Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma
Sarit E Assouline, Torsten Holm Nielsen, Stephen Yu, Miguel Alcaide, Lauren Chong, David MacDonald, Axel Tosikyan, Vishal Kukreti, Abbas Kezouh, Tina Petrogiannis-Haliotis, Marco Albuquerque, Daniel Fornika, Sepideh Alamouti, Remi Froment, Celia M T Greenwood, Kathleen Klein Oros, Errol Camglioglu, Ayushi Sharma, Rosa Christodoulopoulos, Caroline Rousseau, Nathalie Johnson, Michael Crump, Ryan D Morin, Koren K Mann, Sarit E Assouline, Torsten Holm Nielsen, Stephen Yu, Miguel Alcaide, Lauren Chong, David MacDonald, Axel Tosikyan, Vishal Kukreti, Abbas Kezouh, Tina Petrogiannis-Haliotis, Marco Albuquerque, Daniel Fornika, Sepideh Alamouti, Remi Froment, Celia M T Greenwood, Kathleen Klein Oros, Errol Camglioglu, Ayushi Sharma, Rosa Christodoulopoulos, Caroline Rousseau, Nathalie Johnson, Michael Crump, Ryan D Morin, Koren K Mann
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.
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Source: PubMed