Ibrutinib May Boost Efficacy of Liso-Cel in CLL With Richter Transformation

Ibrutinib appears to boost the efficacy of lisocabtagene maraleucel (liso-cel; Breyanzi) in patients with chronic lymphocytic leukemia (CLL) who experience Richter transformation (RT), according to a case series published in eJHaem.¹

The report includes a series of 6 patients, and the findings suggest the combination warrants additional study.

The researchers examined outcomes in a series of patients with RT who were treated with liso-cel, including patients who were also taking ibrutinib. | Image credit: AIGen - stock.adobe.com

Patients with RT from CLL to aggressive lymphoma face an extremely poor diagnosis, with a median survival of just 5-12 months following diagnosis.² The authors of the case series noted that allogeneic stem cell transplantation is available for patients who respond to initial chemoimmunotherapy.¹

“However, no effective treatment alternatives for chemoimmunotherapy-refractory Richter transformation currently exist,” they wrote.

They explained that chimeric antigen receptor (CAR) T-cell therapies, which have been successful in treating certain patients with large B-cell lymphoma, have led to inferior outcomes in patients with CLL, and patients with RT were not included in the pivotal trials of 2 of the most prominent CAR T-cell therapies. One reason for the lack of efficacy of CAR T in CLL could be CLL-induced T-cell anergy, they noted.

Reports on the use of the CD19-directed CAR T-cell therapy liso-cel in patients with RT have emerged in recent years, but the number of patients included in the reports has generally been small, the authors said. In the new report, they sought to add to the existing literature by reporting outcomes in a series of patients with RT who were treated with liso-cel, including patients who were also taking ibrutinib.

The case series included 6 patients ranging in age from 56 to 68 years who had RT. Prior lines of therapy before RT ranged from 0 to 9 among the patient cohort, which was evenly split between male and female patients. The patients received liso-cel between September 2021 and November 2023 at a single health care institution.

The investigators reported that the therapy was successfully manufactured for all 6 patients, and the median vein-to-vein time was 34 days. Two patients received bridging chemotherapy treatment in the interim.

The best overall response was 83.3% with the therapy. All of the participants had in vivo CAR expansion. Notably, all 4 of the patients who were still alive as of the study’s completion were receiving concurrent ibrutinib. Those patients all had minimal residual disease (MRD)–negative complete responses. Taken together, the findings show that the 4 patients had a “strong response” to CAR T, the authors said.

In terms of safety, none of the 6 patients experienced grade 3 or above cytokine release syndrome, though one patient experienced grade 3 immune-effector cell-associated neurotoxicity syndrome. That patient was one of the 2 patients in the case series who died.

While their findings are limited by the small sample size, the authors support “further exploration to determine whether combining ibrutinib with liso-cel can improve responses in RT.”

The investigators concluded that ibrutinib appears to improve patient responses to liso-cel. Ibrutinib inhibits both Bruton tyrosine kinase and interleukin-2 inducible kinase (ITK). The latter plays a key role in activating Th1 and Th2 cells, they noted.

“In Th1 cells, ITK signaling is supportive but not critical to redundant resting lymphocyte kinase signaling, whereas in Th2 cells, ITK signaling is essential to activation,” they wrote. “Given the significant influence of T-cell anergy on CAR T efficacy in RT, concurrent ibrutinib with CAR T-cell therapy may be an impactful strategy to overcome this challenge.”

References

1. Smith CJ, Goyal A, Smith BR, et al. Lisocabtagene maraleucel for Richter's transformation-a case series. EJHaem. 2025;6(2):e270011. doi:10.1002/jha2.70011
2. Al-Sawaf O, Robrecht S, Bahlo J, et al. Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials. Leukemia. 2021;35(1):169-176. doi:10.1038/s41375-020-0797-x