Somatic Next Generation Sequencing Panels Identify Potentially Pathogenic Germline Variants in Genes Associated with Hereditary Myeloid Malignancies

Somatic Next Generation Sequencing Panels Identify Potentially Pathogenic Germline Variants in Genes Associated with Hereditary Myeloid Malignancies

Abstracts late response. Conclusion: Our model is able to discriminate between MF patients likely to respond to treatment with a JAK2 inhibitor and th...

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Abstracts late response. Conclusion: Our model is able to discriminate between MF patients likely to respond to treatment with a JAK2 inhibitor and those for whom a change in therapy should be considered.

identified GATA2 variants are rare. The p.P41A variant was previously described as a pathogenic germline allele, whereas p.P161A has not been previously reported as a pathogenic variant in cancer. Our experience suggests the number of patients with pathogenic germline mutations in HMMS genes, including novel pathogenic variants, may increase as the utilization of NGS panels expands.

MPN-189 Somatic Next Generation Sequencing Panels Identify Potentially Pathogenic Germline Variants in Genes Associated with Hereditary Myeloid Malignancies Michael Drazer ,1 Allison West,1 Madina Sukhanova,1 Simone Feurstein,2 Matthew Jones,1 Jeremy Segal,3 Jane Churpeck,1 Lucy Godley1 1

Section of Hematology/Oncology, The University of Chicago

Comprehensive Cancer Center, and the Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, United States; 2 Klinik für Innere Medizin III, Abteilung Hämatologie und Onkologie, Universitätsklinikum, Ulm, Germany; 3Department of Pathology, The University of Chicago Comprehensive Cancer Center,The University of Chicago, Chicago, IL, United States

Background: Hereditary myeloid malignancy syndromes (HMMS) predispose to myelodysplastic syndrome, leukemias, myeloproliferative neoplasms, and bone marrow failure. Genes whose germline variants are implicated in HMMS are often included in next generation sequencing (NGS) panels designed to detect somatic mutations and guide prognostication. These panels cannot distinguish germline mutations from somatic mutations when analyzing DNA derived from leukemia cells. We hypothesized that a 53 gene NGS panel ordered for assessment of mutations in newly diagnosed hematologic malignancies could identify patients with germline mutations causative of HMMS. Methods: We reviewed NGS results for MDS/acute leukemia patients enrolled on research protocols from October 2014 through October 2015. We identified variants in HMMS genes (e.g., ETV6, GATA2, RUNX1, and TP53) meeting the following criteria: exonic non synonymous single nucleotide variant, variant allele frequency  0.40, allele frequency <1% (1000 Genomes). Single site variant sequencing was performed using germline tissue, collected after identification of an HMMS gene variant. Results: We identified nine patients with HMMS-associated gene variants. Among the six patients for whom germline tissue was available, two (33%) individuals possessed germline variants detected via NGS. Both patients had germline GATA2 variants. The first patient possessed a heterozygous germline p.P41A variant and a family history of leukemia (maternal grandmother), anemia (mother), lymphedema (brother), and recurrent viral infections (son, daughter). The second patient had a heterozygous germline p.P161A variant and a family history of lymphoma (mother, brother), and bladder/prostate/colon cancers (father). Conclusions: This study is proof-of-principle that somatic NGS panels identify candidates warranting evaluation for HMMS. In this series, a third of patients with suspected somatic mutations in HMMS genes actually possessed germline mutations. Both

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Clinical Lymphoma, Myeloma & Leukemia September 2016

MPN-198 Myelodysplastic/Myeloproliferative Neoplasms Unclassified (MDS/MPN-U) Overlap: Impact of Hypomethylating Agents? Kaitlin Hendrix , Najla Al Ali, Eric Padron, David Sallman, Alan List, Jeffrey Lancet, Rami Komrokji H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States

Introduction: The 2008 World Health Organization classification recognized a unique overlap category that combines features of MDS and myeloproliferative neoplasms. The least well characterized of the 4 overlap diseases is a rare entity known as MDS/MPN Unclassifiable (MDS/MPN-U), comprising <5% of myeloid disorders. The outcome of this subtype has been reported to be poor. The response to and impact of hypomethylating agents (HMA) on outcome is not well studied. Methods: We identified MDS/MPN-U patients among MDS database, baseline characteristics were reviewed, and responses to HMA utilizing IWG 2006 response criteria were assessed. Kaplan-Meier estimates were used to measure overall survival (OS). Results: Among 127 patients with MDS/MPN-U, 62 patients received HMA treatment. There was no difference in baseline characteristics among those who received HMA or not except that those treated with HMA were less likely to be low risk disease by IPSS, MD Anderson model or very low risk by revised IPSS (R-IPSS). The best overall response (hematological improvement (HI) or better) to HMA was 26%. Only 11 patients underwent allogeneic stem cell transplant. The median OS was 33 months (mo). Among patients with low/int-1 risk by IPSS, the median OS was 39 and 33 mo respectively for those treated with HMA and those who did not. (p 0.50). For Int-2/high risk IPSS, the median OS was 11 and 5 mo for those who received HMA and those who did not. (p 0.02). Based on R-IPSS the median OS for very low/low risk was 47 and 39 mo respectively for those treated with HMA and without (p 0.96), for intermediate risk, the median OS was 39 and 25 mo respectively (p 0.75), and for high and very high risk the median OS was 13 and 5 mo respectively for those treated with HMA and those who did not. (p < 0.005). The median OS for patients with HI+, stable disease or progressive disease was 68, 59, and 36 mo respectively (p 0.08). Conclusions: Treatment with HMA is associated with modest improvement in OS among higher risk MDS/MPN-U. There remains huge unmet need to improve outcome among this group.