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

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.