Key Takeaways from ASH 2016: Novel Genomic Evaluation of Aggressive Lymphomas

Written by: Anna Israyelyan, MD, PhD
Manager, Biopharma Solutions

Published on:
January 25th, 2017

Anna Israyelyan, MD, PhD
Dr. Israyelyan joined CGI in 2015. She has over 15 years of extensive cancer research and management experience in industry and academia covering wide range of medical areas, including basic, translational, and clinical research. Anna is an active member of the American Society of Hematology (ASH), the American Association for Cancer Research (AACR), and American Association for the Advancement of Science (AAAS). Dr. Israyelyan has a scientific advisory role with matrix management of scientific, technical, and operational aspects related to various biopharma projects and collaborations involving biomarkers in solid tumors and hematologic malignancies.

The most compelling things we learned at the American Society of Hematology (ASH) 2016 annual meeting last month were the many advances in the novel molecular characterization, evaluation, and applications for aggressive lymphomas.

At a standing room only session dedicated to diffuse large B-cell lymphoma (DLBCL), various studies outlined the new possibilities in prognosis, treatment, and clinical outcomes of DLBCL patients and orienting future clinical strategies to integrate genomic alterations of such patient tumors.

CGI’s collaboration with DLBCL expert Dr. Imran Siddiqi from Keck School of Medicine of University of Southern California resulted in a highly relevant study (“PD-L1 Expression Identifies  High Risk Diffuse Large B-Cell Lymphoma  and Is  Associated with  Several Genomic Markers) presented during this session covering novel observations that reveal the importance of expression of one of the hottest target molecules, programmed death ligand 1 (PD-L1), in DLBCL patients, as well as shed light onto additional reliable biomarkers in DLBCL.

DLBCL is an aggressive tumor, the most common form of non-Hodgkin lymphoma (NHL), accounting for about 30 percent of newly diagnosed cases of NHL in the United States. The therapeutic blockade of immune checkpoint pathways with inhibitors, in particular anti-PD-L1 antibodies, has become a paradigm-shifting treatment in various solid tumors and seems poised to shift strategies in the treatment of some hematologic malignancies as well, including DLBCL. However, there are several knowledge gaps  about the role of checkpoint blockade in DLBCL, which may be due to the relatively small number of studies, inconsistent use of PD-L1 antibodies and test interpretation methods, as well as the lack of rational and reliable biomarkers for selecting DLBCL patients to benefit from such therapies.

Our study with Dr. Siddiqi explored PD-L1 expression and molecular characteristics in a well-characterized cohort of 52 primary DLBCL patients utilizing CGI’s proprietary, comprehensive and clinically actionable next generation sequencing (NGS) panel, Focus::Lymphoma™, with 220 genes most commonly mutated in B-cell NHL, as well as five anti-PD-L1 antibodies (Abcam EPR1161, Abcam 28-8, DAKO 28-8, DAKO 22C3, and Ventana SP263 clones).

The study found  PD-L1 was expressed at high level (>30% staining) in about 25% of DLBCL cases and identified a high risk subset of DLBCL, associated with non-GCB type, inverse correlation with KMT2D mutation, enriched with mutations associated with ABC type, and predicted poor overall survival. (As an aside, the PD-L1 assays were concordant across antibodies and staining platforms). The study concluded that PD-L1 expression reflected the biology of aggressive subsets of DLBCL, which were also characterized by high risk cytogenetic and molecular biomarkers.

With immunotherapy revolutionizing current treatment strategies of cancer, promising results of the initial Phase I and Phase II trials of checkpoint inhibitors in NHL, the promise of combination therapies, including those of immuno-oncology and targeted drugs, we strongly suspect the treatment landscape of NHL will be altered in 2017.

Currently, there are 7 clinical trials studying PD-L1 inhibitors alone or in combination with other drugs in DLBCL patients.§ Through continued collaborations and research, such as the one with Dr. Siddiqi, as well as our role in supporting dozens of similar biopharma studies, CGI will continue at the forefront in the fight with this disease. Only such efforts will continue to enable and develop reliable biomarkers and companion diagnostics for selecting lymphoma patients most likely to benefit from immune-checkpoint and targeted therapy.

CGI has already developed and validated PD-L1 markers for a wide range of 15 cancer indications, including B-cell lymphomas. It’s this work that sets us apart in the CLIA-compliant commercial cancer laboratory industry. Moreover we offer the most comprehensive and clinically actionable NGS panel in precision medicine, Focus::Lymphoma™, which is being used to power several clinical trials with biotech and pharmaceutical companies, and is also available for use in a clinical setting.  It’s this work that fuels our bench to bedside mission as a company…

Biomarkers in DLBCL and the expert behind it
Dr Siddiqi with CGI West Medical Director, Dr. Nguyen at the ASH 2016 Annual Meeting

§  Based on ClinicalTrials.gov database search.

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