Richter Transformation in Chronic Lymphocytic Leukemia: Current Treatment Challenges and Evolving Therapies

Abstract

Richter transformation (RT) affects 2-10% of chronic lymphocytic leukemia (CLL) patients, evolving into an aggressive lymphoma-most often diffuse large B-cell lymphoma-with poor prognosis, especially when clonally related to CLL. Key risk factors include unmutated IGHV, TP53 and NOTCH1 mutations, stereotyped B-cell receptors, and complex cytogenetics. This review summarizes RT biology, clinical predictors, and treatment outcomes. Traditional chemoimmunotherapy (e.g., R-CHOP) yields complete response rates around 20-30% and median overall survival of 6-12 months; intensified regimens (R-EPOCH, hyper-CVAD) offer only modest gains. Allogeneic hematopoietic stem cell transplantation is potentially curative but limited to fit patients due to high treatment-related mortality. Emerging therapies now include Bruton's tyrosine kinase and BCL-2 inhibitors, which achieve partial responses but short progression-free survival. CD19-directed chimeric antigen receptor T-cell therapies produce overall response rates of 60-65%, though relapses remain frequent. Bispecific antibodies (e.g., CD3×CD20 agents epcoritamab and mosunetuzumab) show promising activity and tolerable toxicity in relapsed/refractory RT. Ongoing trials are exploring combinations with checkpoint inhibitors, triplet regimens, and novel targets such as ROR1, CD47, and CDK9. Continued research into optimized induction, consolidation, and innovative immunotherapies is essential to improve outcomes in this biologically distinct, high-risk CLL-related lymphoma.

Keywords: BCL-2 inhibitors; BTK inhibitors; CAR T-cell therapy; Richter transformation; allogeneic hematopoietic stem cell transplantation; bispecific antibodies; chemoimmunotherapy; chronic lymphocytic leukemia.

Figure 1

Molecular mechanisms underlying Richter transformation. This diagram illustrates how chronic B-cell receptor (BCR) activation interacts with recurrent genetic lesions to drive the pathogenesis of Richter transformation (RT). BCR signaling—often delivered through unmutated or stereotyped IGHV receptors (e.g., subset #8)—activates downstream pathways such as PI3K–AKT and NF-κB. Loss of tumor-suppressor checkpoints (TP53 mutation/deletion and CDKN2A/B loss) removes cell-cycle brakes and apoptotic safeguards, enabling BCR-dependent proliferation of large pleomorphic cells. NOTCH1 mutations, which are associated with biased subset-8 BCR usage and autonomous signaling, potentiate PI3K/AKT and NF-κB pathway activation and markedly increase the risk of transformation. These pathways converge on MYC, promoting metabolic reprogramming and rapid proliferation. Constitutive AKT phosphorylation—observed in high-risk CLL with NOTCH1 or TP53 alterations—further underscores the interplay between BCR, PI3K/AKT and NOTCH1 signaling. Together, chronic antigenic drive and cumulative genetic lesions produce profound genomic instability (chromothripsis, chromoplexy, and whole-genome doubling), resulting in the emergence of aggressive RT clones.

Figure 2

Targeted therapies under investigation for Richter transformation. The diagram highlights key therapeutic targets on transformed B cells and associated immune or signaling interactions. Shown are CD19-directed CAR T-cell products, CD20×CD3 bispecific antibodies, checkpoint inhibitors (PD-1/PD-L1), CD47 blockade, antibody–drug conjugates (ADCs), and small-molecule inhibitors targeting BCL2, BTK, PI3K, and mTOR. These agents represent mechanistically distinct approaches being combined to improve outcomes in Richter transformation.