A phase I trial of PS-341 and fludarabine for relapsed and refractory indolent non-Hodgkin’s lymphoma and chronic lymphocytic leukemia

7580 Background: The safety and efficacy of PS-341 (bortezomib) as a single agent in relapsed and refractory hematologic malignancies has been well documented. Fludarabine is known to be active in indolent non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). PS-341 may potentiate fludarabine activity by inhibiting DNA repair and inducing apoptosis in Bcl-2 over-expressing cells. The safety of this combination was evaluated in an ongoing phase I study. An additional dose level including rituxumab has been added to potentially improve efficacy without significant additional toxicity. Methods: Dose levels were as outlined in the table below. Each cycle was 21 days. Results: To date, 13 patients have received at least one cycle of treatment and are evaluable for toxicity. Diagnoses of patients included CLL, Waldenstom’s macroglobulinemia and MALT, lymphoplasmacytoid, mantle cell and follicular lymphomas. Patients received a median of 3 prior treatments (range 1–6). DLT’s were not observed in the first 4 dose levels, however the first patient on dose level 5 experienced grade 4 neutropenia. Three patients had doses of PS-341 held due to toxicity (2 due to neuropathy and one leukopenia; doses were held during cycles 3, 4 and 2 respectively) and two required dose reductions for grade 2 neuropathy (on cycles 2 and 3). One CRu has been documented (follicular lymphoma), 1 PR (mantle cell) and 6 patients with SD for 1.5 to 3 months. One patient was taken off the study with disease progression after 1 cycle (CLL) and two discontinued treatment due to prolonged cytopenias (MCL) and patient decision. The most 2 most recent patients are not yet evaluable for response. Conclusions: Combination PS-341 and fludarabine appears to be well-tolerated and active in relapsed and refractory NHL and CLL. Enrollment and follow-up of patients on level 5 (addition of rituxan) continues. Initiation of a phase II study of this regimen is anticipated shortly. [Table: see text] No significant financial relationships to disclose.