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Novel combinations of therapies are being explored for the treatment of non-Hodgkin lymphoma (NHL), particularly for previously untreated cases. The Polarix trial, which investigated the addition of polituzumab to the standard R-CHOP regimen, showed sustained progression-free survival benefits for patients over five years, particularly for those with high-risk disease subtypes. Additionally, combining venetoclax with the RCHP regimen demonstrated impressive response rates, particularly achieving a 100% response rate in challenging double and triple-hit lymphoma patients. These findings underscore the potential for precision medicine approaches in improving outcomes for NHL patients with biological complexities.