Phase II Trial of Bortezomib in Mantle Cell Lymphoma.

We report the results of a phase II trial of an investigational new drug bortezomib (PS-341, Velcade) for the treatment of mantle cell lymphoma. Advanced stage previously untreated patients or those given up to two prior chemotherapy regimens were eligible. Additional entry criteria included measurable nodal disease, minimum laboratory requirements, and written informed consent. Central pathology review, to confirm eligibility and the presence of cyclin D1, was required after study entry. Accrual was closed July 2004 having reached the preplanned target of 30 patients. Bortezomib 1.3 mg/m² IV bolus was given days 1, 4, 8 and 11 in 3-week cycles. Patients were assessed by CT scanning after every two cycles of therapy and response assessed according to International Working Group recommendations (Cheson B, J Clin Oncol 1999). Non progressors were to receive a maximum of 4 cycles. Responding patients were to receive bortezomib for 2 cycles following documentation of maximal partial response (PR) or complete response (CR). To date demographic data are available on 26 patients. The median age was 67 (48–78 yrs), all had stage 3 or 4 disease (55% bone marrow involvement), 7 were female and 10 had received no prior chemotherapy. A median of 4 treatment cycles has been given (range 1–7) and 25 patients are evaluable for toxicity. Grade ≥ 2 adverse effects thought to be related to study drug occurred as follows: anorexia 8%, nausea 16%, vomiting 4%, diarrhea 20%, fatigue 60%, dizziness 4%, sensory neuropathy 12%, edema 8%, hypotension 4%, vascular leak syndrome 4%, arthralgia 12%, myalgia 12%, neuropathic pain 12%, dyspnea 12%, rash 12%. Nine patients discontinued therapy because of toxic effects (6 of whom had neuropathy or myalgia). During accrual of the first 14 patients, 5 serious adverse events occurred in patients with pre-existing edema, dyspnea, and/or effusion. Therefore, the eligibility criteria were amended to exclude such patients thereafter and no further serious adverse events have occurred. To date, 24 patients are evaluable for response. Of the 10 patients having no prior chemotherapy there were 3 PR (range 2.5–14.8m) 6 SD (1.3–13.6m) and 1 PD for a response of 30%. Of the 14 previously treated patients we obtained 1 CRu (14.1m), 4 PR (2.4–13.1m), 7 SD (1.2–14.3m) and 2 PD. The overall response rate is 33% (95% C.I. 16–55%) but interestingly it is similar in both previously untreated and treated groups. We conclude that bortezomib is an active agent in mantle cell lymphoma, but at this dose and schedule complete remission is rare. Since higher doses will not be possible given the frequency of neuropathy and myalgia, alternative schedules or novel combinations with other active agents will be of interest to pursue.