Bortezomib After Combination Chemotherapy, Rituximab, and an Autologous Stem Cell Transplant in Treating Patients With Mantle Cell Lymphoma

Objectives

Primary Objective:

To determine the 18-month progression-free survival (PFS) in patients with previously
untreated mantle cell lymphoma who are treated with aggressive chemo-immunotherapy and
autologous stem cell transplant followed by randomization to either maintenance or
consolidation bortezomib therapy

Secondary Objectives:

- To determine the toxicity profiles of maintenance and consolidation bortezomib by
evaluating the number of patients able to complete all maintenance or consolidation
therapy

- To determine the complete response rate to intensive chemo-immunotherapy plus
maintenance or consolidation bortezomib

- To determine time to progression and overall survival using these two treatment regimens

Correlative/Other Pre-Specified Objectives:

- To determine the importance of p53 mutation or deletion on patient outcome with respect
to CR rate, PFS, and OS

- To determine the importance of Ki67, cyclin D1, phosphohistone 3, p27, p21, p16, and
PARP p85 expression in pre-treatment tumor biopsies with respect to CR rate, PFS, and OS

- To determine the relationship between proliferation signature and clinical outcome using
quantitative real-time RT-PCR

- To evaluate the importance of quantitative cyclin D1 expression and expression of cyclin
D1 isoforms in predicting clinical outcome using quantitative real-time RT-PCR

- To evaluate the prognostic significance of microRNAs in mantle cell lymphoma using
microRNA arras

- To explore the correlation of selected microRNA polymorphisms with gene target
expression with clinical outcomes such as response, PFS, and OS

- To determine changes in gene expression profile from diagnosis to relapse samples to
identify genes differentially silenced or over-expressed with disease recurrence

- To determine the importance of early PCR negativity (following Treatment 2) using
bcl-1/IgH junction and/or IgH chain gene rearrangement with respect to maintained PFS
and the success of maintenance or consolidation therapy to converting patients to PCR
negative status

OUTLINE OF INTERVENTIONS:

CHEMOIMMUNOTHERAPY: Patients receive chemoimmunotherapy comprising rituximab* intravenously
(IV) over 4-6 hours on day 1, methotrexate (MTX) IV over 4 hours on day 2, cyclophosphamide
IV over 2 hours, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3, and
prednisone orally (PO) on days 3-7. Beginning 24 hours after completion of MTX, patients
receive leucovorin calcium IV every 6 hours until blood levels of MTX are in a safe range.
Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily (QD) beginning on day
3 and continuing until blood counts recover. Beginning no sooner than day 22, but no later
that day 29 of the first course, patients receive a second course of chemoimmunotherapy as
above. Patients with > 15% persistent bone marrow involvement may receive a third course of
chemoimmunotherapy. Patients are restaged and those with progressive disease are removed from
therapy.

NOTE: *During the first course of chemoimmunotherapy, patients receive rituximab only if the
number of circulating mantle cells is =< 10,000/mm^3, otherwise, rituximab is omitted during
the first course of chemoimmunotherapy.

HIGH-DOSE CONSOLIDATION CHEMOIMMUNOTHERAPY AND PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION:
Approximately 4 weeks after completion of chemoimmunotherapy, patients receive high-dose
consolidation chemoimmunotherapy comprising cytarabine IV over 2 hours and etoposide
phosphate IV continuously on days 1-4, and rituximab IV over 4-6 hours on days 5 and 12 OR 6
and 13. Beginning on day 14 and continuing until completion of PBSC collection, patients
receive G-CSF SC QD. Once blood counts recover, patients undergo 1-3 leukapheresis procedures
for collection of PBSCs on days 22-25.

HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS PBSC TRANSPLANTATION (PBSCT): Beginning 4-6 weeks after
completion of leukapheresis, patients receive carmustine IV over 2 hours on day -6, etoposide
phosphate IV over 4 hours on day -4, and cyclophosphamide IV over 2 hours on day -2. Patients
undergo autologous PBSCT on day 0. Patients also receive G-CSF SC QD beginning on day 4 and
continuing until blood counts recover.

POST-TRANSPLANTATION IMMUNOTHERAPY: Approximately 5 weeks after autologous PBSCT, patients
receive rituximab IV over 4-6 hours once weekly for 2 weeks. Approximately 4 weeks after
completion of post-transplantation immunotherapy, patients proceed to maintenance therapy or
consolidation therapy with bortezomib as described in the Arms section.

After completion of study treatment, patients are followed every 2 months for 2 years, every
6 months for 3 years, and then annually for 5 years.

1. Documentation of Disease

A. Histologic Documentation:

- Histologically documented mantle cell lymphoma with co-expression of CD20 (or
CD19) and CD5 and lack of CD23 expression by immunophenotyping AND at least one
of the following confirmatory tests:

- positive immunostaining for cyclin D1; OR

- the presence of t(11;14) on cytogenetic analysis; OR

- molecular evidence of bcl-1/IgH rearrangement.

- Cases that are CD5-negative and/or CD23-positive will be eligible provided that
the histopathology is consistent with mantle cell lymphoma AND positive for
cyclin D1, t(11;14), or bcl-1/IgH rearrangement.A tissue block should be
submitted to the CALGB Pathology Coordinating Office for central pathology
review.

- A diagnosis based on peripheral blood or bone marrow is allowed. If the diagnosis
is based only on blood, in addition to the immunophenotype and molecular
confirmation above, a peripheral blood smear must be available for central
pathology review. If the diagnosis is based on a bone marrow biopsy, the tissue
block should be submitted.

- Note: Failure to submit pathology materials within 60 days of patient
registration will be considered a major protocol violation.

B. Extent of Disease:

- Stage I-IV. Patients with nodular histology mantle cell lymphoma must have Ann
Arbor stage III or IV disease to be eligible. Patients with mantle zone histology
will not be eligible because of their relatively favorable prognosis. Patients
with other mantle cell histologies are eligible regardless of stage.

- No active CNS disease defined as symptomatic meningeal lymphoma or known CNS
parenchymal lymphoma. A lumbar puncture demonstrating mantle cell lymphoma at the
time of registration to this study is not an exclusion for study enrollment.

2. Prior Treatment:

A. Patients must be previously untreated or have received no more than one prior cycle
of chemotherapy and/or rituximab treatment.

B. No prior radiation therapy for mantle cell lymphoma.

C. ≥ 2 weeks since major surgery.

D. ≥ 3 weeks since prior chemotherapy.

3. Age Eligibility: Age ≥ 18 years and < 70 years

4. Murine Products Hypersensitivity Eligibility: No known hypersensitivity to murine
products.

5. Use of Systemic Corticosteroids Eligibility: No medical condition requiring chronic
use of systemic corticosteroids.

6. Eligibility Criteria on HIV Infection: No HIV infection. Patients with a history of
intravenous drug abuse or any behavior associated with an increased risk of HIV
infection should be tested for exposure to the HIV virus. Patients who test positive
or who are known to be infected are not eligible due to an increased risk of infection
with this regimen. An HIV test is not required for entry on this protocol, but is
required if the patient is perceived to be at risk.

7. Non-pregnant and non-nursing: Non-pregnant and non-nursing. Treatment under this
protocol would expose an unborn child to significant risks. Women and men of
reproductive potential should agree to use an effective means of birth control.

8. HepBSAg or HepC Ab Eligibility: Patients who test positive for HepBSAg or HepC Ab are
eligible provided all of the following criteria are met:

A. bilirubin ≤ 2 x upper limit of normal; AND

B. AST ≤ 3 x upper limit of normal; AND

C. liver biopsy demonstrates ≤ grade 2 fibrosis and no cirrhosis.

Hepatitis B surface Ag(+) patients will be treated with lamivudine (3TC) throughout
protocol therapy and for 6-12 months thereafter.

9. Secondary Malignancy Eligibility: Patients with a "currently active" second
malignancy, other than non-melanoma skin cancers are not eligible. This includes
Waldenstrom's Macroglobulinemia, since such patents have experienced transient
increases in IgM following initiation of rituximab, with the potential for
hyperviscosity syndrome requiring plasmapheresis. Patients are not considered to have
a "currently active" malignancy if they have completed anti-cancer therapy, and are
considered by their physician to be at less than 30% risk of relapse.

10. Initial Required Laboratory Values:

- LVEF by MUGA or ECHO ≥ 45%

- Creatinine ≤ 2.0 mg/dL

- Total Bilirubin ≤ 2.0 mg/dL (Unless attributable to Gilbert's Disease)

- u-HCG or serum HCG Negative (If patient of childbearing potential).