NCCN Guidelines® Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2026

Area of Science:

• Hematology
• Oncology
• Clinical Guidelines

Background:

• Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2i) have improved survival in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
• Time-limited BCL2i regimens show higher rates of undetectable measurable residual disease (uMRD) compared to BTKi monotherapy or chemoimmunotherapy (CIT).
• Pirtobrutinib and lisocabtagene maraleucel represent advanced options for relapsed/refractory disease post-BTKi and BCL2i therapies.

Purpose of the Study:

• To highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL.
• To address the management of Richter transformation, a poor-prognosis complication of CLL/SLL.
• To incorporate newer therapeutic options into treatment guidelines.

Main Methods:

• Review of randomized clinical trials and recent therapeutic advancements.
• Analysis of treatment outcomes, including rates of undetectable measurable residual disease (uMRD).
• Consideration of molecular analysis for clonal relationships in Richter transformation.

Main Results:

• BCL2i-containing regimens achieve higher uMRD rates than BTKi monotherapy or CIT.
• Pirtobrutinib and lisocabtagene maraleucel are emerging options for patients with relapsed or refractory disease.
• Molecular analysis aids in selecting optimal treatment for CLL/SLL and Richter transformation.

Conclusions:

• NCCN Guideline Insights provide crucial updates for CLL/SLL and Richter transformation management.
• Novel agents like pirtobrutinib and lisocabtagene maraleucel are integrated into evolving treatment paradigms.
• Personalized treatment selection, informed by molecular data, is key for improved patient outcomes.