Abstract
Introduction: Hypomethylating agent with venetoclax (HMA-VEN) is standard therapy for older/unfit pts with newly diagnosed (ND) AML. We reported factors conferring resistance to VEN-based lower-intensity therapy including FLT3, RAS, TP53 mutations (DiNardo. Blood 2020). However, data on evolution of genomic landscape after HMA-VEN therapy are limited. We report the evolution of mutations in the largest series of pts relapsing after HMA-VEN as assessed by targeted sequencing.
Methods: Pts received decitabine 20 mg/m 2 on D1-10 until CR/CRi, followed by 5-day cycles. VEN dose was 400 mg/d (NCT03404193; DiNardo. Lancet Haematol 2020). FLT3 inhibitors used in 5 pts included sorafenib (3) and gilteritinib (2). Pts could proceed to stem cell transplantation (SCT) after response, if eligible. Next-generation sequencing (NGS) targeting entire coding regions of 81 myeloid genes was performed on screening and progression BM samples. Analytical sensitivity was established at 5%. Pts with ND AML and NGS panel available at baseline and relapse were included in the analysis.
Results: Out of 103 ND pts, we selected 41 pts with available NGS treated between February 2018 - March 2020 (Table 1). 31 pts (76%) relapsed after initial response including CR (19), CRi (9), and MLFS (3), and 10 pts (24%) had no response. Pts received a median of 3 cycles (range 1-11). 29 pts (71%) discontinued therapy due to AML progression / death. 7 pts (14%) stopped HMA-VEN for SCT and relapsed later. 4 pts relapsed after being off therapy and 1 pt relapsed while off VEN. Median duration of response was 6.7 mo (range 0.9-23.5). 14 pts had early relapse by <6 mo, 12 pts relapsed between 6-12 mo, and 5 pts had late relapse at >12 mo.
Median no. of mutations at baseline in refractory pts was 3 (range 1-9), in relapsing pts was 3 (range 1-10), and at time of relapse was 4 (range 0-10; Fig 1). At relapse, pts gained a median of 1 new mutation (range 0-3), lost a median of 1 mutation (range 0-6), and had a median of 1 persistent mutation (range 0-6). Most frequent new mutations gained at relapse occurred in genes involved in activated signaling in 29% pts (n=9), DNA methylation in 23% (n=7), tumor suppression in 23% (n=7), epigenetic modification in 10% (n=3), transcription factors in 6% (n=2), cohesion complex in 3% (n=1), and SH2B3 and BRINP3 in 1 pt each (Fig 1A). Subclonal JAK1 and BRAF were unique activated signaling mutations gained compared to ones lost.
Most frequently cleared mutations at the time of relapse included genes involved in activated signaling in 39% (n=12), DNA methylation 26% (n=8), epigenetic modification in 13% (n=4), NPM1 in 6% (n=2), cohesion complex in 6% (n=2), ubiquitin complex in 3% (n=1), RNA splicing in 3% (n=1), tumors suppression in 3% (n=1), and transcription factors in 3% (n=1, Fig 1B). Most frequent mutations persisting at time of relapse included genes involved in DNA methylation in 42% (n=13), tumor suppression in 42% pts (n=13), RNA splicing in 35% (n=11), activated signaling in 19% (n=6), epigenetic modification in 16% (n=5), NPM1 in 16% (n=5), transcription factors in 13% (n=4), and cohesion complex and BRINP3 in 1 pt each (Fig 1C).
Among pts suffering early relapse (<6 mo), most frequent new mutations were noted in DNA methylation pathway in 50% pts (n=7/14) and most frequently persisting mutations were in TP53 in 64% (n=9/14). Among pts with intermediate duration of response (6-12 mo), most frequent new mutations occurred in activating signaling genes in 33% pts (n=4/12), tumor suppressors in 25% (n=3/12), and most frequently persistent mutations were noted in DNA methylation pathway in 58% (n=7/12). In 5 pts with late relapse (>12 mo), all pts lost activating signaling mutations and had relative paucity of new emergent mutations among these 81 genes. Only 1 pt gained a new mutation in SH2B3, 1 pt had same persistent TP53 P278A at relapse post-SCT, and 2 pts had DNA methylation pathway mutations in DNMT3A and TET2, respectively.
In contrast, most frequent mutations noted in refractory pts were TP53 in 60% pts (n=6), activating signaling genes in 50% (n=5) including JAK2 and MPL, RNA splicing in 40% (n=4), and ASXL1 in 30% (n=3).
Conclusion: Emergence of new mutations in epigenetic modifiers, transcription factors, and cohesion complex can contribute to relapsed in AML after HMA-VEN. Persistent mutations in DNA methylation genes and tumor suppressors are common at relapse. Mutations in TP53, RAS pathway, JAK2 and MPL are frequent in refractory pts.
DiNardo: AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Amgen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; FATE Therapeutics: Research Funding; ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Hanmi: Research Funding; Trovagene: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kadia: Novartis: Consultancy; Cure: Speakers Bureau; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; Aglos: Consultancy; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Pfizer: Consultancy, Other; Amgen: Other: Grant/research support; Jazz: Consultancy; Liberum: Consultancy; BMS: Other: Grant/research support; AstraZeneca: Other; Cellonkos: Other; Astellas: Other; Genfleet: Other; Ascentage: Other. Borthakur: Astex: Research Funding; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Short: Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Amgen: Consultancy, Honoraria; Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Astellas: Research Funding. Pemmaraju: Samus: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Sager Strong Foundation: Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; Aptitude Health: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Other, Research Funding; Incyte: Consultancy; Springer Science + Business Media: Other; Protagonist Therapeutics, Inc.: Consultancy; Plexxicon: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Alvarado: Jazz Pharmaceuticals: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding. Takahashi: Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Ravandi: Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Prelude: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Astex: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian: KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; Jazz: Research Funding; Aptitude Health: Honoraria; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Precision Biosciences: Honoraria; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Astellas Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; KisoJi: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding.
