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).

journal_name

Blood

journal_title

Blood

authors

Assouline SE,Nielsen TH,Yu S,Alcaide M,Chong L,MacDonald D,Tosikyan A,Kukreti V,Kezouh A,Petrogiannis-Haliotis T,Albuquerque M,Fornika D,Alamouti S,Froment R,Greenwood CM,Oros KK,Camglioglu E,Sharma A,Christodoulopoul

doi

10.1182/blood-2016-02-699520

subject

Has Abstract

pub_date

2016-07-14 00:00:00

pages

185-94

issue

2

eissn

0006-4971

issn

1528-0020

pii

blood-2016-02-699520

journal_volume

128

pub_type

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