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

Abstract

Key Points• Panobinostat induces responses in 28% of patients with relapsed and refractory DLBCL that are typically durable off therapy.• MEF2B mutations predicted for response whereas early increase in ctDNA abundance was a strong predictor of subsequent treatment failure.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 5 27) or transformed (n 5 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). (Blood. 2016;128(2):185-194)

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

“…Beyond R-CHOP, it predicts for a poor response to intensified induction regimens, salvage chemotherapy, autologous stem cell transplant (ASCT), and the novel histone deacetylase inhibitor panobinostat. 63,68,70,71 BCL2 and MYC protein expression in DE-DLBCL may be considered a functional readout of the cumulative genomic alterations that ultimately lead to their overexpression, mainly BCR and NF-kB signaling in the ABC patients and translocations in the GCB patients. These mechanisms may be clinically relevant, given that targeting BCR signaling and BCL2 may be an effective strategy in ABC-DE-DLBCL but not in GCB-DE-DLBCL or in patients with IG translocations.…”

Multiplex Droplet Digital PCR Quantification of Recurrent Somatic Mutations in Diffuse Large B-Cell and Follicular Lymphoma

“…Overall, the correlation between our ddPCR VAF estimates and the VAF estimates obtained through targeted hybrid capture coupled with next-generation sequencing (13,34 ) Table 1), in addition to the expected results every time that we tested different assays on the same cell line DNA sample (Figs. 2 and 4).…”

“…FFPE samples were processed with the QiAamp DNA FFPE tissue kit (Qiagen). DNA samples were stored at Ϫ20°C in Tris-EDTA buffer for several months (13,34 ). Liquid biopsies were also collected within a clinical trial (n ϭ 17) testing the efficacy of the drug Panobinostat (a histone deacetylase inhibitor) (34 ) plus 4 additional plasma samples, 2 from 2 additional DLBCL patients and 2 samples collected from patients with lymphoplasmacytic lymphoma (see online Supplemental Table 1).…”

“…Liquid biopsies were also collected within a clinical trial (n ϭ 17) testing the efficacy of the drug Panobinostat (a histone deacetylase inhibitor) (34 ) plus 4 additional plasma samples, 2 from 2 additional DLBCL patients and 2 samples collected from patients with lymphoplasmacytic lymphoma (see online Supplemental Table 1). We used the QiAamp circulating DNA kit (Qiagen) to extract cfDNA from plasma (34 ). cfDNA samples were stored in AVE Buffer (Qiagen) at Ϫ20°C during several months.…”

Clinical Trials in the Genomic Era

“…55 An emerging solution is the use of deep sequencing to measure low levels of circulating tumor DNA, which have been demonstrated as good measures of response and relapse. 56,57 Alternative end points may include the ratio PFS targeted : PFS prior line (ie, a comparison of PFS generated by the study drug with that of the preceding therapy) whereby a value . 1.3 has been considered clinically meaningful.…”