Search for a command to run...
Acute myeloid leukemia (AML) is the most commonly diagnosed acute leukemia in adults. Despite newly approved treatment, AML still results in poor outcomes especially in older patients (pts). Cytogenetic abnormalities, gene mutations, and their combinations contribute to the pathogenesis and pt outcomes in AML. The PTPN11 gene encodes the phosphatase Shp2, which activates the RAS-MAPK pathway. Despite the relatively high frequency of PTPN11 mutations in AML, little is known about associations of PTPN11 mutations with other genomic features and their influence on outcomes of pts with standard 7+3 chemotherapy. In addition, primary resistance to targeted therapy, such as venetoclax and enasidenib, has been preliminarily noted in PTPN11+ pts. This study sought to determine the type and frequency of PTPN11 mutations as well as associations with clinical, cytogenetic, and genomic features and outcome in adult AML pts treated with 7+3 induction chemotherapy followed by consolidation chemotherapy on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. 1,725 newly diagnosed AML pts, defined by the European LeukemiaNet 2017 recommendations (excluding acute promyelocytic leukemia), were examined using targeted next generation sequencing analysis and centrally reviewed metaphase cytogenetics. Missense, nonsense, or frameshift variants not reported in the 1000 Genomes database, dbSNP137 or dbSNP142, were considered mutations. Fisher's exact test was used to determine mutation association and complete remission (CR) rates while continuous variables are from Wilcoxon rank sum test. The median follow-up was 9 years. We identified 140 pts (8.1%) with PTPN11 mutations with the majority (61%) located in the N-terminal SH2 domain (Figure 1). 98 younger (<60 years of age) and 42 older (≥60 years of age) pts were PTPN11+. Variant allele frequency (VAF) varied from 0.05 to 0.54, with 59 (42%) mutations having a VAF > 0.3. NPM1 (61% vs 31%, P < .001) and DNMT3A (R882 or other) mutations (39% vs 22%, P < .001) were more likely to co-occur with PTPN11 mutations than wild-type (WT) PTPN11 (Figure 2). PTPN11 mutations were less common in FLT3-ITD pts than in those without (17% vs 25%, P = .07). PTPN11 mutations were more common in inv(3)(q21q26)/t(3;3)(q21;q26) pts (26%, P = .004) and were rare in pts with core-binding factor AML, inv(16)/t(16;16) (3%, P = .03) and t(8;21) (0%, P =.005). Clinical features of PTPN11+ pts were similar to those of WT pts except for elevated platelet counts (P < .001) and more extramedullary involvement (P = .03). For all pts, there was no difference in CR rate, disease-free (DFS), overall (OS), and event-free (EFS) survival between PTPN11+ and PTPN11- pts. DFS of older PTPN11+ pts was shorter (3-y rates: 5% vs 15%, P = .04). Given that PTPN11 mutations often co-occur with NPM1 mutations, which are typically associated with favorable outcome (in the absence of a high FLT3-ITD ratio), we focused on the contribution of PTPN11 mutations to outcomes in the NPM1+/FLT3-WT subset. Compared with PTPN11-/NPM1+/FLT3-WT, PTPN11+ pts had a lower CR rate (38% vs 64%, P = .001) and shorter EFS (3-y rates: 10% vs 21%, P = .01), whereas there was no significant differences in OS (3-y rates: 23% vs 32%, P = .13) or DFS (3-y rates: 27% vs 33%, P = .75). When considering the role of PTPN11 mutations with WT NPM1, there was a reduction in survival in PTPN11+/NPM1- pts compared with PTPN11-/NPM1- pts. Younger PTPN11+/NPM1- pts had a lower CR rate (45% vs 71%, P = .002) and shorter OS (3-y rates: 30% vs 41%, P = .04), and EFS (3-y rates: 13% vs 27%, P = .008). Compared to older PTPN11-/NPM1-, older PTPN11+/NPM1- pts had a lower CR rate (18% vs 43%, P = .04) and shorter DFS (3-y rates: 0% vs 10%, P = .02) and EFS (3-y rates: 0% vs 4%, P = .02), whereas OS (3-y rates: 12% vs 10%, P = .58) had no significant difference. To our knowledge, this study is the largest cohort of PTPN11+ pts in adult AML and demonstrates specific mutational and cytogenetic associations. When considering PTPN11+ pts based on NPM1 mutation status, we showed that PTPN11 mutations associated with worse outcome in both NPM1+ and NPM1- AML pts when treated with intensive chemotherapy. Developing targeted treatments to this genomic group in AML represents a research priority. Support: U10CA180821, U10CA180882, U24CA196171, R35CA198183; https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT00048958, NCT00899223, NCT00900224 Disclosures Mims: Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. Stone:Takeda: Consultancy; Trovagene: Consultancy; Pfizer: Consultancy; Gemoab: Consultancy; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Actinium: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Arog: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Biolinerx: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Syntrix: Consultancy; Syros: Consultancy; Elevate: Consultancy; Syndax: Consultancy; Daiichi-Sankyo: Consultancy; Stemline: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy. Wang:Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy. Kolitz:Pfizer: Membership on an entity's Board of Directors or advisory committees; Magellan: Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding. Eisfeld:Vigeo Therapeutics: Consultancy; Karyopharm: Current Employment, Current equity holder in publicly-traded company. Byrd:Syndax: Research Funding; Vincera: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Acerta Pharma: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other.