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BackgroundRecurrent 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.MethodsA 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.ResultsWe 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.DiscussionOur 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.

Leukemias are the most common type of pediatric cancer around the world. Prognosis has improved during the last decades, and many patients are cured with conventional treatment as chemotherapy; however, many patients still present with a refractory disease requiring additional treatments, including hematopoietic stem cell transplantation. Immunotherapy with monoclonal antibodies or cellular therapy is a promising strategy for treating refractory or relapsed hematological malignancies. Particularly, CAR-T cells have shown clinical efficacy in clinical trials, and different products are now commercially approved by regulatory agencies in the USA and Europe. Many challenges still need to be solved to improve and optimize the potential of these therapies worldwide. Global access to cell therapy is a significant concern, and different strategies are being explored in the middle- and low-income countries. In Mexico, leukemias represent around 50% of total cancer diagnosed in pediatric patients, and the rate of relapsed or refractory disease is higher than reported in other countries, a multi-factorial problem. Although significant progress has been made during the last decades in leukemia diagnosis and treatment, making new therapies available to Mexican patients is a priority, and cell and gene therapies are on the horizon. Efforts are ongoing to make CAR-T cell therapy accessible for patients in Mexico. This article summarizes a general landscape of childhood leukemias in Mexico, and we give a perspective about the current strategies, advances, and challenges ahead to make gene and cell therapies for leukemia clinically available.

Acute lymphoblastic leukemia (ALL) is the most common malignancy among Mexican and Hispanic children and the first cause of death by disease in Mexico. We propose a “triple-hit” explanation for the survival gap affecting this population. The first hit can be attributed to epidemiology and social, cultural, and economic burdens. The second hit refers to cancer biology, with a high incidence of unfavorable genetic characteristics associated with an unfavorable response to treatment and, subsequently, poor survival. Finally, the third hit relates to sub-optimal treatment and support. Society and culture, leukemia biology, and treatment approach limitations are key factors that should not be seen apart and must be considered comprehensively in any strategy to improve the prognosis of Mexican and Hispanic children with ALL.