S44 Conclusions While accumulating evidence consistently indicates that HDMTXbased CNS prophylaxis is ineffective for generic DLBCL patients selected based on historical risk factors, it may still hold value in a more selective MCD-like subpopulation, such as testicular lymphoma. However, achieving a significant reduction in rates of CNS recurrence may require a paradigm shift. This involves implementing high-sensitivity screening approaches at diagnosis to improve the detection of CNS invasion, stratifying therapeutic approaches based on molecular factors in addition to clinical factors, and evaluating outcomes with novel approaches that incorporate targeted therapies and cellular therapies based on biological rationale (Fig. 1). Acknowledgments Adam Olszewski is a Scholar in Clinical Research of The Leukemia and Lymphoma Society. References 1. Wilson MR, Bobillo S, Cwynarski K. CNS prophylaxis in aggressive B-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2022;2022(1):138-145. 2. Yahng SA, Yhim HY, Kwak JY, et al. Prophylactic efficacy of intrathecal versus intravenous methotrexate for CNS relapse in high-risk diffuse large B-cell lymphoma: a phase III randomized, controlled study. EHA2023 Congress. 2023:Abs. S229. 3. Olszewski AJ, Chorzalska AD, Petersen M, et al. Detection of clonotypic DNA in the cerebrospinal fluid as a marker of central nervous system invasion in lymphoma. Blood Adv. 2021;5(24):5525-5535. 4. Ollila TA, Kurt H, Waroich J, et al. Genomic subtypes may predict the risk of central nervous system recurrence in diffuse large B-cell lymphoma. Blood. 2021;137(8):11201124. 5. Thieblemont C, Altmann B, Frontzek F, et al. Central nervous system relapse in younger patients with diffuse large B-cell lymphoma: a LYSA and GLA/ DSHNHL analysis. Blood Adv. 2023. Figure 1 Roadmap for research and future approaches to CNS prophylaxis in DLBCL.
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