Study Suggests Adding BTKi to Chemo May Improve Early Outcomes in Richter Transformation in CLL

A new retrospective analysis is shedding light on how frontline treatment strategies may influence survival and response rates in patients with Richter transformation (RT), a rare but aggressive evolution of chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL).¹

The single-center study suggests that combining traditional chemoimmunotherapy (CIT) with a Bruton tyrosine kinase inhibitor (BTKi) may improve complete response (CR) rates and progression-free survival (PFS) compared with CIT alone, although the effect on overall survival (OS) remains uncertain.

Richter transformation affects only a small percentage of CLL patients—typically between 2% and 10%²—but its impact is profound. Once the disease transforms into RT-DLBCL, outcomes tend to be substantially worse than in de novo DLBCL, and standard CIT regimens like R-CHOP often produce limited benefit. Because BTK inhibitors already have established activity in CLL and some emerging activity in RT, investigators at the University of California, San Francisco set out to determine whether adding a BTKi to frontline CIT could improve outcomes in real-world practice.

The research team, publishing their findings in Blood, examined medical records from 56 patients diagnosed with RT-DLBCL between 2012 and 2024, with a median age of 72 years. To isolate the effect of frontline BTKi use, they excluded anyone who had previously received BTKi therapy for CLL.

Among the entire cohort, objective response rate (ORR) reached 62.5%, with CR in 57.1% of patients. Median overall survival (OS) across all patients was 57.2 months, a figure notably higher than many historical reports and potentially reflective of improved supportive care, newer therapies, or changes in diagnostic sensitivity, noted the researchers.

The group observed clear differences in outcomes based on treatment given. Patients were grouped based on whether they received CIT alone or CIT combined with a BTKi, either concurrently or followed by BTKi maintenance. Fourteen patients received the combination approach, while 24 received CIT alone.

All 14 patients receiving the BTKi combination achieved a CR, compared with just 58.3% of those treated with CIT alone. This difference reached statistical significance and marks one of the strongest signals favoring BTKi addition in frontline RT reported to date. There were also differences in PFS, with median PFS not reached among patients receiving CIT plus BTKi compared with just 11.8 months in the CIT-only group.

“Notably, these response rates and survival outcomes exceed those previously reported with an alternative novel combination of CIT and venetoclax,” wrote the researchers.

Despite these improvements in response depth and disease control, OS did not statistically differ between groups. Median OS was not reached in the CIT plus BTKi cohort and was 75 months in the CIT-only cohort. Only 1 patient in the BTKi group died from lymphoma; most deaths were unrelated to disease progression. The investigators note that longer follow-up and larger cohorts are needed to determine whether the early response advantage ultimately leads to better long-term survival.

One intriguing finding was that CIT plus BTKi may be particularly beneficial for patients with non-GCB RT-DLBCL, a subgroup historically associated with inferior outcomes. In this study, non-GCB patients receiving the combination therapy had numerically longer survival than GCB patients, although the sample size was too small to draw firm conclusions.

The data also showed substantially different outcomes depending on prior CLL-directed therapy. Patients who had never been treated for CLL experienced the longest survival, whereas those previously exposed to CIT or targeted agents had significantly shorter survival: 12.3 months and 8.9 months, respectively.

Additionally, patients with germinal center B-cell (GCB) RT-DLBCL tended to live longer than those with non-GCB disease, though the difference did not reach statistical significance.

References

1. Ma S, Ai W, Ho C, et al. Outcomes of patients with Richter transformation (RT) treated with frontline chemoimmunotherapy (CIT) and BTK inhibitor (BTKi). Blood. 2025;146(S1):2110. doi:10.1182/blood-2025-2110
2. Eyrrer T. Richter transformation—is there light at the end of this tunnel? Hematology Am Soc Hematol Educ Program. 2023;2023(1):427-432. doi:10.1182/hematology.2023000442