Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

Hodkinson, Brendan P.; Schäffer, Michael; Brody, Joshua; Jurczak, Wojciech; Carpio, Cecilia; Ben‐Yehuda, Dina; Avivi, Irit; Forslund, Ann; Özcan, Muhıt; Alvarez, John; Ceulemans, Rob; Fourneau, Nele; Younes, Anas; Balasubramanian, Sriram

doi:10.1016/j.tranon.2020.100977

Cited by 16 publications

(8 citation statements)

References 64 publications

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“…Recently, Hodkinson et al 57 reported biomarker analyses using tissue biopsies collected in the LYM1002 trial. 11 A direct comparison between these data and our ctDNA analysis results was not feasible due to different collection time points.…”

Section: Discussionmentioning

confidence: 99%

Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab

et al. 2021

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To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Utilizing the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib plus nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3 day 1. Overall, 172 ctDNA samples from 67 patients were analyzed using LyV4.0 ctDNA CAncer Personalized Profiling by deep Sequencing assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved by 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired C481S BTK mutations implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.

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Section: Discussionmentioning

confidence: 99%

Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab

et al. 2021

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“…48 Of note, LRP1B mutations correlated with favorable response to immune checkpoint inhibitors across diverse cancer types including DLBCL. 55,56 Despite that LRP1B belongs to established tumor suppressors, its precise role in the biology of MCL (and other lymphomas), and its potential application as a prognostic or predictive factor remain to be elucidated in larger patient cohorts and functional translational studies. Mutations of KMT2D found frequently at diagnosis and newly in two patients at relapse (in total 8 out of 25 patients at relapse, 32%) are known to correlate with adverse prognosis in MCL.…”

Section: Discussionmentioning

confidence: 99%

Sequencing‐based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy

Karolová,

Kazantsev,

Svatoň

et al. 2023

American J Hematol

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Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole‐exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.

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“…It was described, for example, that melanoma responders to antiPD-1 therapy had significantly increased numbers of CD69 + NK cells [ 55 ]. Another study reported that CRTAM was the most upregulated gene in responders to immunotherapy with diffuse large B-cell lymphoma [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential Implications in Response to Immunotherapy

Ramos-Paradas

Gómez-Sánchez

Rosado

et al. 2022

JCM

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Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent histology. While immunotherapy with checkpoint inhibitors has shown outstanding results in NSCLC, the precise identification of responders remains a major challenge. Most studies attempting to overcome this handicap have focused on adenocarcinomas or squamous cell carcinomas. Among NSCLC subtypes, the molecular and immune characteristics of lung large cell carcinoma (LCC), which represents 10% of NSCLC cases, are not well defined. We hypothesized that specific molecular aberrations may impact the immune microenvironment in LCC and, consequently, the response to immunotherapy. To that end, it is particularly relevant to thoroughly describe the molecular genotype–immunophenotype association in LCC–to identify robust predictive biomarkers and improve potential benefits from immunotherapy. We established a cohort of 18 early-stage, clinically annotated, LCC cases. Their molecular and immune features were comprehensively characterized by genomic and immune-targeted sequencing panels along with immunohistochemistry of immune cell populations. Unbiased clustering defined two novel subgroups of LCC. Pro-immunogenic tumors accumulated certain molecular alterations, showed higher immune infiltration and upregulated genes involved in potentiating immune responses when compared to pro-tumorigenic samples, which favored tumoral progression. This classification identified a set of biomarkers that could potentially predict response to immunotherapy. These results could improve patient selection and expand potential benefits from immunotherapy.

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Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

Cited by 16 publications

References 64 publications

Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab

Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab

Sequencing‐based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy

Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential Implications in Response to Immunotherapy

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