Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia

Abstract

The present study aimed to determine the safety and activity of the histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia (WM). Eligibility criteria included patients with relapsed/refractory WM with any number of prior therapies. Patients received panobinostat at 30 mg 3 times a week; 12 of 36 (33%) patients were enrolled at 25 mg dose. A total of 36 patients received therapy. The median age was 62 years (range, 47-80) and the median number of prior therapies was 3 (range, 1-8). All of the patients had received prior rituximab. Minimal response (MR) or better was achieved in 47% of patients (90% confidence interval [CI], 33-62), with 22% partial remissions and 25% MR. In addition, 18 (50%) patients achieved stable disease and none showed progression while on therapy. The median time to first response was 1.8 months (range, 1.7-3.2). The median progression-free survival was 6.6 months(90% CI, 5.5-14.8). Grade 3 and 4 toxicities included thrombocytopenia (67%), neutropenia (36%), anemia (28%), leukopenia (22%), and fatigue (11%). We conclude that panobinostat is an active therapeutic agent in patients with relapsed/ refractory WM. This study (www.clinicaltrials.gov identifier: NCT00936611) establishes a role for histone deacetylase inhibitors as an active class of therapeutic agents in WM.

Figures

Figure 1

CONSORT diagram of the study design.

Figure 2

Waterfall of the maximum difference in IgM from baseline throughout the study (including follow-up; N = 36).

Figure 3

Duration of response, progression-free, and event-free survival in patients treated with panobinostat. (A) Kaplan-Meier estimation of the duration of response (MR or better) end point (n = 17). (B) Kaplan-Meier estimation of the PFS end point (n = 36): PFS was similar to TTP. (C) Kaplan-Meier estimation of the EFS end point (n = 36).

Figure 4

Correlative studies on samples obtained from patients treated with panobinostat. (A) Immunohistochemistry for CD20 and percentage BM involvement in pre- and posttreatment samples. (B) ELISA for acetylated histone 3 (H3) in PBMCs of samples before therapy in 10 patients with the clinical responses that were obtained in these patients. (C) ELISA for acetylated H3 in PBMCs of samples before and after therapy in 3 patients. Although the levels before and after therapy were not statistically different, there was a trend of increases in the level of acetylated H3 after therapy that is consistent with the activity of HDAC inhibitors.