Trial Outcomes & Findings for Tacrolimus/Sirolimus/Methotrexate vs Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma (NCT NCT00928018)

NCT ID: NCT00928018

Last Updated: 2019-02-01

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

139 participants

Primary outcome timeframe

2 years

Results posted on

2019-02-01

Participant Flow

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	66	73
Overall Study COMPLETED	65	73
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sirolimus-Containing Regimen n=66 Participants 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	Sirolimus-Free Regimen n=73 Participants 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 n=139 Participants Total of all reporting groups
Age, Continuous	58 years n=93 Participants	57 years n=4 Participants	57 years n=27 Participants
Sex: Female, Male Female	24 Participants n=93 Participants	29 Participants n=4 Participants	53 Participants n=27 Participants
Sex: Female, Male Male	42 Participants n=93 Participants	44 Participants n=4 Participants	86 Participants n=27 Participants
Region of Enrollment United States	66 participants n=93 Participants	73 participants n=4 Participants	139 participants n=27 Participants

PRIMARY outcome

Timeframe: 2 years

Outcome measures

Outcome measures
Measure	Sirolimus-Containing Regimen n=66 Participants 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	Sirolimus-Free Regimen n=73 Participants 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	Aggressive Group: Sirolimus-Containing Regimen 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: Sirolimus-Free Regimen 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.
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 Interval 57.0 to 79.0	68 percentage of participants Interval 57.0 to 78.0	—	—

SECONDARY outcome

Timeframe: 2 years

Outcome measures

Outcome measures
Measure	Sirolimus-Containing Regimen n=66 Participants 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	Sirolimus-Free Regimen n=73 Participants 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	Aggressive Group: Sirolimus-Containing Regimen 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: Sirolimus-Free Regimen 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.
To Compare 2-year Progression-free Survival Between the Two Treatment Arms	61 percentage of participants Interval 48.0 to 71.0	58 percentage of participants Interval 45.0 to 68.0	—	—

SECONDARY outcome

Timeframe: 2 years

Outcome measures

Outcome measures
Measure	Sirolimus-Containing Regimen n=66 Participants 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	Sirolimus-Free Regimen n=73 Participants 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	Aggressive Group: Sirolimus-Containing Regimen 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: Sirolimus-Free Regimen 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.
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 Interval 16.0 to 37.0	30 percentage of participants Interval 20.0 to 41.0	—	—
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 Interval 7.0 to 23.0	12 percentage of participants Interval 6.0 to 21.0	—	—

SECONDARY outcome

Timeframe: 6 months

Outcome measures

Outcome measures
Measure	Sirolimus-Containing Regimen n=66 Participants 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	Sirolimus-Free Regimen n=73 Participants 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	Aggressive Group: Sirolimus-Containing Regimen 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: Sirolimus-Free Regimen 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.
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	25 percentage of participants	—	—
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	4 percentage of participants	—	—

SECONDARY outcome

Timeframe: 2 years

Outcome measures

Outcome measures
Measure	Sirolimus-Containing Regimen n=66 Participants 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	Sirolimus-Free Regimen n=73 Participants 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	Aggressive Group: Sirolimus-Containing Regimen 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: Sirolimus-Free Regimen 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.
To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms.	59 percentage of participants	63 percentage of participants	—	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Sirolimus-Containing Regimen n=38 Participants 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	Sirolimus-Free Regimen n=40 Participants 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	Aggressive Group: Sirolimus-Containing Regimen n=28 Participants 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: Sirolimus-Free Regimen n=33 Participants 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.
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	63 percentage of participants	54 percentage of participants	76 percentage of participants
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	53 percentage of participants	46 percentage of participants	64 percentage of participants
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	33 percentage of participants	32 percentage of participants	27 percentage of participants
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	15 percentage of participants	21 percentage of participants	9 percentage of participants

Adverse Events

Sirolimus-Containing Regimen

Serious events: 15 serious events

Other events: 41 other events

Deaths: 0 deaths

Sirolimus-Free Regimen

Serious events: 15 serious events

Other events: 54 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Philippe Armand, MD, PhD

Dana Farber Cancer Institute

Phone: 617-632-2305

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Sirolimus-Containing Regimen n=66 participants at risk 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	Sirolimus-Free Regimen n=73 participants at risk 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
Renal and urinary disorders Acute Kidney Injury/Renal Failure	4.5% 3/66 • Number of events 3 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Other: Relapse/Progressive disease	3.0% 2/66 • Number of events 2 • 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. 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	4.1% 3/73 • Number of events 3 • 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. 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
Immune system disorders GVHD	0.00% 0/66 • 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. 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	5.5% 4/73 • Number of events 4 • 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. 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
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Treatment Related Secondary Malignancy	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Blood and lymphatic system disorders Hemolysis	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Blood and lymphatic system disorders Thrombotic Microangiopathy	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Cardiac disorders Pericardial Effusion	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Cardiac disorders Heart Failure	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Cardiac disorders Supraventricular and Nodal Arrhythmia	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Gastrointestinal disorders Ascites	1.5% 1/66 • Number of events 1 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Gastrointestinal disorders Obstuction--GI, small bowel	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Gastrointestinal disorders Gastrointestinal pain	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
General disorders Edema	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
General disorders Multi-organ failure	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Hepatobiliary disorders Liver failure	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Immune system disorders Other- Systemic inflammatory response syndrome (SIRS)	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Investigations Leukopenia	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Investigations Thrombocytopenia	3.0% 2/66 • Number of events 2 • 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. 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	0.00% 0/73 • 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. 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
Musculoskeletal and connective tissue disorders Fracture	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Nervous system disorders Encephalopathy	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Nervous system disorders Seizure	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Nervous system disorders Altered mental status	0.00% 0/66 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Nervous system disorders Memory impairment	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Nervous system disorders Hemorrhage, CNS (cerebrovascular)	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Nervous system disorders Confusion	0.00% 0/66 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Respiratory, thoracic and mediastinal disorders Adult Respiratory Distress Syndrome (ARDS)	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/66 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Respiratory, thoracic and mediastinal disorders Hypoxia	4.5% 3/66 • Number of events 3 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Respiratory, thoracic and mediastinal disorders Other--Respiratory failure/lung injury	3.0% 2/66 • Number of events 2 • 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. 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	0.00% 0/73 • 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. 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
Respiratory, thoracic and mediastinal disorders Pulmonary hemorrhage	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Vascular disorders Other--Stroke	1.5% 1/66 • Number of events 1 • 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. 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	0.00% 0/73 • 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. 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
Vascular disorders Pulmonary embolism	3.0% 2/66 • Number of events 2 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Infections and infestations Infection	12.1% 8/66 • Number of events 11 • 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. 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	8.2% 6/73 • Number of events 6 • 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. 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

Other adverse events
Measure	Sirolimus-Containing Regimen n=66 participants at risk 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	Sirolimus-Free Regimen n=73 participants at risk 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
Renal and urinary disorders TMA/renal failure/hemolysis	18.2% 12/66 • Number of events 12 • 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. 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	8.2% 6/73 • Number of events 6 • 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. 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
Blood and lymphatic system disorders Neutropenia	18.2% 12/66 • Number of events 12 • 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. 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	21.9% 16/73 • Number of events 16 • 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. 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
Investigations Thrombocytopenia	16.7% 11/66 • Number of events 11 • 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. 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	19.2% 14/73 • Number of events 14 • 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. 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
Investigations Leukopenia	9.1% 6/66 • Number of events 6 • 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. 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	11.0% 8/73 • Number of events 8 • 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. 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
Infections and infestations Infection	4.5% 3/66 • Number of events 3 • 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. 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	23.3% 17/73 • Number of events 17 • 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. 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
Metabolism and nutrition disorders Hyperlipidemia	3.0% 2/66 • Number of events 2 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Gastrointestinal disorders Anorexia	3.0% 2/66 • Number of events 2 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Eye disorders Cataract	3.0% 2/66 • Number of events 2 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Nervous system disorders Confusion/psychosis/encephalopathy	12.1% 8/66 • Number of events 8 • 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. 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	5.5% 4/73 • Number of events 4 • 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. 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
Gastrointestinal disorders Diarrhea	4.5% 3/66 • Number of events 3 • 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. 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	5.5% 4/73 • Number of events 4 • 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. 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
Vascular disorders Hematoma	3.0% 2/66 • Number of events 2 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Metabolism and nutrition disorders Hyperglycemia	4.5% 3/66 • Number of events 3 • 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. 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	4.1% 3/73 • Number of events 3 • 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. 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
Respiratory, thoracic and mediastinal disorders Respiratory	3.0% 2/66 • Number of events 2 • 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. 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	13.7% 10/73 • Number of events 10 • 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. 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
Hepatobiliary disorders Hepatic	6.1% 4/66 • Number of events 4 • 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. 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	20.5% 15/73 • Number of events 15 • 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. 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
Gastrointestinal disorders Stomatitis/mucositis	1.5% 1/66 • Number of events 1 • 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. 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	5.5% 4/73 • Number of events 4 • 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. 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
Gastrointestinal disorders Nausea/vomiting	6.1% 4/66 • Number of events 4 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Gastrointestinal disorders Abdominal pain	1.5% 1/66 • Number of events 1 • 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. 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	6.8% 5/73 • Number of events 5 • 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. 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
Nervous system disorders Neuropathy	6.1% 4/66 • Number of events 4 • 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. 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	0.00% 0/73 • 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. 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
Musculoskeletal and connective tissue disorders Weakness	4.5% 3/66 • Number of events 3 • 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. 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	1.4% 1/73 • Number of events 1 • 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. 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
Vascular disorders Thrombosis	1.5% 1/66 • Number of events 1 • 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. 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	11.0% 8/73 • Number of events 8 • 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. 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
Immune system disorders Allergic Reaction	0.00% 0/66 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Cardiac disorders Cardiac	4.5% 3/66 • Number of events 3 • 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. 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	9.6% 7/73 • Number of events 7 • 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. 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
Metabolism and nutrition disorders Dehydration	1.5% 1/66 • Number of events 1 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Nervous system disorders Pain	1.5% 1/66 • Number of events 1 • 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. 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	11.0% 8/73 • Number of events 8 • 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. 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
Metabolism and nutrition disorders Hyponatremia	1.5% 1/66 • Number of events 1 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Cardiac disorders Hypotension	1.5% 1/66 • Number of events 1 • 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. 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	2.7% 2/73 • Number of events 2 • 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. 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
Skin and subcutaneous tissue disorders Rash	1.5% 1/66 • Number of events 1 • 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. 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	5.5% 4/73 • Number of events 4 • 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. 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