Phase I Trial of Bortezomib in Combination with Rituximab-HyperCVAD/Methotrexate and Cytarabine for Untreated Mantle Cell Lymphoma

Background: Though mantle cell lymphoma (MCL) outcome has improved over the last two decades - especially with dose-intense or high-dose therapy - MCL patients still relapse particularly in >65yo. Bortezomib has shown single agent activity of 33% in relapsed MCL and has been safely combined with conventional as well as intensified doxorubicin-containing regimens, but not with high doses of the methotrexate/cytarabine combination, where there is concern about lung toxicity. Materials and methods: MCL pts from ages 18 through 79, with adequate organ function unless due to lymphoma, and without HIV-1 infection or any significant medical/mental condition were treated under IRB-approved study using R-HCVAD alternating with R-M/A (JCO October 1, 2005) with doxorubicin given by bolus. Bortezomib was added to R-HCVAD as a fixed dose of 1.3 mg/m2 IV given at the end of the first infusion of cyclophosphamide on day 2 and after doxorubicin bolus on day 5. Bortezomib was added to R-M/A after rituximab on day 1 and on day 6, in increasing doses of 0.7, 1, and 1.3 mg/m2 in cohorts of 3 patients. As an additional precaution, the first cohort of patients received a −1 dose level of the cytarabine adjusted by age. Dose limiting toxicity was defined initially as a drop of 10% from baseline in diffusing lung capacity (DLCO) and later increased to 25% (grade 1 toxicity according to National Cancer Institute criteria) after the first cycle of R-MA with bortezomib. Results: Since April 2007, sixteen patients have been entered on the trial, ages 40 to 70 years (median 58). Currently 2/3 patients have been entered in the last cohort. There has been no DLT. After 59 cycles, toxicities according to NCI criteria were as follows: BR-HCVAD Phase I Toxicity in 59 cycles | Variable | Grade1 (%) | Grade2 (%) | Grade3 (%) | Grade4 (%) | |:-------------------------------------------------------------:| ---------- | ---------- | ---------- | ---------- | | *First R-M/A cycle of each patient. 15/16 patients evaluable. | | Thrombocytopenia | 7 (12) | 3 (5) | 8 (14) | 26 (44) | | Neutropenia | 3 (5) | 5 (8) | 4 (7) | 28 (47) | | Anemia | 11 (19) | 23 (39) | 11 (19) | 2 (3) | | Neutropenic fever | | | 5 (8) | 1 (2) | | Dyspnea | | | | | | DLCO* | 2 (3) | | | | | Neurological | 5 (8) | | | | | Sensory | | 1 (2) | | | As expected, responses are excellent with 11 complete responders and 4 partial responders out of 15 evaluable patients, of whom 3 are still on treatment. Conclusion: Bortezomib can be safely combined with R-M/A. Accrual is ongoing and more patients and dose levels will be reported on at the meeting.