Early Studies Show Some Patients With Richter Transformation of CLL Respond to Zanubrutinib

Two new studies involving the use of the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) for the treatment of Richter transformation (RT) of chronic lymphocytic leukemia (CLL) have produced “encouraging” results, according to investigators.

The results show about 15% of patients achieved a complete response (CR) to zanubrutinib, either alone or in combination with the programmed death-1 inhibitor tislelizumab, and some patients achieved sustained responses. The new data were reported in HemaSphere.

Between 5% and 10% of patients with CLL will experience the transformation of CLL into the more aggressive Richter syndrome. However, current therapies for relapsed/refractory disease are generally ineffective and come with a poor prognosis, noted the study authors.

Zanubrutinib, a next-generation BTK inhibitor, has emerged as a possible treatment strategy for this hard-to-treat group. Two new phase 1/2 studies explored the therapy in patients with B-cell malignancies, including patients with RT. The investigators said the findings from each offer reasons for optimism.

The first study, BGB-3111-AU-003, was a 2-part open-label study that looked at zanubrutinib alone. A dose-escalation study was the first part of the study. Following that, 13 patients with locally histologically confirmed RT were enrolled in the second part and were treated with zanubrutinib at a recommended dose of 160 mg twice daily until unacceptable toxicity or disease progression. All of the patients experienced at least 1 treatment-emergent adverse event (AE) and 9 experienced a grade 3 AE.

“Six (46.2%) patients developed serious AEs, with retroperitoneal mass, acute myocardial infarction, and bacteremia leading to treatment discontinuation in 3 (23.1%) of them,” the authors reported. Two patients—one with myocardial infarction and one with bacteremia—died, they added. No patients experienced atrial fibrillation/flutter or tumor lysis syndrome (TLS).

Eight patients achieved a response, of which 2 were complete and 6 were partial, the authors wrote. Of the 3 patients who had previously been treated with the BTK inhibitor ibrutinib (Imbruvica), 1 did not respond to zanubrutinib, 1 achieved a 76-week partial response (PR), and 1 died before the first response assessment, they said. Four patients had a continued response at the study’s end and were enrolled in a long-term extension study. The estimated median progression-free survival was 17.3 months (95% CI, 2.8-not estimable). One patient was event free at 32.2 months at the study’s final assessment before discontinuation.

The second study, BGB-3111-A317-001, was a 2-part open-label study of zanubrutinib plus tislelizumab, where patients in the second part of the study were given 200 mg of tislelizumab every 3 weeks and 160 mg of zanubrutinib twice daily. Patients were treated in 21-day cycles until unacceptable toxicity or progression.

Seven patients were enrolled. All experienced at least 1 AE, and 5 experienced AEs of at least grade 3. Four of the 5 patients who experienced a serious AE discontinued the study. Three patients experienced TLS, but one experienced it before receiving tislelizumab and the other 2 cases were deemed unrelated to the study drugs. All 3 TLS cases resolved within 5 days. No serious AEs led to death, the authors said.

Three patients in the second study achieved a response. One patient had a CR lasting 17.5 months, and another patient had a PR that lasted 2.9 months. A third patient had a PR lasting more than 4 years.

Taken together, the investigators said the results show zanubrutinib has antineoplastic activity in patients with RT from CLL. Though they said cross-trial comparisons cannot be made, they said it is notable that about 15% of patients with RT from each study had a CR.

“Advantages of combination with tislelizumab, as with other PD-1 inhibitors, require confirmation from additional studies,” they said.

Reference

Tam C, Munoz J, Cull G, et al. Zanubrutinib, alone and in combination with tislelizumab, for the treatment of richter transformation of chronic lymphocytic leukemia. Hemasphere. Published online March 24, 2023. doi:10.1097/HS9.0000000000000870