The Results of a Phase I Study using Velcade (Bortezomib), Cladribine, and Rituximab (VCR) in treating Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium size B cell lymphoma. There is no standardized treatment for this disease. The conventional chemotherapy results in a high incidence of treatment related toxicity with frequent disease relapse. Cladribine is a hypomethylating agent that indirectly downregulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Velcade (Bortezomib) is a FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this phase 1 study, we evaluated the safety and efficiency of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL.

Patients and Methods: This is a single arm, open label, investigator initiated Phase 1 study conducted at PennState Hershey Cancer Institute. This study employed a standard 3+3 dose-escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. The treatment scheme and Cladribine dose escalation levels (1, 2, and 3) are as follows: the therapy consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m² infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3-5 mg/m² (3 mg/m² for level 1, 4 mg/m² for level 2, and 5 mg/m² for level 3) infusion was given on days 1-5 for 6 cycles. If the patient's was older than 70 years old, Cladribine was only given on days 1-3 of each cycle. Velcade 1.6 mg/m2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1-3, then Day 5 and 19 during Cycles 4-6, then once per month as maintenance therapy until toxicity or progression of the disease. The primary endpoint of this study was to investigate the dose-limiting toxicity (DLT), safety, and efficiency of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression-free survival (PFS) and overall survival (OS). The analysis was done by intent to treat. This study is registered with clinicaltrials.gov (NCT01439750).

Results: No subject experienced dose limited toxicity (DLT) at either level 1 or 2, one possible DLT (infectious colitis) was observed on a subject during 2^nd cycle at level 3. Then no additional DLTs were seen in 3 subjects added to level 3. Overall, this study recruited 13 subjects, with a median age of 64 years old (range from 55 to 83), and a total of 11 male and 2 females. Ten subjects were never previously treated, while 3 either relapsed or failed previous treatments. The majority of subjects tolerated this regimen well. The patient with a history of DLT became the only mortality of this cohort 7 months later as a result of multiple organ failure. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 62% (8/13). In newly diagnosed subject cohort, the RR and OS rates were 100% (9/9), PFR was 89% (8/9), and CR rate was 78% (7/9), of which 2 patients have been followed for more than 3 years and 4 patients for more than 2 years. However, in relapsed/refractory subject cohort, 1 subject achieved CR for 7 months but then relapsed, 2 subjects had no response. There were 2 blastoid subjects, one was newly diagnosed and achieved CR.

No severe systemic toxicity was observed in this study. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint.

Correlative studies measured cyclin D1 expression levels using mononuclear cells as opposed to formalin-preserved tissue, a technique which allows for monitoring the levels over time. Although limited by a small sample size, the results indicated that the G/G (or A/A) genotype at G870A polymorphism site as well as a rapid decline of cyclin D1 and D1a during treatment may be correlated to a less aggressive disease course. Further studies are needed to explore the underlining mechanism.

Conclusions: The VCR combination is a well tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m² is a tolerable dose with manageable toxicity. A phase II trial to further evaluate the activity and toxicity of VCR regimen is warranted.