Abstract
Background: The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. Methods: We describe 235 patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. Results: Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), acute myeloid leukemia (11%), myeloproliferative neoplasm (9.2%), acute lymphoblastic leukemia (8.8%), and multiple myeloma (7.5%). Most patients (N = 197/227 (87%)) harbored ≥1 genomic alteration(s); 170/227 (75%), ≥1 potentially actionable alteration(s) targetable by an FDA-approved (mostly off-label) or an investigational agent. Altogether, 546 distinct alterations were seen, most commonly involving TP53 (10.8%), TET2 (4.6%), and DNMT3A (4.2%). The median tumor mutational burden (TMB) was low (1.7 alterations/megabase); 12% of patients had intermediate or high TMB (higher TMB correlates with favorable response to anti-PD1/PDL1 inhibition in solid tumors). In conclusion, 96.5% of patients with hematologic malignancies have adequate tissue for comprehensive genomic profiling. Most patients had unique molecular signatures, and 75% had alterations that may be pharmacologically tractable with gene- or immune-targeted agents.
Highlights
Recent advances in generation sequencing (NGS) have allowed for unprecedented insights into the genomic alterations that underlie oncogenesis, tumor biology, and survival
In contrast to solid tumors, with few exceptions, the clinical utility of Comprehensive Genomic Profiling (CGP) for therapeutic decision-making for hematological malignancies has been limited and genomic information has largely been confined to diagnosis, classification, and prognostication
Master precision medicine studies matching patients to diverse cognate agents based on CGP are being widely performed across solid tumors [2,3] but are in nascent stages in the hematologic field
Summary
Recent advances in generation sequencing (NGS) have allowed for unprecedented insights into the genomic alterations that underlie oncogenesis, tumor biology, and survival. Cumulative gains in understanding of cancer genomics and immuno-oncology are being rapidly translated into clinical practice, for metastatic solid tumors, shifting the treatment paradigm from cytotoxic chemotherapy to a biologically informed approach where oncogenic alterations are matched with targeted agents [2,3]. The drug-target pairing that aligns a deranged molecular pathway with a cognate therapeutic agent constitutes the hallmark of precision medicine, and has demonstrated superior response rates as compared to nonselective chemotherapy in tumors such as melanoma, lung cancer, and chronic myelogenous leukemia [4,5]. Incorporating generation sequencing (NGS) of hematologic malignancies into clinical management remains limited.
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