Phase 2 Study of Three Doses of Single Agent Bortezomib in Patients with Fludarabine-Refractory B-Cell CLL.

Bortezomib (formerly PS-341, VELCADE®) is a selective inhibitor of the ubiquitin-proteasome pathway, which plays an important role in degrading regulatory proteins that control cell cycle functions, neoplastic growth and tumor spread. It has been approved by the FDA for the treatment of relapsed and refractory myeloma patients (pts). Phase I and II trials have suggested activity in B-cell indolent and aggressive lymphomas including mantle cell lymphoma. Preclinical studies have also shown that B-CLL cells undergo apoptotic cell death following inhibition of the proteasome pathway. We therefore conducted a multicenter phase II study to assess the safety and efficacy of 3 doses of bortezomib in pts with B cell CLL who were refractory to or intolerant to fludarabine. Pts with an ANC ≥ 1 x 10⁹/L and platelets ≥ 30 x 10⁹/L were eligible. Bortezomib was given as i.v. push on days 1, 4, 8, and 11 of a 21 day course for a maximum of 9 courses. Pts were initially randomized to 1.0 (n=5) versus 1.3mg/m²/dose (n=9) and later, after review of preliminary data, to 1.3 versus 1.5mg/m²/dose (n=8). Twenty-two pts were enrolled. Median age 62 yrs (range 46-83). Median number of prior therapies 4 (2–11). Median number of yrs from diagnosis to therapy 5.5 (0.8–14.2). b2-microglobulin > 5.5 mg/L in 10 pts (45%). Fifteen pts (68%) had ≥ Rai stage 3. Of 19 evaluable pts no responses according to NCIWG criteria were demonstrated [stable disease 8 pts (42%), progressive disease 11 pts (58%)] based on investigator assessment. When analyzed by specific sites of disease, five pts (23%) experienced ≥ 50% decrease in ALC and 6 pts (27%) showed ≥ 50% decrease in lymphadenopathy. Bortezomib was well tolerated throughout all 3 dosing groups. Most common toxicities were ≤ grade 2 and included nausea (n=9;42%), headache (6;27%), diarrhea (5;23%), vomiting (5;23%), dyspnea (5;23%), anorexia (5;23%), and peripheral neuropathy (3;14%/ grade 3 in 1 pt). Pharmacodynamic evaluation of 20S proteasome inhibition at 1 hour postdose was similar to that reported for these doses in other studies, and was highest in the 1.5mg/m² dosing group. We conclude that bortezomib as single agent is not effective in pts with fludarabine-refractory B-cell CLL at these doses. However, in view of the evidence of clinical activity, further exploration of bortezomib in combination with other agents might be the appropriate next step to define the optimal role of this new agent in the management of advanced CLL.