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Background: Recurrent genetic alterations contributing to leukemogenesis have been identified in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), and some are useful for refining classification, prognosis, and treatment selection. IKZF1plus is a complex biomarker associated with a poor prognosis. It is characterized by IKZF1 deletion coexisting with PAX5, CDKN2A/2B, or PAR1 region deletions. The mutational spectrum and clinical impact of these alterations have scarcely been explored in Mexican pediatric patients with B-ALL. Here, we report the frequency of the IKZF1plus profile and the mutational spectrum of IKZF1, PAX5, CDKN2A/2B, and ERG genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL. Methods: A total of 206 pediatric patients with de novo B-ALL were included. DNA was obtained from bone marrow samples at diagnosis before treatment initiation. A custom-designed next-generation sequencing panel was used for mutational analysis. Kaplan-Meier analysis was used for OS estimation. Results: We identified the IKZF1plus profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age (p=0.04), a trend toward high-risk stratification (p=0.06), and a decrease in 5-year Overall Survival (OS) (p=0.009) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for IKZF1 (35.9%) and CDKN2A/2B (35.9%) but lower for PAX5 (26.6%). IKZF1MUT group was older at diagnosis (p=0.0002), and most of them were classified as high-risk (73.8%, p=0.02), while patients with CDKN2A/2BMUT had a higher leukocyte count (p=0.01) and a tendency toward a higher percentage of blasts (98.6%, >50% blasts, p=0.05) than the non-mutated patients. A decrease in OS was found in IKZF1MUT and CDKN2A/2BMUT patients, but the significance was lost after IKZF1plus was removed. Discussion: Our findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome. [ABSTRACT FROM AUTHOR]

Background: Recurrent genetic alterations contributing to leukemogenesis have been identified in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), and some are useful for refining classification, prognosis, and treatment selection. IKZF1 plus is a complex biomarker associated with a poor prognosis. It is characterized by IKZF1 deletion coexisting with PAX5 , CDKN2A/2B , or PAR1 region deletions. The mutational spectrum and clinical impact of these alterations have scarcely been explored in Mexican pediatric patients with B-ALL. Here, we report the frequency of the IKZF1 plus profile and the mutational spectrum of IKZF1, PAX5, CDKN2A/2B , and ERG genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL., Methods: A total of 206 pediatric patients with de novo B-ALL were included. DNA was obtained from bone marrow samples at diagnosis before treatment initiation. A custom-designed next-generation sequencing panel was used for mutational analysis. Kaplan-Meier analysis was used for OS estimation., Results: We identified the IKZF1 plus profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age ( p=0.04 ), a trend toward high-risk stratification ( p=0.06 ), and a decrease in 5-year Overall Survival (OS) ( p=0.009 ) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for IKZF1 (35.9%) and CDKN2A/2B (35.9%) but lower for PAX5 (26.6%). IKZF1 MUT group was older at diagnosis ( p=0.0002 ), and most of them were classified as high-risk (73.8%, p=0.02 ), while patients with CDKN2A/2B MUT had a higher leukocyte count ( p=0.01 ) and a tendency toward a higher percentage of blasts (98.6%, >50% blasts, p=0.05 ) than the non-mutated patients. A decrease in OS was found in IKZF1 MUT and CDKN2A/2B MUT patients, but the significance was lost after IKZF1 plus was removed., Discussion: Our findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, AM, declared a shared affiliation with the author RE-E to the handling editor at the time of review., (Copyright © 2024 Garcia-Solorio, Núñez-Enriquez, Jiménez-Olivares, Flores-Lujano, Flores-Espino, Molina-Garay, Cervera, Casique-Aguirre, Peñaloza-Gonzalez, Baños-Lara, García-Soto, Galván-Díaz, Olaya-Vargas, Aguilar, Mata-Rocha, Garrido-Hernández, Solís-Poblano, Luna-Silva, Cano-Cuapio, Aristil-Chery, Herrera-Quezada, Carrillo-Sanchez, Muñoz-Rivas, Flores-Lagunes, Mendoza-Caamal, Villegas-Torres, González-Osnaya, Jiménez-Hernández, Torres-Nava, Martín-Trejo, Gutiérrez-Rivera, Espinosa-Elizondo, Merino-Pasaye, Pérez-Saldívar, Jiménez-Morales, Curiel-Quesada, Rosas-Vargas, Mejía-Arangure and Alaez-Verson.)