Trial Outcomes & Findings for High-Dose Interferon Alfa in Treating Patients With Stage II or Stage III Melanoma (NCT NCT00003641)

Last Updated: 2025-09-18

Results Overview

Relapse-free survival (RFS) was defined as time from randomization to disease relapse or death from any cause, whichever occurred first. Patients without disease relapse were censored at last disease assessment date known of free of relapse. Kaplan-Meier method was used to estimate 5-year RFS rate in the intent-to-treat (ITT) patients.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

1150 participants

Primary outcome timeframe

assessed every 3 months for 2 years, every 6 months for 3 years

Results posted on

2025-09-18

Participant Flow

The study was activated on December 22, 1998, accrued its first patient on March 25, 1999, and closed to accrual on October 26, 2010 with final accrual of 1150 patients

Participant milestones

Participant milestones
Measure	Observation Patients undergo observation for 4 weeks.	Interferon Alfa-2b Patients receive high-dose interferon alfa-2b IV over 20 minutes daily for 5 consecutive days. Treatment repeats weekly for 4 weeks in the absence of unacceptable toxicity. interferon alfa-2b: Given IV
Overall Study STARTED	569	581
Overall Study Treated	2	569
Overall Study Toxicity Assessed	439	568
Overall Study COMPLETED	0	407
Overall Study NOT COMPLETED	569	174

Reasons for withdrawal

Reasons for withdrawal
Measure	Observation Patients undergo observation for 4 weeks.	Interferon Alfa-2b Patients receive high-dose interferon alfa-2b IV over 20 minutes daily for 5 consecutive days. Treatment repeats weekly for 4 weeks in the absence of unacceptable toxicity. interferon alfa-2b: Given IV
Overall Study Withdrawal by Subject	0	100
Overall Study Adverse Event	0	38
Overall Study Disease progression	0	2
Overall Study Unknown/missing	0	22
Overall Study Should not receive interferon therapy	2	0
Overall Study Never started interferon	567	12

Baseline Characteristics

High-Dose Interferon Alfa in Treating Patients With Stage II or Stage III Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Observation n=569 Participants Patients undergo observation for 4 weeks.	Interferon Alfa-2b n=581 Participants Patients receive high-dose interferon alfa-2b IV over 20 minutes daily for 5 consecutive days. Treatment repeats weekly for 4 weeks in the absence of unacceptable toxicity. interferon alfa-2b: Given IV	Total n=1150 Participants Total of all reporting groups
Age, Continuous	52 years n=5 Participants	52 years n=7 Participants	52 years n=5 Participants
Sex/Gender, Customized Female	248 participants n=5 Participants	244 participants n=7 Participants	492 participants n=5 Participants
Sex/Gender, Customized Male	320 participants n=5 Participants	336 participants n=7 Participants	656 participants n=5 Participants
Sex/Gender, Customized Missing	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants

PRIMARY outcome

Timeframe: assessed every 3 months for 2 years, every 6 months for 3 years

Population: all randomized patients

Outcome measures

Outcome measures
Measure	Observation n=569 Participants Patients undergo observation for 4 weeks.	Interferon Alfa-2b n=581 Participants Patients receive high-dose interferon alfa-2b IV over 20 minutes daily for 5 consecutive days. Treatment repeats weekly for 4 weeks in the absence of unacceptable toxicity. interferon alfa-2b: Given IV
5-year Relapse-free Survival Rate	0.70 proportion of participants Interval 0.66 to 0.74	0.70 proportion of participants Interval 0.66 to 0.74

SECONDARY outcome

Timeframe: assessed every 3 months for 2 years, every 6 months for 3 years

Population: all randomized patients

Overall survival (OS) was defined as time from randomization to death from any cause. Patients still alive were censored at last known alive date. Kaplan-Meier method was used to estimate 5-year OS rate in the ITT patients.

Outcome measures

Outcome measures
Measure	Observation n=569 Participants Patients undergo observation for 4 weeks.	Interferon Alfa-2b n=581 Participants Patients receive high-dose interferon alfa-2b IV over 20 minutes daily for 5 consecutive days. Treatment repeats weekly for 4 weeks in the absence of unacceptable toxicity. interferon alfa-2b: Given IV
5-year Overall Survival Rate	0.83 proportion of participants Interval 0.79 to 0.86	0.83 proportion of participants Interval 0.8 to 0.86

Adverse Events

Observation

Serious events: 20 serious events

Other events: 74 other events

Deaths: 0 deaths

Interferon Alfa-2b

Serious events: 325 serious events

Other events: 558 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study statistician

ECOG-ACRIN Statistical Office

Phone: 617-632-3012

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Observation n=439 participants at risk Patients undergo observation for 4 weeks	Interferon Alfa-2b n=568 participants at risk Patients receive high-dose interferon alfa-2b IV over 20 minutes daily for 5 consecutive days
Immune system disorders Allergic reaction	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Ear and labyrinth disorders INNER EAR/HEARING	0.46% 2/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.00% 0/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Blood and lymphatic system disorders Anemia	0.23% 1/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.00% 0/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Leukocytes decreased	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	6.7% 38/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Neutrophils decreased	1.8% 8/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	22.9% 130/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Platelets decreased	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.53% 3/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Blood and lymphatic system disorders Hematologic-other	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Cardiac disorders Supraventricular arrhythmias	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Nervous system disorders Vasovagal episode	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Cardiac disorders Cardiac-ischemia	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Cardiac disorders Cardiac-left ventric	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Vascular disorders Hypertension	0.46% 2/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.88% 5/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Vascular disorders Hypotension	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Cardiac disorders Myocarditis	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Vascular disorders Thrombosis/embolism	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders Fatigue	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	12.3% 70/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders Fever	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.70% 4/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders Rigors/chills	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders CONSTITUTIONAL	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Skin and subcutaneous tissue disorders Rash/desquamation	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.88% 5/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Metabolism and nutrition disorders Anorexia	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	1.9% 11/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders Constipation	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.70% 4/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Metabolism and nutrition disorders Dehydration	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders Nausea	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	4.9% 28/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders STOMATITIS	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders Vomiting	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	3.3% 19/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders GI-other	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Renal and urinary disorders Hematuria	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Alkaline phosphatase increased	0.46% 2/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Blood bilirubin increased	0.23% 1/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.70% 4/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations GGT increased	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Aspartate aminotransferase increased	0.23% 1/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	13.0% 74/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Alanine aminotransferase increased	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	5.3% 30/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Infections and infestations Catheter-related infection	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Infections and infestations Infection w/ grade 3 or 4 neutropenia	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Infections and infestations INFECTION W/ UNKNOWN ANC	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Infections and infestations Infection w/o neutropenia	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Infections and infestations INFECTION-OTHER	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.35% 2/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Metabolism and nutrition disorders HYPERGLYCEMIA	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Metabolism and nutrition disorders HYPERTRIGLYCERIDEMIA	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	0.18% 1/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.

Other adverse events
Measure	Observation n=439 participants at risk Patients undergo observation for 4 weeks	Interferon Alfa-2b n=568 participants at risk Patients receive high-dose interferon alfa-2b IV over 20 minutes daily for 5 consecutive days
Blood and lymphatic system disorders Anemia	2.7% 12/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	21.7% 123/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Leukocytes decreased	1.4% 6/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	56.5% 321/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Neutrophils decreased	0.91% 4/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	49.8% 283/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Platelets decreased	0.46% 2/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	35.2% 200/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders Fatigue	2.5% 11/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	79.9% 454/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders Fever	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	45.1% 256/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders Rigors/chills	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	60.2% 342/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Skin and subcutaneous tissue disorders Sweating	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	14.6% 83/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Weight loss	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	21.1% 120/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Skin and subcutaneous tissue disorders Alopecia	0.23% 1/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	5.3% 30/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Skin and subcutaneous tissue disorders Rash/desquamation	0.68% 3/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	11.3% 64/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Metabolism and nutrition disorders Anorexia	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	49.8% 283/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders Constipation	0.46% 2/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	18.7% 106/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders Nausea	0.23% 1/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	59.9% 340/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Nervous system disorders Taste disturbance	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	31.0% 176/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders Vomiting	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	23.4% 133/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Gastrointestinal disorders GI-other	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	7.2% 41/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Alkaline phosphatase increased	0.46% 2/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	12.1% 69/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Blood bilirubin increased	0.46% 2/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	7.6% 43/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Aspartate aminotransferase increased	1.8% 8/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	65.7% 373/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Investigations Alanine aminotransferase increased	0.91% 4/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	14.1% 80/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Nervous system disorders Dizziness/lightheadedness	0.00% 0/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	16.7% 95/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Psychiatric disorders Insomnia	0.68% 3/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	19.9% 113/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Psychiatric disorders Anxiety/agitation	1.6% 7/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	16.0% 91/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Psychiatric disorders Depression	0.91% 4/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	15.8% 90/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Nervous system disorders Neuropathy-sensory	1.8% 8/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	7.2% 41/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Musculoskeletal and connective tissue disorders Arthralgia	0.91% 4/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	24.1% 137/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Nervous system disorders Headache	1.8% 8/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	47.5% 270/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
Musculoskeletal and connective tissue disorders Myalgia	0.68% 3/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	40.3% 229/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.
General disorders Pain-other	3.9% 17/439 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.	5.8% 33/568 • Assessed at the end of treatment (4 weeks) and for 30 days following the last dose of protocol drug, or until the initiation of subsequent treatment, whichever comes first Prior to diagnosis of relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported was collected via the long-term follow up form, assessed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter until 15 years after randomization.These long term toxicities were included here as well.