Biology and BTK Rationale in Primary CNS Lymphoma

Dr. Lakshmi Nayak provides an overview of primary CNS lymphoma (PCNSL), highlighting its aggressive nature, the predominance of diffuse large B-cell lymphoma histology, and the frequent activated B-cell molecular profile. She discusses the high frequency of MYD88 and CD79B mutations, which converge on constitutive NF-κB signaling, as well as the challenges associated with relapse and refractory disease despite high-dose methotrexate-based therapy and consolidation approaches. Dr. Christian Grommes expands on the biological and anatomical features that distinguish PCNSL from systemic lymphomas. Because PCNSL is confined to the central nervous system, the blood-brain barrier presents an important therapeutic challenge and limits penetration of many conventional systemic lymphoma regimens. He further explains that alterations in MYD88 and CD79B implicate the B-cell receptor signaling pathway, with Bruton tyrosine kinase (BTK) serving as a central component of this pathway. These biological characteristics provide a mechanistic rationale for investigating BTK inhibition as a targeted treatment strategy in PCNSL.