Phase II Trial of Single Agent Panobinostat (LBH589) In Relapsed or Relapsed/Refractory Waldenstrom Macroglobulinemia

This study aimed to determine the safety and activity of panobinostat (LBH589) in patients with relapsed or relapsed/refractory Waldenstrom Macroglobulinemia (WM). This was based on our preclinical studies showing that panobinostat induces significant activity in cell lines and patient samples.

Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any prior lines of therapy, 2) measurable disease and symptomatic disease, 3) off prior chemotherapy> 3 weeks, or biological/novel therapy for WM > 2 weeks. Patients received panobinostat at 30 mg three times a week (Mondays, Wed and Fridays). Patients were assessed after every cycle for the first 6 cycles and then every 3 months thereafter. Subjects who had response or stable disease were allowed to continue on therapy until disease progression or unacceptable toxicity. A planned restaging was performed at the end of cycle 6 including CT scans and bone marrow biopsies.

Twenty-seven patients have been enrolled to date. The median age is 62 years (47-80), the median lines of prior therapy is 3 (range, 1–7). All of the patients received prior rituximab. The median hemoglobin at screening is 10.3 g/dL (range 8.2–14.3), the median IgM M-spike by protein electropheresis at study entry is 1.9 g/dL (range, 0.63–5.1), and median serum IgM at baseline is 3610 mg/dL (range, 804- 10, 300). The median bone marrow involvement at enrollment was high for patients with WM, 50%, range (5-95%), with more than 10 patients having 70% or higher bone marrow involvement at baseline. The median number of cycles on therapy is 4 (range 1 – 12). 4 of the patients came off due to toxicity. Minimal response (MR) or better has been achieved in 15 (60%) of patients, with 6 (24%) PR, 9 (36%) MR. In addition, 9 (36%) patients achieved stable disease and 1 (4%) showed progression. The median decrease in IgM is 1020 mg/dL (0- 3970 decrease in IgM) with a median % decrease of 37.13%. Responses were prompt. The median time to first response was 2 cycles (range, 2–4). Bone marrow biopsies at the end of study (or at 6 months follow up) are available on 7 patients, of which 3 showed a significant decrease in bone marrow involvement and 4 showed stable involvement. The 4 patients who had stable bone marrow disease showed 1 PR and 3 MR responses by paraprotein level. Grade 3 and 4 toxicities include 4 (15%) cases of anemia including 1 case of hemolytic anemia, 1 (3%) case of grade 4 leucopenia (but the patient had grade 3 leucopenia at baseline), 7 (26%) of neutropenia, 14 (52%) of thrombocytopenia, 1 (4%) grade 3 GI bleed due to thrombocytopenia, 1 (3%) Grade 4 hyperglycemia and 1 (3%) grade 3 syncope and 3 (27%) grade 3 fatigue. The most common grade 2 toxicities were thrombocytopenia, anemia, and fatigue. There were 5 (20%) cases of asymptomatic pulmonary infiltrates of ground glass opacity observed on routine CT scans in follow up. Of these, 3 came off study for other reasons not related to the pulmonary infiltrates, 1 received a course of corticosteroids and had improvement of infiltrates, and 1 had dose reduction of therapy. All patients except for 2 have been dose reduced due to thrombocytopenia, fatigue, diarrhea, or anemia. Dose reductions include 25 mg three times a week, 20 mg three times a week and 20 mg three times every other week. The protocol was amended to allow a starting dose of 25 mg three times a week, which is better tolerated than 30 mg in this patient population.

Panobinostat is an active therapeutic agent in patients with relapsed or refractory WM, with an overall response rate of 60% in patients with relapsed or refractory WM. The dose schedule of 25 mg three times a week is better tolerated in this patient population. Further studies to include this agent in combination with rituximab or bortezomib are being evaluated.

Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Keryx Biopharmaceuticals: Honoraria. Treon:Millennium Pharmaceuticals, Genentech BiOncology, Biogen IDEC, Celgene, Novartis, Cephalon: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; Novartis Corporation: Research Funding; Genentech: Consultancy, Research Funding.