Pixantrone, Cytarabine, Methylprednisolone, and Cisplatin in Treating Patients With Aggressive Non-Hodgkin's Lymphoma in First Relapse
Pixantrone, Cytarabine, Methylprednisolone, and Cisplatin in Treating Patients With Aggressive Non-Hodgkin's Lymphoma in First Relapse
RATIONALE: Drugs used in chemotherapy, such as pixantrone, cytarabine, methylprednisolone,
 and cisplatin, work in different ways to stop cancer cells from dividing so they stop growing
 or die. Combining more than one drug may kill more cancer cells.

 PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy in treating
 patients who have relapsed aggressive non-Hodgkin's lymphoma.
OBJECTIVES:

 -  Determine the antitumor activity of pixantrone, cytarabine, methylprednisolone, and
 cisplatin in patients with aggressive non-Hodgkin's lymphoma in first relapse.

 -  Determine the safety and tolerability of this regimen in these patients.

 -  Determine the validity and safety of this regimen as a mobilization regimen before
 high-dose chemotherapy with stem cell support in these patients.

 OUTLINE: This is an open-label, multicenter study.

 -  Salvage therapy: Patients receive pixantrone IV over 1 hour on day 1; cisplatin IV over
 30 minutes on days 1-4; methylprednisolone IV over 15-30 minutes on days 1-5; and
 cytarabine IV over 2 hours on day 5. Treatment repeats every 21 days for 2 courses in
 the absence of disease progression or unacceptable toxicity.

 After 2 courses of salvage therapy, patients are re-evaluated and treated as follows:

 -  Complete response (CR) or partial response (PR): Patients with a CR or PR who are
 suitable candidates for autologous stem cell transplantation (ASCT) proceed to
 mobilization therapy, high-dose chemotherapy, and ASCT. Patients with a CR or PR who are
 unsuitable candidates for ASCT continue to receive salvage therapy for up to 6 courses
 in the absence of disease progression or unacceptable toxicity.

 -  Stable disease: Patients with stable disease continue to receive salvage therapy for up
 to 6 courses. Patients who have a CR or PR after 3-4 courses of salvage therapy and who
 are suitable candidates for ASCT proceed to mobilization therapy, high-dose
 chemotherapy, and ASCT off study at the investigator's discretion.

 -  Mobilization therapy (optional regimen; regimen used for mobilization is at the
 investigator's discretion): Patients receive rituximab* IV on days 1 and 7;
 pixantrone IV over 1 hour on day 2; cisplatin IV over 30 minutes on days 2-5;
 cytarabine IV over 2 hours on day 6; and methylprednisolone IV over 15-30 minutes
 on days 2-6. Patients also receive filgrastim (G-CSF) subcutaneously once daily
 beginning on day 7 and continuing until blood counts recover. Patients receive 1 or
 more courses of mobilization therapy during which stem cells are harvested.
 Patients then proceed to high-dose chemotherapy and subsequent re-infusion of
 harvested stem cells.

 NOTE: *If this mobilization regimen is used, patients with T-cell lymphoma do not receive
 rituximab

 -  High-dose chemotherapy and ASCT: Patients receive high-dose chemotherapy and ASCT per
 institutional standard practice.

 Patients are followed every 3 months for 2 years.

 PROJECTED ACCRUAL: A total of 75 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed aggressive non-Hodgkin's lymphoma (NHL)

 -  Any stage, with or without B symptoms

 -  The following subtypes are eligible:

 -  Diffuse large cell (B and T cell types)

 -  Anaplastic large cell

 -  Diffuse mixed cell

 -  Immunoblastic large cell

 -  Follicular large cell

 -  Transformed follicular NHL

 -  Diffuse aggressive not otherwise classified

 -  Burkitt-like lymphoma

 -  Bone marrow positive or negative

 -  At least 1 measurable lesion

 -  Patients with bone marrow as the only site of disease are eligible without a
 measurable lesion

 -  No more than 1 episode of progressive disease, occurring after a response (complete
 response [CR], complete response unconfirmed [CR_u], or partial response [PR]) to
 prior chemotherapy* NOTE: *Patients with less than a CR, CRu, or PR and no
 progression, but who are good candidates for high-dose chemotherapy with stem cell
 support may be eligible (will be decided on an individual basis)

 -  No chemotherapy-refractory disease, defined as follows:

 -  Stable or progressive disease documented at restaging immediately after the
 completion of induction therapy

 -  No lymphoblastic lymphoma, or mantle cell lymphoma

 PATIENT CHARACTERISTICS:

 Age

 -  18 and over

 Performance status

 -  WHO 0-1

 Life expectancy

 -  At least 3 months

 Hematopoietic

 -  Neutrophil count at least 1,500/mm^3*

 -  Platelet count at least 100,000/mm^3* NOTE: *Lower values may be accepted if clearly
 due to bone marrow involvement by lymphoma

 Hepatic

 -  Bilirubin no greater than 1.5 times upper limit of normal (ULN)*

 -  AST or ALT no greater than 2.0 times ULN*

 -  Alkaline phosphatase no greater than 2.0 times ULN*

 -  No history or clinical symptoms of hepatitis B or hepatitis C virus

 -  Patients with seropositivity due to prior vaccination for hepatitis B are
 eligible NOTE: *Higher values may be accepted if clearly due to liver involvement
 by lymphoma

 Renal

 -  Creatinine no greater than 1.5 mg/dL

 Cardiovascular

 -  LVEF at least 50% by MUGA

 -  No clinically significant cardiovascular abnormalities

 -  No New York Heart Association grade II-IV cardiovascular disease

 -  No myocardial infarction within the past 6 months

 -  No severe cardiac arrhythmia

 -  No uncontrolled hypertension

 Other

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception during and for 6 months after study
 participation

 -  HIV negative

 -  No clinically significant neurological abnormalities

 -  No condition that would preclude study safety or interfere with study results

 -  No concurrent serious uncontrolled infection

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Prior rituximab immediately after the first chemotherapy regimen allowed

 Chemotherapy

 -  See Disease Characteristics

 -  See Biologic therapy

 -  At least 6 months since prior anthracycline therapy (e.g., cyclophosphamide,
 doxorubicin, vincristine, and prednisone [CHOP])

 -  More than 2 years since prior fludarabine

 -  More than 2 years since prior nitrosoureas

 -  More than 1 year since prior platinum-based chemotherapy or cytarabine, unless a CR or
 CR_u was achieved

 -  No prior cumulative dose of cisplatin greater than 600 mg/m^2

 -  No prior single or cumulative dose of doxorubicin greater than 450 mg/m^2

 Endocrine therapy

 -  Not specified

 Radiotherapy

 -  No prior radiotherapy to the whole pelvis

 -  No prior radioimmunotherapy

 Surgery

 -  More than 4 weeks since prior major thoracic and/or abdominal surgery

 -  At least 1 week since prior minor surgery

 Other

 -  Recovered from prior therapy

 -  Alopecia allowed

 -  Grade 1 peripheral neuropathy allowed

 -  More than 30 days since prior participation in another investigational drug study

 -  No other concurrent investigational drugs