Prognostic impact of variant allele frequency in intensively treated patients with NPM1-mutated AML: a PETHEMA study.
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Gil José Vicente, Sargas Claudia, Ayala Rosa, Gutierrez Norma C, Pérez-Simón José Antonio, Gómez-Casares María Teresa, Larrayoz María José, Prados de la Torre Esther, Cano-Ferri Isabel, Navarro Irene, Gil Cristina, Bernal Del Castillo Teresa, Rodríguez-Arbolí Eduardo, Pérez Santaolalla Esther, Colmenares Rafael, Tormo Mar, Bergua Burgues Juan Miguel, Amigo María-Luz, Rodríguez-Medina Carlos, Serrano Josefina, Oliva Ana, Alonso-Domínguez Juan Manuel, Noriega Víctor, Algarra Jesús-Lorenzo, Olave Mayte T, García Perez Maria Jose, Couto María Del Carmen, Almela-Gallego Agata, García-Fortes María, Madrigal-Toscano Dolores Dolores, Hermosín Lourdes, Colorado Mercedes, García-Boyero Raimundo, Ibañez-Alis Francisco, Solé-Rodríguez María, Martinez Chamorro Carmen, Mateos Maria C, García Garay María Del Carmen, Solana-Altabella Antonio, Martín-Herreros Beatriz, Martínez-López Joaquín, Chillon M Carmen, Soria Elena, Bilbao-Sieyro Cristina, Calasanz Maria J José, Sánchez-García Joaquin, Barragan Eva, Montesinos Pau
Аннотация
NPM1-mutated acute myeloid leukemia (AML) is genetically well-defined, but clinical outcomes remain heterogeneous, suggesting that quantitative clonal features may refine current risk stratification. We analyzed 688 intensively treated NPM1-mutated AML integrating variant allele frequency (VAF), mutation order, and clonal architecture inferred by PyClone and ClonEvol. Co-mutations were present in 97% of patients (median = 3 per case), dominated by DNMT3A (49%), FLT3-ITD (46%), TET2 (22%), and IDH2 (20%). Prognostic modelling of NPM1 VAF identified an optimal cut-off of 31.44%, defining NPM1high and NPM1low groups. NPM1low correlated with splicing-related alterations and independently predicted inferior overall (HR = 1.46; p = 0.037) and relapse-free survival (HR = 1.40; p = 0.036). Gene-specific VAF analyses revealed divergent effects across partners, high DNMT3A, FLT3-OTHER, KRAS, and PTPN11 burdens were adverse, whereas high IDH2 VAF was protective. Combined models showed that patients with NPM1high and favorable co-mutation VAFs had the best outcomes, while dual unfavorable burdens conferred the poorest survival. Mutation ordering inferred from VAFs positioned NPM1 after epigenetic and splicing lesions but before signaling and transcription-factor mutations. Non-canonical orders, such as early FLT3-OTHER/TKD or WT1 prior to NPM1, significantly stratified outcomes. Clonal reconstruction revealed predominantly linear evolutionary trajectories (84.3%), with increased mutational burden and clonal diversity associating with inferior survival. Notably, intra-clonal co-localization of NPM1 with IDH1 or TET2 was associated with improved outcomes, whereas co-localization with WT1 predicted dismal prognosis. These results demonstrate that quantitative and structural dimensions of clonality refine the biological and prognostic landscape of NPM1-mutated AML beyond mutational status alone.