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EZH2 mutations at diagnosis in follicular lymphoma: a promising biomarker to guide frontline treatment.

ABSTRACT: EZH2 is mutated in nearly 25% of follicular lymphoma (FL) cases. Little is known about how EZH2 affects patients' response to therapy. In this context, the aim of this study was to retrospectively analyze the frequency of mutations in EZH2 at diagnosis in tissue and ctDNA in patients with FL and to assess the patients' outcomes after receiving immunochemotherapy, depending on the EZH2 mutation status. Among the 154 patients included in the study, 27% had mutated EZH2 (46% with high-grade and 26% with low-grade FL). Of the mutated tissue samples, the mutation in ctDNA was identified in 44% of cases. EZH2 mutation in ctDNA was not identified in any patient unmutated in the tissue.Unmutated patients who received R-CHOP had significantly more relapses than patients who received R-Bendamustine (16/49 vs. 2/23, p = 0.040). Furthermore, our results show that patients with mutated EZH2 treated with R-CHOP vs. those treated with R-Bendamustine present a lower incidence of relapse (10% vs. 42% p = 0.09 at 4 years), a higher PFS (92% vs. 40% p = 0.039 at 4 years), and higher OS (100% vs. 78% p = 0.039 at 4 years). Based on these data, RCHOP could be a more suitable regimen for mutated patients, and R-bendamustine for unmutated patients. These findings could mean the first-time identification of a useful biomarker to guide upfront therapy in FL.

SUBMITTER: Martinez-Laperche C

PROVIDER: S-EPMC9476261 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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EZH2 mutations at diagnosis in follicular lymphoma: a promising biomarker to guide frontline treatment.

Martínez-Laperche C C Sanz-Villanueva L L Díaz Crespo F J FJ Muñiz P P Martín Rojas R R Carbonell D D Chicano M M Suárez-González J J Menárguez J J Kwon M M Diez Martín J L JL Buño I I Bastos Oreiro M M

BMC cancer 20220914 1

EZH2 is mutated in nearly 25% of follicular lymphoma (FL) cases. Little is known about how EZH2 affects patients' response to therapy. In this context, the aim of this study was to retrospectively analyze the frequency of mutations in EZH2 at diagnosis in tissue and ctDNA in patients with FL and to assess the patients' outcomes after receiving immunochemotherapy, depending on the EZH2 mutation status. Among the 154 patients included in the study, 27% had mutated EZH2 (46% with high-grade and 26% ...[more]

PMID: 36104682

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Project description:BackgroundThe tumor microenvironment (TME), including infiltrating T-cells, is thought to play a major role in the pathogenesis and prognosis of follicular lymphoma (FL) and may contribute to its widely varied disease course. We hypothesized that programmed death-1 inhibition may be most effective in untreated, immunocompetent FL patients. Thus, we developed a phase 2 study to evaluate the efficacy of pembrolizumab as the initial treatment for indolent B-cell lymphoma.MethodsAdults with FL or marginal zone lymphoma and an indication for treatment were eligible. Patients received pembrolizumab 200 mg IV in 21-day cycles for up to 18 cycles, until progression or unacceptable toxicity. Early response assessment was obtained after cycle 3 with computed tomography (CT), and a fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) was obtained after cycle 6 to determine candidacy for continuation in the study. Immunosecretome profiling was performed at baseline and on cycle 2 day 1.ResultsNine patients with FL were enrolled between February 2019 and April 2021, including eight (89%) with advanced stage, seven (78%) with intermediate/high Follicular Lymphoma International Prognostic Index, and six (67%) with high-tumor burden by Groupe d'Etude des Lymphomes Folliculaires. The best overall response rate by FDG PET-CT was 33% (three partial metabolic responses). Three patients (33%) had stable disease, and three (33%) had progressive disease (including one patient who only had a follow-up CT). By CT four (44%) experienced a reduction in target lesions, but all were less than partial responses. Grade 3 or higher immune-related adverse events (IRAEs) were seen in two (22%) patients, both with transaminitis and one of whom had concurrent hypophysitis. Another patient had grade 1 pneumonitis, requiring treatment with steroids. No associations between the immunosecretome profile and clinical outcomes could be detected.ConclusionFrontline pembrolizumab for FL is associated with limited responses and a clinically significant rate of IRAEs. Alternative strategies for targeting the TME in FL should be explored.

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EZH2 mutations at diagnosis in follicular lymphoma: a promising biomarker to guide frontline treatment.

Publications

EZH2 mutations at diagnosis in follicular lymphoma: a promising biomarker to guide frontline treatment.

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