RATIONALE: Drugs used in chemotherapy, such as methotrexate and leucovorin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Glucarpidase may help return the level of methotrexate in the blood to a safe range. Giving high-dose methotrexate together with glucarpidase and leucovorin may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of methotrexate when given together with glucarpidase and leucovorin in treating patients with newly diagnosed primary central nervous system lymphoma.

OBJECTIVES:

Primary

• To determine the dose-limiting toxicity of methotrexate (MTX) when given in combination with glucarpidase in patients with newly diagnosed primary CNS lymphoma (PCNSL).
• To determine the incidence of immediate reactions related to the use of glucarpidase in these patients.
• To define a safer, more practical, and simpler regimen for delivering multiple courses of high-dose MTX using glucarpidase and 'short' leucovorin calcium rescue in these patients.
• To monitor quality of life and mental function during and after therapy in these patients.

Secondary

• To use this regimen as a platform for phase III studies in PCNSL.
• To record disease response, duration of response, and overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of high-dose methotrexate (HD-MTX).

Patients receive HD-MTX IV over 4 hours on day 1. Beginning 22 hours after the start of HD-MTX, patients receive glucarpidase IV over 15 minutes on day 2 followed by leucovorin calcium orally or IV on days 2-7. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Within 2-4 weeks after completion of study treatment, patients achieving maximum response are stratified according to age (< 60 years vs ≥ 60 years) and may undergo whole brain radiotherapy (WBRT) once daily, 5 days a week, for 3 to 5 weeks.

Patients undergo blood sample collection periodically to assess glucarpidase antibodies and MTX levels.

Patients are assessed for mucositis incidence and severity periodically, and complete quality of life assessments using the EORTC QLQ-30 questionnaire and the Mini-Mental State questionnaire at baseline, during, and after completion of study.

After completion of study treatment, patients are followed at 6 weeks after WBRT, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter.

DISEASE CHARACTERISTICS:

• Histologically confirmed newly diagnosed primary CNS lymphoma (PCNSL)

  • Previously untreated disease
  • Diffuse large B-cell lymphoma histology

• Must be clinically eligible to receive standard 3 g/m² methotrexate if outside trial

• No clinically significant effusions or edema

PATIENT CHARACTERISTICS:

Inclusion criteria:

• ECOG performance status 0-3
• Neutrophils ≥ 1 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Bilirubin < 1.5 times upper limit of normal
• Glomerular filtration rate (initially measured by EDTA/isotope method) ≥ 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after completion of study therapy

Exclusion criteria:

• HIV positivity
• Dementia or neurological dysfunction not considered to be due to the PCNSL
• Other serious or uncontrolled medical conditions
• Prior malignancy, except adequately treated nonmelanoma skin cancer or carcinoma in situ

PRIOR CONCURRENT THERAPY:

• No prior cytotoxic chemotherapy
• No concurrent prophylactic antibiotics
• No concurrent co-trimoxazole