Deeper Insights Into RT Could Help Spark New CLL/SLL Therapies

New research is helping to change the way investigators and clinicians think about and treat Richter transformation (RT) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).

In a new review article, investigators outlined the latest research, offering insights into both how RT develops and how best to treat it. Their findings were published in the journal Biomedicines.¹

They noted that RT of CLL/SLL most often manifests as diffuse large B-cell lymphoma, and most resulting RT cases are clonally related to the antecedent CLL clone. Such cases tend to have a worse prognosis compared with cases with clonally related DLBCL, they said.

Treatment in such cases generally involves anthracycline-based chemoimmunotherapy regimens, similar to what is used in de novo DLBCL, they said.

“However, response rates remain low, complete remissions are infrequent, and survival outcomes are poor, with median OS (overall survival) generally limited to less than 1 year,” they wrote.²

Neither intensified chemoimmunotherapy nor alternative regimens appear to be sufficient to significantly improve outcomes, the authors said, and curative strategies like allogeneic stem cell transplantation have limited applicability in this patient population.

“Collectively, these limitations highlight the inadequacy of current standard therapies and underscore the urgent need for more effective, biologically informed treatment strategies,” they explained.

The investigators said recent multiomics analyses of DLBCL-RT have helped to elucidate temporal dynamics of clonally related DLBCL. They noted that a comprehensive study of 19 patients with RT showed that tiny CLL subclones with genomic, immunogenetic, and transcriptomic features of RT cells are present at CLL diagnosis and can sit dormant for many years before transformation occurs.³

Such evidence has helped to convince researchers that RT is not, in fact, a stochastic event, but rather the result of predetermined evolutionary features. The new paradigm, the authors explained, has important implications for therapeutic approaches.

“First, RT should be approached as a disease of dynamic clonal ecosystems, where targeted agents reshape selection more than they eradicate risk,” they said.

That finding means it will be “essential” to reassess RT biology in the post–Bruton tyrosine kinase (BTK) inhibitor and B-cell lymphoma-2 (BCL2) inhibitor era, they said.

Additionally, they said research indicates that RT develops “within a profoundly immunosuppressive microenvironment” with PD-1–high malignant B cells, PD-L1–rich myeloid networks, exhausted T cells, expanded regulatory cells, and M2-skewed macrophages. All of this, the authors said, suggests that immune architecture and checkpoint circuitry are more important than mere “immune presence.”

The authors then outlined the latest therapeutic insights. They said targeted therapies like BTK inhibitors, immune checkpoint inhibitors, and bispecific antibodies are becoming more important facets of the treatment landscape, with most evidence suggesting the best hope is the use of combination strategies. For instance, they said BTK or BCL2 inhibition in combination with PD-1 blockade has been shown to potentially lead to durable control of RT, “but only if therapies are matched to the dominant resistance layer, ie, tumor-intrinsic escape, immune exclusion/dysfunction, or both.”

They said upcoming trials assessing combination therapies pairing the noncovalent BTK inhibitor pirtobrutinib (Jaypirca; Eli Lilly) or the CD3 x CD20 bispecific antibody epcoritamab (Epkinly; AbbVie and Genmad) with standard chemoimmunotherapy have drawn considerable attention.

Ultimately, though, they said significant progress in treating RT will likely depend on the ability to detect high-risk subclones and assess spatial and systemic immune profiles to more precisely—and more quickly—target RT.

References

1. Maher N, Karami A, Matti BF, et al. Molecular pathogenesis and targeted treatment of Richter transformation. Biomedicines. 2026;14(2):347. doi:10.3390/biomedicines14020347
2. Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol. 2018;180(2):259-266. doi:10.1111/bjh.15035
3. Nadeu F, Royo R, Massoni-Badosa R, et al. Detection of early seeding of Richter transformation in chronic lymphocytic leukemia. Nat Med. 2022;28(8):1662-1671. doi:10.1038/s41591-022-01927-8