# Molecular Pathogenesis and Targeted Treatment of Richter Transformation

## TL;DR

Richter transformation is a deadly progression of CLL/SLL into aggressive lymphoma, and this paper reviews its molecular causes and new treatment strategies.

## Contribution

The paper integrates recent multi-omic insights and therapeutic advances to propose a refined biological and therapeutic framework for Richter transformation.

## Key findings

- Clonally related Richter transformation often originates from pre-existing subclones detectable years before clinical symptoms.
- Genetic lesions in TP53, CDKN2A/B, NOTCH1, and MYC drive aggressive growth and genomic instability in Richter transformation.
- An immunosuppressive tumor microenvironment involving PD-1/PD-L1 interactions and exhausted T cells supports immune escape in Richter transformation.

## Abstract

Richter transformation (RT) represents a rare but highly lethal evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), most frequently manifesting as diffuse large B-cell lymphoma (DLBCL). Despite therapeutic advances in CLL, DLBCL-RT remains characterized by rapid progression, profound treatment refractoriness, and short survival with conventional chemoimmunotherapy, underscoring the need for a refined biological and therapeutic framework. A defining feature of RT is clonal relatedness: most cases arise through linear or branched evolution of the antecedent CLL clone and carry an inferior prognosis compared with clonally unrelated cases that resemble de novo DLBCL. Recent multi-omic data further indicate that clonally related RT commonly originates from minute, transformation-primed subclones detectable years before clinical emergence, shifting RT from a late stochastic event to an early-established evolutionary trajectory. At transformation, recurrent genetic lesions of TP53, CDKN2A/B, NOTCH1, and MYC cooperate with B-cell receptor-associated programs, epigenetic reconfiguration, and metabolic rewiring toward OXPHOS- and mTOR-driven states, collectively promoting genomic instability and aggressive growth. In parallel, RT develops within a profoundly immunosuppressive microenvironment marked by PD-1-expressing malignant B cells, PD-L1-rich myeloid niches, exhausted T cells, expanded regulatory T cells, and M2-skewed macrophages interconnected by redundant checkpoint and cytokine networks. Therapeutic strategies are rapidly evolving, including pathway inhibitors, immune checkpoint blockade, T-cell-engaging bispecific antibodies, CAR-T therapies, and antibody–drug conjugates. This review integrates current insights into RT pathogenesis, immune escape, and emerging therapies, highlighting opportunities for biomarker-driven patient stratification, rational combinations, and earlier interception of transformation-prone disease.