Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma

Grommes, Christian; Pastore, Alessandro; Palaskas, Nicolaos; Tang, Sarah; Campos, Carl; Schartz, Derrek; Codega, Paolo; Nichol, Donna; Clark, Owen; Hsieh, Wan-Ying; Rohle, Daniel; Rosenblum, Marc K.; Viale, Agnès; Tabar, Viviane; Brennan, Cameron; Gavrilovic, Igor T.; Kaley, Thomas; Nolan, Craig; Omuro, Antonio; Pentsova, Elena; Thomas, Alissa A.; Tsyvkin, Elina; Noy, Ariela; Palomba, M. Lia; Hamlin, Paul A.; Sauter, Craig S.; Moskowitz, Craig H.; Wolfe, J. M.; Doğan, Ahmet; Won, Minhee; Glass, Jon; Peak, Scott; Lallana, Enrico C.; Hatzoglou, Vaios; Reiner, Anne S.; Gutin, Philip H.; Huse, Jason T.; Panageas, Katherine S.; Graeber, Thomas G.; Schultz, Nikolaus; DeAngelis, Lisa M.; Mellinghoff, Ingo K.

doi:10.1158/2159-8290.cd-17-0613

Cited by 329 publications

(341 citation statements)

References 57 publications

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“…This is notable given evidence that aggressive lymphomas with both MYD88 L265P and CD79B mutations frequently have a response to ibrutinib and presumably have “chronic active” B-cell receptor signaling. 4,16,24 …”

Section: Resultsmentioning

confidence: 99%

“…MCD included cases with both MYD88 L265P and CD79B mutations, a genotype that has been associated with a response to ibrutinib in relapsed or refractory ABC DLBCL 4 and is common in primary central nervous system lymphoma, which has an ABC phenotype and which often has a response to ibrutinib. 16,24 Moreover, MCD tumors had extensive extranodal involvement and acquired mutations in genes that are recurrently mutated in primary extranodal lymphomas. Together, these observations suggest that the pathogenesis of nodal MCD DLBCL is related to that of primary extranodal lymphomas.…”

Section: Discussionmentioning

confidence: 99%

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Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Schmitz¹,

Wright

Huang³

et al. 2018

N Engl J Med

1,683

1,936

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BACKGROUND Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell–like [ABC], germinal-center B-cell–like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on “chronic active” B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.)

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Schmitz¹,

Wright

Huang³

et al. 2018

N Engl J Med

1,683

1,936

View full text Add to dashboard Cite

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“…21 PIM1, which cooperates with MYC in lym-phomagenesis, is frequently identified as a target of aberrant somatic hypermutation in PCNSL. 22 …”

Section: Molecular Pathogenesismentioning

confidence: 99%

“…Ibrutinib monotherapy was well tolerated in general at the 560 mg and 840 mg dose levels with the exception of 1 case of pulmonary aspergillosis, an infectious complication that is uncommon in CNS lymphoma patients. 22 …”

Section: The Potential Of Novel Agents In Cns Lymphomasmentioning

confidence: 99%

Biology of CNS lymphoma and the potential of novel agents

Rubenstein

2017

Hematology

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Primary and secondary CNS lymphomas are aggressive brain tumors that pose an immense challenge to define in terms of molecular pathogenesis, as well as to effectively treat. During the past 10 years improvements in survival have been achieved with the implementation of anti-CD20 immunotherapy and optimization of dose-intensive consolidation strategies. The applications of whole-exome sequencing, comparative genomic hybridization, transcriptional profiling, and examination of the tumor microenvironment, particularly in the context of clinical investigation, provide insights that create a roadmap for the development and implementation of novel targeted agents for this disease. A body of genetic evidence strongly suggested that primary CNS lymphomas (PCNSLs) are likely largely dependent on NF-κB prosurvival signals, with enrichment of mutations involving the B-cell receptor pathway, in particular myeloid differentiation primary response 88 and cluster of differentiation 79B. The first set of early-phase investigations that target NF-κB in PCNSL have now been completed and support the NF-κB hypothesis but at the same time reveal that much work needs to be done to translate these results into meaningful advances in survival for a large fraction of patients. Insights into secondary prosurvival pathways that mediate drug resistance is a priority for investigation. Similarly, further evaluation of the immune-suppressive mechanisms in the CNS lymphoma tumor microenvironment is requisite for progress. Combinatorial interventions that promote the antitumor immune response have significant potential. With increasing availability of targeted agents, there is also a need to develop more sensitive imaging tools, not only to detect this highly invasive brain neoplasm but also potentially to define an evolving molecular phenotype to facilitate precision medicine.

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“…Targeted therapy with ibrutinib (an inhibitor of Bruton's tyrosine kinase involved in the NF-kB pathway) produced an impressive response rate in the recurrent setting [15,16]. Studies are starting to evaluate this agent in newly diagnosed PCNSL and in combination with chemotherapy.…”

Section: Improving Diagnosis and Management Of Primary Brain Tumorsmentioning

confidence: 99%

Improving diagnosis and management of primary brain tumors

Delattre

2017

Current Opinion in Neurology

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Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma

Cited by 329 publications

References 57 publications

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Biology of CNS lymphoma and the potential of novel agents

Improving diagnosis and management of primary brain tumors

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