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      Tazemetostat in relapsed/refractory follicular lymphoma: a propensity score–matched analysis of E7438-G000-101 trial outcomes

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          Abstract

          Purpose: In the tazemetostat E7438-G000-101 trial of relapsed/refractory (R/R) follicular lymphoma (FL), apparent superior efficacy was suggested for mutant-type (MT) EZH2 versus wild-type (WT) status. However, clinical disparities might have contributed to this conclusion. This study aimed to estimate outcomes after minimizing differences in baseline characteristics.

          Methods: Propensity scores for each participant with WT ( n = 54) and MT ( n = 45) status were generated based on the likelihood of being selected given their baseline characteristics. Participants were matched using a 1:1 nearest-neighbor approach.

          Results: The propensity-matched sample included 56 participants (28 WT, 28 MT). Objective response rates (95% confidence interval [CI]) were 35% (22–48) in WT and 69% (55–83) in MT prior to matching and 50% (31–69) in WT and 71% (54–88) in MT after matching. Median progression-free survival values (95% CI) were 11.1 (5.4–16.7) in WT and 13.8 months (11.1–22.1) in MT prior to matching and 14.3 (11.1–∞]) and 14.8 months (10.7–∞]) in WT and MT matched groups, respectively.

          Conclusions: This analysis suggests that efficacy outcomes for tazemetostat observed in participants with WT EZH2 R/R FL may have been similar to those in participants with MT had the 2 cohorts been more closely matched.

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          Most cited references8

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          Genetics of follicular lymphoma transformation.

          Follicular lymphoma (FL) is an indolent disease, but 30%-40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, we show here that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and antiapoptotic genes are introduced early in the common precursor, whereas tFL is specifically associated with alterations deregulating cell-cycle progression and DNA damage responses (CDKN2A/B, MYC, and TP53) as well as aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B cell-type de novo DLBCL but also displays unique combinations of altered genes with diagnostic and therapeutic implications. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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            Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis

            Mutations in the gene encoding the KMT2D (also called MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of KMT2D mutations and their role in lymphomagenesis are unknown. Here we show that FL/DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B-cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B-cells and enhances B cell proliferation in mice. In mice overexpressing BCL2, which develop GC-derived lymphomas resembling human tumors, genetic ablation of Kmt2d leads to a further increase in tumor incidence. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may represent a rational therapeutic approach for targeting early tumorigenic events.
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              Germinal centres and B cell lymphomagenesis.

              Germinal centres (GCs) are involved in the selection of B cells secreting high-affinity antibodies and are also the origin of most human B cell lymphomas. Recent progress has been made in identifying the functionally relevant stages of the GC and the complex trafficking mechanisms of B cells within the GC. These studies have identified transcription factors and signalling pathways that regulate distinct phases of GC development. Notably, these factors and pathways are hijacked during tumorigenesis, as revealed by analyses of the genetic lesions associated with various types of B cell lymphomas. This Review focuses on recent insights into the mechanisms that regulate GC development and that are relevant for human B cell lymphomagenesis.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Impact Journals LLC
                Oncotarget
                Impact Journals LLC
                1949-2553
                2022
                11 May 2022
                : 13
                : 677-683
                Affiliations
                1Analysis Group, Inc., Menlo Park, CA 94025, USA
                2Epizyme, Inc., Cambridge, MA 02139, USA
                3Lymphoma Research Foundation, New York, NY 10005, USA
                Author notes
                Correspondence to: David G. Proudman, email : david.proudman@ 123456analysisgroup.com
                Article
                28229
                10.18632/oncotarget.28229
                9093865
                35574216
                e725a7cb-eb7a-44ba-9dbc-a0deafa819aa
                Copyright: © 2022 Proudman et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 02 February 2022
                : 26 April 2022
                Categories
                Research Paper

                Oncology & Radiotherapy
                tazemetostat,propensity score matching,wild-type ezh2,follicular lymphoma,objective response rate

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