• Phase I: Maximum Tolerated Dose [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
• Phase II: To determine the frequency and duration of complete and partial responses [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]

The proteasome inhibitor Bortezomib in combination with Rituximab, Cyclophosphamide and Prednisone will increase progression free survival, event free survival and overall survival of patients in with relapsed/refractory indolent B cell lymphoproliferative disorders and Mantle Cell Lymphoma (MCL).

This is a Phase I/II study to evaluate the safety and efficacy of bortezomib for patients with indolent and mantle cell lymphomas. The primary objective in Phase I is to determine the maximum tolerated dose (MTD) of bortezomib when given in combination with rituximab, cyclophosphamide, and prednisone (RCP). The primary objective in Phase II is to determine the frequency and duration of complete and partial responses in patients treated with bortezomib

• RCP (RCB or P) administered every 21 days for a total of 68 cycles.

• Follicular Lymphoma (Grade I, II, III)
• B-Cell Small Lymphocytic Lymphoma
• Chronic Lymphocytic Leukemia
• Marginal Zone Lymphoma
• Waldenstrom's Macroglobulinemia
• Mantle Cell Lymphoma

Inclusion Criteria:

• Patients must have histologically confirmed (using the WHO Classification): chronic lymphocytic leukemia/B cell small lymphocytic lymphoma, any marginal zone lymphoma, follicular lymphoma, grade I, II, III, Waldenstrom's macroglobulinemia (all in cohort 1 of the phase II portion of the study), or mantle cell lymphoma (cohort 2 of the phase II portion of the study). Patients with transformed indolent lymphomas will be enrolled on the phase I portion, but not the phase II portion of the study.
• For the phase I portion of this study, all patients must have assessable disease. For the phase II portion all NHL patients (except SLL/CLL and Waldenstrom's macroglobulinemia, discussed below) must have measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded as >2 cm with conventional techniques or as >1 cm with spiral CT scan). Lymph nodes measuring < 1 cm in the short axis are considered normal. For chronic lymphocytic leukemia, patients must have an absolute lymphocytosis > 5 x 109/L with a B cell phenotype (CD19 or CD20 co expression with CD5, CD 23 +/), with > 30% bone marrow lymphocytes. Staging will be made according to the modified Rai as outlined.
• Patients must have received at least one but no more than three prior regimens of conventional cytotoxic therapy, and must be off all cytotoxic chemotherapy for at least four weeks prior to study enrollment (6 weeks for BCNU or mitomycin C, 12 weeks with recovery to baseline counts for radioimmunotherapy). Patients are allowed to have received one course of prior radioimmunotherapy (RIT: either tositumomab or ibritumomab). Prior recipients of stem cell transplantation will be included, with the preparative cytoreductive and high dose therapies counted collectively as one prior therapy.
• Patients must not have received any therapeutic monoclonal antibodies (e.g. rituximab, tositumomab, ibritumomab alemtuzumab, etc.) within 3 months of enrollment (except for patients enrolled on the phase I portion, who may have received rituximab up to 7 days prior to enrollment). Patients who have been treated with monoclonal antibodies within 3 months may be enrolled if they show progression of disease on this therapy, as long as they have not received the treatment within 7 days of enrollment.
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of bortezomib in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric single agent trials, if applicable.

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 12 weeks or lack of recovery to baseline counts for RIT) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients who have received a therapeutic monoclonal antibody within 3 months (except those with objective evidence of PD).
• Patients may not be receiving any other investigational agents.
• Patients with known brain metastases or meningeal disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Patients who have had any major surgery within four weeks of study entry.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, cerebrovascular accident (CVA) or transient ischemic attack within 6 months of study enrollment, unstable angina pectoris, cardiac arrhythmia, EKG evidence of acute ischemia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because bortezomib is a novel agent that may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with bortezomib, breastfeeding should be discontinued if the mother is treated with this agent.