• Toxicity as measured by physical exam every 3 weeks and laboratory tests weekly [ Designated as safety issue: Yes ]
  

OBJECTIVES:

• Determine the safety and toxicity of bortezomib and fludarabine with or without rituximab in patients with relapsed or refractory indolent non-Hodgkin's lymphoma or chronic lymphocytic leukemia.
• Determine the maximum tolerated dose of bortezomib in combination with fludarabine in these patients.
• Determine the biological effect of this regimen on apoptotic markers, cell cycle kinase inhibitors, and DNA repair in these patients.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and fludarabine IV over 30 minutes on days 1-3 or 1-5. Patients may also receive rituximab IV over 1 hour on day 1. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of chronic lymphocytic leukemia (CLL) OR indolent non-Hodgkin's lymphoma (NHL) of any of the following subtypes:

  • Follicular lymphoma

    • Grade I follicular small cleaved cell
    • Grade II follicular mixed cell
    • Grade II follicular large cell
    • Diffuse small cleaved cell
  • Small lymphocytic lymphoma
  • Lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia)
  • Extranodal marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue [MALT] lymphoma)
  • Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma)
  • Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes)

  • Mantle cell lymphoma

    • No blastic phase mantle cell lymphoma

• Relapsed or refractory, progressive disease

  • First, second, or third relapse

• Measurable disease, meeting 1 of the following criteria:

  • At least 1 unidimensionally measurable lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan (for NHL patients)
  • Lymphocytosis > 50,000/mm^3 OR evidence of progressive bone marrow infiltration failure (e.g., hemoglobin 10 g/dL) OR thrombocytopenia (i.e., platelet count < 100,000/mm^3) with > 30% infiltration of bone marrow by leukemia (for CLL patients)
  • Quantitation of IgM paraprotein (for Waldenstrom's macroglobulinemia patients)
• No measurable lymphadenopathy (for CLL and Waldenstrom's macroglobulinemia patients)
• No brain metastases
• No evidence of CNS lymphoma

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• More than 12 weeks

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 75,000/mm^3 (greater than 50,000/mm^3 if lymphomatous bone marrow involvement is present)

Hepatic

• Bilirubin no greater than 2.0 mg/dL
• AST/ALT no greater than 4 times normal

Renal

• Creatinine clearance greater than 40 mL/min

Cardiovascular

• No history of uncontrolled orthostatic hypotension
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No uncontrolled concurrent illness
• No grade 2 or greater neuropathy
• No history of allergy or anaphylaxis to mannitol, bortezomib, fludarabine, or boron
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 4 weeks since prior monoclonal antibody (MoAB) therapy

  • Patients who have received MoAB therapy within the past 3 months must have documented disease progression since receiving this therapy
• No prior allogeneic stem cell transplantation

Chemotherapy

• More than 4 weeks since prior chemotherapy
• Prior fludarabine allowed

Endocrine therapy

• At least 1 week since prior steroids

Radiotherapy

• At least 3 months since prior radioimmunotherapy
• More than 4 weeks since prior radiotherapy

Surgery

• Not specified

Other

• No prior bortezomib
• No other concurrent investigational agents or treatments for the malignancy