
Heart Failure	0/66 (0%)	0	1/73 (1.4%)	1
Supraventricular and Nodal Arrhythmia	0/66 (0%)	0	1/73 (1.4%)	1
Gastrointestinal disorders
Ascites	1/66 (1.5%)	1	1/73 (1.4%)	1
Obstuction--GI, small bowel	1/66 (1.5%)	1	0/73 (0%)	0
Gastrointestinal pain	1/66 (1.5%)	1	0/73 (0%)	0
General disorders
Edema	0/66 (0%)	0	1/73 (1.4%)	1
Multi-organ failure	0/66 (0%)	0	1/73 (1.4%)	1
Hepatobiliary disorders
Liver failure	1/66 (1.5%)	1	0/73 (0%)	0
Immune system disorders
GVHD	0/66 (0%)	0	4/73 (5.5%)	4
Other- Systemic inflammatory response syndrome (SIRS)	0/66 (0%)	0	1/73 (1.4%)	1
Infections and infestations
Infection	8/66 (12.1%)	11	6/73 (8.2%)	6
Investigations
Leukopenia	0/66 (0%)	0	1/73 (1.4%)	1
Thrombocytopenia	2/66 (3%)	2	0/73 (0%)	0
Musculoskeletal and connective tissue disorders
Fracture	1/66 (1.5%)	1	0/73 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other: Relapse/Progressive disease	2/66 (3%)	2	3/73 (4.1%)	3
Treatment Related Secondary Malignancy	1/66 (1.5%)	1	0/73 (0%)	0
Nervous system disorders
Encephalopathy	1/66 (1.5%)	1	0/73 (0%)	0
Seizure	0/66 (0%)	0	1/73 (1.4%)	1
Altered mental status	0/66 (0%)	0	2/73 (2.7%)	2
Memory impairment	0/66 (0%)	0	1/73 (1.4%)	1
Hemorrhage, CNS (cerebrovascular)	0/66 (0%)	0	1/73 (1.4%)	1
Confusion	0/66 (0%)	0	2/73 (2.7%)	2
Renal and urinary disorders
Acute Kidney Injury/Renal Failure	3/66 (4.5%)	3	1/73 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
Adult Respiratory Distress Syndrome (ARDS)	1/66 (1.5%)	1	0/73 (0%)	0
Aspiration	0/66 (0%)	0	1/73 (1.4%)	1
Dyspnea	0/66 (0%)	0	1/73 (1.4%)	1
Hypoxia	3/66 (4.5%)	3	1/73 (1.4%)	1
Other--Respiratory failure/lung injury	2/66 (3%)	2	0/73 (0%)	0
Pulmonary hemorrhage	1/66 (1.5%)	1	0/73 (0%)	0
Vascular disorders
Other--Stroke	1/66 (1.5%)	1	0/73 (0%)	0
Pulmonary embolism	2/66 (3%)	2	2/73 (2.7%)	2
Other (Not Including Serious) Adverse Events
	Sirolimus-Containing Regimen		Sirolimus-Free Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/66 (62.1%)		54/73 (74%)
Blood and lymphatic system disorders
Neutropenia	12/66 (18.2%)	12	16/73 (21.9%)	16
Cardiac disorders
Cardiac	3/66 (4.5%)	3	7/73 (9.6%)	7
Hypotension	1/66 (1.5%)	1	2/73 (2.7%)	2
Eye disorders
Cataract	2/66 (3%)	2	1/73 (1.4%)	1
Gastrointestinal disorders
Anorexia	2/66 (3%)	2	1/73 (1.4%)	1
Diarrhea	3/66 (4.5%)	3	4/73 (5.5%)	4
Stomatitis/mucositis	1/66 (1.5%)	1	4/73 (5.5%)	4
Nausea/vomiting	4/66 (6.1%)	4	1/73 (1.4%)	1
Abdominal pain	1/66 (1.5%)	1	5/73 (6.8%)	5
Hepatobiliary disorders
Hepatic	4/66 (6.1%)	4	15/73 (20.5%)	15
Immune system disorders
Allergic Reaction	0/66 (0%)	0	2/73 (2.7%)	2
Infections and infestations
Infection	3/66 (4.5%)	3	17/73 (23.3%)	17
Investigations
Thrombocytopenia	11/66 (16.7%)	11	14/73 (19.2%)	14
Leukopenia	6/66 (9.1%)	6	8/73 (11%)	8
Metabolism and nutrition disorders
Hyperlipidemia	2/66 (3%)	2	2/73 (2.7%)	2
Hyperglycemia	3/66 (4.5%)	3	3/73 (4.1%)	3
Dehydration	1/66 (1.5%)	1	2/73 (2.7%)	2
Hyponatremia	1/66 (1.5%)	1	2/73 (2.7%)	2
Musculoskeletal and connective tissue disorders
Weakness	3/66 (4.5%)	3	1/73 (1.4%)	1
Nervous system disorders
Confusion/psychosis/encephalopathy	8/66 (12.1%)	8	4/73 (5.5%)	4
Neuropathy	4/66 (6.1%)	4	0/73 (0%)	0
Pain	1/66 (1.5%)	1	8/73 (11%)	8
Renal and urinary disorders
TMA/renal failure/hemolysis	12/66 (18.2%)	12	6/73 (8.2%)	6
Respiratory, thoracic and mediastinal disorders
Respiratory	2/66 (3%)	2	10/73 (13.7%)	10
Skin and subcutaneous tissue disorders
Rash	1/66 (1.5%)	1	4/73 (5.5%)	4
Vascular disorders
Hematoma	2/66 (3%)	2	1/73 (1.4%)	1
Thrombosis	1/66 (1.5%)	1	8/73 (11%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.