Final Results of the Phase II Trial of Single Agent Panobinostat (LBH589) in Relapsed or Relapsed/Refractory Waldenstrom Macroglobulinemia
Authors: Ghobrial Irene M. , Banwait Ranjit , Poon Tiffany , Campigotto Federico , Boswell Erica N , Chuma Stacey , Kunsman Janet , Donovan Amanda , Bagshaw Meghan , Warren Diane , Anderson Kenneth C. , Richardson Paul G. , Weller Edie , Murphy Timothy J. , Matous Jeffrey 
Published: October 2019

Abstract
Abstract 2706

INTRODUCTION:
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. METHODS: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, 2) measurable disease and symptomatic disease, 3) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. Patients received panobinostat initially at 30 mg three times a week (Mondays, Wednesdays 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. RESULTS: Thirty eight patients have been enrolled on this study from August 2009 to March 2011. Two patients withdrew prior to receiving treatment. Out of the 36 patients that received treatment, 35 patients were evaluable for response. The median age is 62 years (range, 47–67) and the median lines of prior therapy is 2 (range, 1–7). All of the patients had received prior rituximab. The median hemoglobin at screening is 10.7 g/dL, the median IgM M spike by protein electropheresis at study entry is 1.96 g/dL (range, 0.63–5.1), and median serum IgM at baseline is 3610 mg/dL (range, 804–10, 300mg/dL). The median bone marrow involvement at enrollment was high for patients with WM 48% (range, 5–95%), with 14 patients having 70% or higher bone marrow involvement at baseline. The median number of cycles on therapy is 3 (range, 1–12). Minimal response (MR) or better has been achieved in 49% of patients (17/35), with 6/35 PR and 11/35 MR. In addition, 16/35 (46%) patients achieved stable disease and 2/35 (6%) showed progression within the first 60 days of therapy. The median decrease in IgM is 760 mg/dL (range, 0–3970mg/dL decrease in IgM), which is a median decrease in IgM of 32% (range, 0–79%). The median time to first response was 2 cycles (range, 2–4). At 6 months on therapy, bone marrow biopsies are available on 9 patients, of which 5 show a significant decrease in bone marrow involvement, 3 are stable, and 1 show increase in bone marrow involvement. Of the 8 patients showing a decrease or stable bone marrow involvement from baseline, 4 are in PR and 4 are in MR by IgM level. Grade 3 and 4 toxicities include anemia (22%) including 1 case of hemolytic anemia, leukopenia (11%), neutropenia (33%), thrombocytopenia (61%), hypophosphatemia (3%), fatigue (11%), nausea (3%), 1 grade 3 GI bleed, and 2 grade 3 syncope. The most common grade 2 toxicities were anemia, leukopenia, neutropenia, fatigue and GI symptoms. There were 4 cases of asymptomatic pulmonary infiltrates of ground glass opacity observed on routine CT scans in follow up consistent with idiopathic pneumonia/pneumonitis. Of these, 4 came off study and 1 received corticosteroids while on therapy and had improvement in the infiltrates on further follow up. Subsequently, the protocol was amended to allow a starting dose of 25 mg, which proved to be better tolerated than 30 mg in this patient population with less fatigue and cytopenias;14/36 (39%) patients were enrolled on the 25 mg dose. CONCLUSIONS: Panobinostat is an active therapeutic agent in patients with relapsed or refractory WM, with an overall response rate of 49% in patients showing MR or better, and a clinical benefit rate of 95% of stable disease or better. The drug was generally well tolerated but the observation of pulomanary toxicity in some patients warrants further evaluation. The dose schedule of 25 mg three times a week is better tolerated than 30 mg dosing in this patient population. Further studies to include this agent in combination with rituximab and/or bortezomib warrant further evaluation.

Disclosures:
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, Research Funding; Noxxon: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: panobinostat in WM. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Matous:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Cephalon: Speakers Bureau.