Recent Advances Raise Hopes of Better Addressing Richter Transformation

Recent research has helped scientists better understand the biology and evolution of Richter transformation (RT) among people with chronic lymphocytic leukemia (CLL), potentially laying the groundwork for the development of better strategies to prevent the disease progression.

Those are the key takeaways from a review published in Seminars in Cancer Biology.¹

The investigators noted that an estimated 2% to 10% of patients with CLL will experience RT, the transformation of CLL into a more aggressive lymphoma.² Those patients tend to experience rapid clinical decline following transformation. Treatment can also be difficult; conventional chemotherapy has proven generally ineffective and more aggressive approaches are limited by toxicity, the authors said.

“Allogeneic stem cell transplantation offers a potential curative option but is feasible only in a minority of patients due to age, comorbidities, and disease aggressiveness,” they wrote.

Newer therapies, such as bispecific T-cell engagers and chimeric antigen receptor T-cell therapies, have raised hopes, although efforts to refine such therapies and identify the most effective options remain ongoing, they said.

The investigators noted that RT is clonally related to the CLL clone in about 70% to 80% of cases. They said understanding this clonal relationship “is crucial to understand the biology of the disease” and may help guide treatment decisions.

“Biologically, RT is driven by genomic instability, loss of cell cycle control, MYC activation, NOTCH alterations, and immune evasion mechanisms, including PD-1/PD-L1 upregulation,” they wrote. The timing of RT, they added, can vary significantly. Sometimes there is an accelerated phase before transformation; other times, RT’s “seeds may be traced back years before their clinical manifestation.

“These could include additional (epi)genetic alternations, but also changes in the tumor microenvironment that promote the rapid outgrowth of RT clones,” they wrote.

Looking forward, they said there is a need for additional study to better understand some of the inter- and intrapatient heterogeneity among patients, including the molecular landscape of chemotherapy-free RT. They said there also is a need to better identify risk factors for RT that could help clinicians more closely monitor patients at a particularly high risk.

The investigators said research involving murine models has also helped to show that multiple co-occurring driver alterations are necessary for the transformation of CLL clones, a finding that aligns with studies in humans with RT.

“Loss of the negative cell cycle regulators CDKN2A, CDKN2B, and TP53 was identified as one such combination, which contributes to transformation by allowing BCR (B-cell receptor)-stimulated CLL cells to bypass the G1/S checkpoint in the absence of additional microenvironmental growth signals,” they wrote.

They said further studies should examine the broader applicability of this mechanism, as well as the certain frequent combinations of genetic alterations could portend imminent transformation. In therapeutic terms, the authors said there are pressing questions related to BCR pathway inhibitors and Bruton tyrosine kinase (BTK) inhibitors.

“Particularly relevant questions are the mechanisms resulting in reduced BCR dependency and the reasons for the rapid acquisition of resistance in patients that initially respond to BTK inhibitor therapy,” they said.

However, given that RT appears to result from multiple deregulated pathways, the authors said successfully treating the disease will likely require targeting multiple pathways. They also said addressing gaps in knowledge related to the mechanism of action of immune checkpoint inhibitors in RT will be essential, as they may prove to have a role in preemptive treatment of RT.

“Continued integration of genomic insights, translational research, and collaborative clinical trial design will be essential to accomplish this task and improve outcomes for patients facing this aggressive complication of CLL,” they concluded.

References

1. Nadeu F, Efremov DG. The biology and evolution of Richter transformation in chronic lymphocytic leukemia. Semin Cancer Biol. Published online February 13, 2026. doi:10.1016/j.semcancer.2026.02.002
2. Ben-Dali Y, Hleuhel MH, da Cunha-Bang C, et al. Richter's transformation in patients with chronic lymphocytic leukaemia: a nationwide epidemiological study. Leuk Lymphoma. 2020;61(6):1435-1444. doi:10.1080/10428194.2020.1719092