Background: The understanding of chronic lymphoproliferative disease has advanced significantly with the incorporation of next-generation sequencing (NGS) techniques, allowing for more detailed molecular characterization of the disease. New classifications, such as the ICC and the 5th edition of the WHO Classification, already recognize the importance of genetic alterations in the definition of subtypes and risk stratification. Genetic sequencing, particularly through targeted panels, has been increasingly used to identify mutations with diagnostic, prognostic and predictive impact, aiding in the personalization of treatment. However, these panels are usually expensive and seldom used in low and low-middle income countries. Moreover, most studies describing molecular findings did not include patients with different backgrounds, including latinos. To address this gap, we implemented a NGS painel in our center, and here we describe the first clinical and molecular characteristics of a real-world Brazilian cohort with lymphoid malignancies.

Methods: We retrospectively analyzed 57 Brazilian patients diagnosed with mature lymphoproliferative disorders who underwent molecular testing using a targeted NGS panel for lymphoid malignancies.

Results: The cohort included 57 patients (28 female), with a median age of 53 years. Diagnosis comprised aggressive B-cell lymphomas (n = 25), T-cell lymphoproliferative diseases (n = 12), chronic lymphocytic leukemia / small lymphocytic lymphoma (n = 6) and other B-cell lymphomas (n = 14). The median tumor mutational burden (TMB) was 4.7 mut/Mb (range: 0.0 – 192.7), and microsatellite instability (MSI) was identified in only one patient (1.8%). At least one molecular alteration was identified in 95% of the population and the most frequently mutated genes included TP53 (25%), MYD88 (12%) and SOCS1 (12%). Mutations affected genes involved in epigenetic/chromatin regulation (42%), TCR/BCR/NF-κB signaling (35%), JAK/STAT signaling (23%), other signaling pathways (32%), transcription factors (35%), immune response/cell trafficking (18%), and apoptosis/DNA damage/cell cycle regulation (49%).

NGS contributed directly to diagnostic clarification in 9 patients by either excluding or supporting a specific diagnosis. Notably, one patient initially diagnosed with anaplastic large cell lymphoma (ALCL) was found to harbor an IGH rearrangement along with SOCS1 and CCND3 mutations, which supported reclassification as classic Hodgkin lymphoma (cHL). Another case, initially interpreted as plasmablastic lymphoma, showed a mutation profile (TNFRSF14, B2M, CD58) inconsistent with that diagnosis. In a third case, the absence of hallmark MCL alterations (e.g., CCND1) aided in excluding mantle cell lymphoma. Finally, mutational findings (CCND3 mutation) supported a diagnosis of splenic diffuse red pulp small B-cell lymphoma, in concordance with the clinical and immunophenotypic context.

Importantly, 26 patients (46%) harbored potentially actionable biomarkers, including alterations in the BTK pathway, EZH2, MEK pathway, JAK-STAT signaling, MTOR, NPM1::ALK, and MSI-high status, indicating potential eligibility for targeted therapies. On the other hand, 5 patients (9%) had molecular changes predictive of resistance to therapy.

Conclusion: This real-world analysis includes, to our knowledge, the largest reported Latin dataset of lymphoproliferative disease patients with molecular data and shows that Brazilians have similar driver mutations compared with non-Latino patients. Targeted NGS identified clinically relevant mutations in the vast majority of patients and contributed directly to diagnosis in 16% of cases. A substantial subset (46%) harbored potentially actionable alterations, emphasizing the role of molecular profiling in guiding personalized therapy for lymphoid malignancies. Our study is limited by its retrospective nature and limited sample size, and further research is needed to corroborate these data. However, this first report of NGS Panel in Brazilian patients highlights the impact of these panels both in diagnosis and in individualized therapy.

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2025
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