• Event-free survival [ Designated as safety issue: No ]
• Toxicity [ Designated as safety issue: Yes ]

• Event-free survival
• Toxicity

• Overall survival [ Designated as safety issue: No ]
• Disease response [ Designated as safety issue: No ]

• Overall survival
• Disease response

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known if combination chemotherapy with vinblastine is more effective than combination chemotherapy with vincristine in treating advanced anaplastic large cell lymphoma.

PURPOSE: Randomized phase III trial to compare the effectiveness of two combination chemotherapy regimens with either vinblastine or vincristine in treating patients who have newly diagnosed advanced anaplastic large cell lymphoma.

OBJECTIVES:

• Compare the efficacy of a consolidation chemotherapy regimen comprising doxorubicin and prednisone in combination with vincristine vs vinblastine, in terms of event-free survival, in patients with advanced anaplastic large cell lymphoma.
• Compare overall survival of patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Correlate biological tumor characteristics and outcome in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study.

• Induction therapy: Patients receive doxorubicin IV over 15 minutes on days 1 and 22; vincristine IV on days 1, 8, 15, 22, and 29; oral prednisone 3 times daily on days 1-28; and intrathecal (IT) methotrexate on days 1, 8, and 22 (patients with CNS disease at diagnosis receive additional methotrexate IT on days 15, 29, and 36).

Patients then begin consolidation therapy on day 43.

• Consolidation therapy: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive course-specific regimens.

    • Courses 1-3: Patients receive doxorubicin IV over 15 minutes, vincristine IV, and methotrexate IT on day 1 and oral prednisone three times daily and oral mercaptopurine once daily on days 1-5.
    • Courses 4-5: Patients receive doxorubicin, vincristine, prednisone, and mercaptopurine as in courses 1-3.
    • Courses 6-15: Patients receive vincristine, prednisone, and mercaptopurine as in courses 1-3 and methotrexate IV on day 1.

  • Arm II: Patients receive course-specific regimens.

    • Courses 1-3: Patients receive doxorubicin, methotrexate IT, prednisone, and mercaptopurine as in arm I and vinblastine IV over 1 minute on days 1, 8, and 15.
    • Courses 4-5: Patients receive doxorubicin, prednisone, and mercaptopurine as in arm I and vinblastine as in arm II (courses 1-3).
    • Courses 6-15: Patients receive prednisone and mercaptopurine as in arm I, vinblastine as in arm II (courses 1-3), and methotrexate IV on day 1.

In both arms and all courses, treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed monthly for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 200-250 patients (100-125 per treatment arm) will be accrued for this study within 5 years.

• Drug: doxorubicin hydrochloride
• Drug: mercaptopurine
• Drug: methotrexate
• Drug: prednisone
• Drug: vinblastine
• Drug: vincristine sulfate

• Active Comparator: In courses 1-3, patients receive doxorubicin IV over 15 minutes, vincristine IV, and methotrexate intrathecally (IT) on day 1 and oral prednisone three times daily and oral mercaptopurine once daily on days 1-5. In courses 4 and 5, patients receive doxorubicin, vincristine, prednisone, and mercaptopurine as in courses 1-3. In courses 6-15, patients receive vincristine, prednisone, and mercaptopurine as in courses 1-3 and methotrexate IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity.
• Experimental: In courses 1-3, patients receive doxorubicin, methotrexate IT, prednisone, and mercaptopurine as in arm I and vinblastine IV over 1 minute on days 1, 8, and 15. In courses 4 and 5, patients receive doxorubicin, prednisone, and mercaptopurine as in arm I and vinblastine as in arm II (courses 1-3). In courses 6-15, patients receive prednisone and mercaptopurine as in arm I, vinblastine as in arm II (courses 1-3), and methotrexate IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity.

DISEASE CHARACTERISTICS:

• Newly diagnosed advanced anaplastic large cell lymphoma

  • CD30+ disease
  • Murphy stage III or IV
• No B-cell large cell lymphoma
• No disease limited to the skin (regardless of how wide-spread)

PATIENT CHARACTERISTICS:

Age

• Under 21

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST or ALT less than 2.5 times ULN (unless due to lymphoma)

Renal

• Not specified

Cardiovascular

• Shortening fraction at least 27% by echocardiogram OR
• Ejection fraction at least 50% by radionuclide angiogram

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• Prior steroids for management of a mediastinal mass allowed

Radiotherapy

• Prior limited-dose radiotherapy for a mediastinal mass allowed

Surgery

• Not specified