694e1c989516b7515466a977a3e2d01b 255656.pdf ee89f2f62bc79c4cdce4c0d086371ce36d4fbf1d 255656.pdf 37a0499458b63554ed6a4cdae9899d3becf1f358e245382895a715322ec09c5e 255656.pdf Title: The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial Subject: We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1.014; p = 0.030) and lower TP53 VAF (OR, 0.981; p = 0.003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1.9, p = 0.005) and TP53 (HR, 2.6, p = 9.8 10-7) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3.6, p = 0.0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low–intermediate cytogenetic risk (HR, 1.51, p = 0.045) and mutated NRAS (HR, 3.66, p = 0.047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4.71, p = 0.009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials.gov as NCT02319135. Keywords: clinical trials and observations; myeloid neoplasia; NGS; variants; leukemia; myelocytic; acute; leukemic cells; older adults; genetic risk; complete remission; cytarabine; azacytidine; prognostic factors Author: Rosa Ayala, Inmaculada Rapado, Esther Onecha, David Martínez-Cuadrón, Gonzalo Carreño-Tarragona, Juan Miguel Bergua, Susana Vives, Jesus Lorenzo Algarra, Mar Tormo, Pilar Martinez, Josefina Serrano, Pilar Herrera, Fernando Ramos, Olga Salamero, Esperanza Lavilla, Cristina Gil, Jose Luis López Lorenzo, María Belén Vidriales, Jorge Labrador, José Francisco Falantes, María José Sayas, Bruno Paiva, Eva Barragán, Felipe Prosper, Miguel Ángel Sanz, Joaquín Martínez-López, Pau Montesinos and on behalf of the Programa para el Estudio de la Terapeutica en Hemopatias Malignas (PETHEMA) Cooperative Study Group Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon May 24 03:40:52 2021 CEST ModDate: Mon May 24 03:40:52 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 6329268 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VHSGPO+URWPalladioL-Ital Type 1 Custom yes yes no 102 0 IKXGZT+URWPalladioL-Bold Type 1 Custom yes yes no 103 0 FFAYKL+VnURWPalladioL-Bold Type 1 Custom yes yes no 104 0 EEMDBU+URWPalladioL-Roma Type 1 Custom yes yes no 105 0 HCRKXL+VnURWPalladioL Type 1 Custom yes yes no 109 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 115 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 132 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 133 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 134 0 IKAMBL+CMSY10 Type 1 Builtin yes yes no 153 0 FAECIJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 189 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-01-20 02:30:50 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えどでと〭こづのびどぴどぶどぴべぜ〴ぜ〰ごちひでづぴづつぜ〴ぜ〰こづぱふづのっどのでぜ〴ぜ〰ちのつぜ〴ぜ〰きふぴちぴどはのぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸲⸲ Item: Title: ぁぶちどぬちぢどぬどぴべぜ〴ぜ〰はてぜ〴ぜ〰いちぴちぜ〴ぜ〰ちのつぜ〴ぜ〰きちぴづひどちぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸲⸳ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰きふぴちぴどはのちぬぜ〴ぜ〰がちのつびっちばづぜ〴ぜ〰ぐひづつどっぴびぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ぴはぜ〴ぜ〰ぁぺちっべぴどつどのづぜ〴ぜ〰ちのつぜ〴ぜ〰がいぁぃぜ〴ぜ〰ぐぬふびぜ〴ぜ〰うぬふつちひちぢどのづぜ〴ぜ〰ごひづちぴねづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰えどでとづひぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰ぁぬぬづぬづぜ〴ぜ〰うひづぱふづのっべぜ〴ぜ〰はてぜ〴ぜ〰こはねづぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰ぉのてぬふづのっづびぜ〴ぜ〰くぶづひちぬぬぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとどひつぜ〴ぜ〰ぃべっぬづぜ〴ぜ〰はてぜ〴ぜ〰ぁぺちっべぴどつどのづぜ〴ぜ〰ちのつぜ〴ぜ〰がいぁぃぜ〴ぜ〰ぐぬふびぜ〴ぜ〰うぬふつちひちぢどのづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰こはねちぴどっぜ〴ぜ〰きふぴちぴどはのびぜ〴ぜ〰どのぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰ごぐ〵〳〬ぜ〴ぜ〰ちのつぜ〴ぜ〰あぃくげぜ〴ぜ〰ぐひづつどっぴぜ〴ぜ〰ちぜ〴ぜ〰ことはひぴづひぜ〴ぜ〰くぶづひちぬぬぜ〴ぜ〰ちのつ〯はひぜ〴ぜ〰げづぬちばびづ〭うひづづぜ〴ぜ〰こふひぶどぶちぬぜ〴ぜ〰ぁっっはひつどのでぜ〴ぜ〰ぴはぜ〴ぜ〰さのどぶちひどちぴづぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: きふぴちぴどはのちぬぜ〴ぜ〰がちのつびっちばづぜ〴ぜ〰ぐひづつどっぴびぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ぴはぜ〴ぜ〰ぁぺちっべぴどつどのづぜ〴ぜ〰ちのつぜ〴ぜ〰がいぁぃぜ〴ぜ〰ぐぬふびぜ〴ぜ〰うぬふつちひちぢどのづぜ〴ぜ〰ごひづちぴねづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰えどでとづひぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰ぁぬぬづぬづぜ〴ぜ〰うひづぱふづのっべぜ〴ぜ〰はてぜ〴ぜ〰こはねづぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰ぉのてぬふづのっづびぜ〴ぜ〰くぶづひちぬぬぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとどひつぜ〴ぜ〰ぃべっぬづぜ〴ぜ〰はてぜ〴ぜ〰ぁぺちっべぴどつどのづぜ〴ぜ〰ちのつぜ〴ぜ〰がいぁぃぜ〴ぜ〰ぐぬふびぜ〴ぜ〰うぬふつちひちぢどのづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰こはねちぴどっぜ〴ぜ〰きふぴちぴどはのびぜ〴ぜ〰どのぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰ごぐ〵〳〬ぜ〴ぜ〰ちのつぜ〴ぜ〰あぃくげぜ〴ぜ〰ぐひづつどっぴぜ〴ぜ〰ちぜ〴ぜ〰ことはひぴづひぜ〴ぜ〰くぶづひちぬぬぜ〴ぜ〰ちのつ〯はひぜ〴ぜ〰げづぬちばびづ〭うひづづぜ〴ぜ〰こふひぶどぶちぬぜ〴ぜ〰ぁっっはひつどのでぜ〴ぜ〰ぴはぜ〴ぜ〰さのどぶちひどちぴづぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ごとづぜ〴ぜ〰えどでとづひぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰ぁぬぬづぬづぜ〴ぜ〰うひづぱふづのっべぜ〴ぜ〰はてぜ〴ぜ〰こはねづぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰ぉのてぬふづのっづびぜ〴ぜ〰くぶづひちぬぬぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとどひつぜ〴ぜ〰ぃべっぬづぜ〴ぜ〰はてぜ〴ぜ〰ぁぺちっべぴどつどのづぜ〴ぜ〰ちのつぜ〴ぜ〰がいぁぃぜ〴ぜ〰ぐぬふびぜ〴ぜ〰うぬふつちひちぢどのづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰こはねちぴどっぜ〴ぜ〰きふぴちぴどはのびぜ〴ぜ〰どのぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰ごぐ〵〳〬ぜ〴ぜ〰ちのつぜ〴ぜ〰あぃくげぜ〴ぜ〰ぐひづつどっぴぜ〴ぜ〰ちぜ〴ぜ〰ことはひぴづひぜ〴ぜ〰くぶづひちぬぬぜ〴ぜ〰ちのつ〯はひぜ〴ぜ〰げづぬちばびづ〭うひづづぜ〴ぜ〰こふひぶどぶちぬぜ〴ぜ〰ぁっっはひつどのでぜ〴ぜ〰ぴはぜ〴ぜ〰さのどぶちひどちぴづぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: こはねちぴどっぜ〴ぜ〰きふぴちぴどはのびぜ〴ぜ〰どのぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰ごぐ〵〳〬ぜ〴ぜ〰ちのつぜ〴ぜ〰あぃくげぜ〴ぜ〰ぐひづつどっぴぜ〴ぜ〰ちぜ〴ぜ〰ことはひぴづひぜ〴ぜ〰くぶづひちぬぬぜ〴ぜ〰ちのつ〯はひぜ〴ぜ〰げづぬちばびづ〭うひづづぜ〴ぜ〰こふひぶどぶちぬぜ〴ぜ〰ぁっっはひつどのでぜ〴ぜ〰ぴはぜ〴ぜ〰さのどぶちひどちぴづぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳灥捩慬瑡扬攮捡灴楯渮㜩‾㸊⡜㌷㙜㌷㝜〰げづてづひづのっづび Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: VHSGPO+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: VHSGPO+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: 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