Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma

Abstract

The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n = 27) or transformed (n = 13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates, and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. Eleven of 40 patients (28%) responded to panobinostat (95% confidence interval [CI] 14.6-43.9) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI 9.4 to "not reached"). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response. We detected ctDNA in at least 1 plasma sample from 96% of tested patients. A significant increase in ctDNA at day 15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL, and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days after treatment initiation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT01238692).

© 2016 by The American Society of Hematology.

Figures

Figure 1

Responses and mutations affecting candidate genes detected in tumor or liquid biopsies. (A) This waterfall plot shows the magnitude of response calculated as percent change relative to baseline. *Patients who progressed early and did not have a response assessment. (B) Mutations detected using a combination of exome and targeted sequencing are shown for the HME genes and additional genes of interest (MYD88, STAT6, and FAS). Patients are shown with those demonstrating a sustained response on the right and are in the same order as those in (A). For 4 patients (indicated with an asterisk), plasma was used as the sole source of tumor DNA for mutation detection.

Figure 2

Overview of panobinostat response duration. (A) This shows the Kaplan-Meier progression-free survival (PFS) curve for all patients on the trial (solid line) contrasted with responders (dashed line) (N = 40 patients). (B) This plot shows treatment duration (red bar) and PFS (blue bar) or each patient. +, ongoing response at last follow-up.

Figure 3

Correlating treatment response with ctDNA fluctuations. Shown are the ctDNA levels in all patients with detectable ctDNA in at least 1 of 2 samples collected at day 0 (entry to trial) and day 15. Patients for whom the changes in ctDNA levels did not attain statistical significance between days 0 and 15 are marked with an asterisk (*). (A-B) ctDNA levels in patients who had responded to panobinostat at the first clinical assessment. Although not all differences achieved statistical significance (eg, patient 13), there was a consistent trend toward reduced ctDNA. (C-D) ctDNA levels for patients who did not respond to the drug, with patients showing a concordant trend of increasing ctDNA in (C), and those who did not in (D). §Patients showed initial response at the first assessment but were not considered responders as per the study protocol (<6 months CR or PR). Patient 39 had progressive disease for the duration of the trial.

Figure 4

Correlating treatment response with ctDNA fluctuations. Shown are Kaplan-Meier survival curves comparing the outcome of patients with significant increases in ctDNA between day 0 and day 15 (red) to those with significant decreases (black). (A) PFS for patients with increased ctDNA was significantly shorter (P = .0049, log-rank test) with a hazard ratio of 1.73 (95% CI 1.49-21.2). (B) OS was also significantly shorter for patients with increases in ctDNA (P = .00117, log-rank test) with a hazard ratio of 16.52 for progression (95% CI 1.89-144.3).