Medically reviewed by Dr. Brian Koffman
The Bottom Line:
After discontinuing a non-covalent Bruton tyrosine kinase inhibitor (BTKi), venetoclax is clinically active in patients with chronic lymphocytic leukemia (CLL) or Richter transformation who have not received it in the past. CAR-T therapy may also be an option, but this requires further study.
Who Performed the Research and Where Was it Presented:
Dr. Meghan Thompson from Memorial Sloan Kettering Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2022.
Two types of BTKi are distinguished by how they bind to the BTK enzyme. Covalent BTKi bind irreversibly; this group includes ibrutinib, acalabrutinib, and zanubrutinib. Non-covalent BTKi bind reversibly, and this group includes pirtobrutinib and nemtabrutinib. Non-covalent BTKi are a relatively new treatment option, and they have not yet been approved specifically for CLL, though pirtobrutinib has been approved for mantle cell lymphoma. Some patients have to discontinue non-covalent BTKi due to progressive disease or side effects, but there is little clinical data to guide treatment selection.
In this interview, Dr. Sameer Parikh, Associate Professor of Medicine at the Mayo Clinic, interviewed Dr. Meghan Thompson, Assistant Attending Physician and leukemia specialist at Memorial Sloan Kettering Cancer Center. They discussed treatment options for patients with CLL or Richter transformation after discontinuing a non-covalent BTKi.
Methods and Participants:
This was a retrospective, multicenter study of patients treated with any non-covalent BTKi for CLL or Richter transformation who had discontinued non-covalent BTKi for any reason.
- Researchers identified 63 patients (48 CLL, 15 Richter transformation) who were treated with and subsequently discontinued non-covalent BTKi therapy.
- Patients were heavily pretreated with a median of 4 prior therapies.
- Almost all patients (94%) had previously been treated with a covalent BTKi, and 57% had previously been treated with venetoclax.
- The overall response rate or ORR to non-covalent BTKi was 58.8% for CLL and 46.7% for Richter’s Transformation (RT).
- The median duration of non-covalent BTKi before discontinuation was 9 and 4 months for CLL and RT, respectively.
- Overall, 74% of patients progressed on non-covalent BTKi.
- Other reasons for discontinuing non-covalent BTKi included death unrelated to progressive disease, stem cell transplant, toxicity, CAR-T therapy, and doctor or patient preference.
- Patients who had not previously received venetoclax responded well to venetoclax after discontinuing non-covalent BTKi (overall response rate = 70%).
- Chemoimmunotherapy produced poor outcomes in both CLL and Richter transformation.
- CAR-T therapy produced high response rates (overall response rate = 86%), but the follow-up was short, so it is hard to say whether these results would hold over a longer time period.
- Overall, non-covalent BTKi also appears to be well-tolerated with low rates of discontinuations due to side effects.
This study provides information regarding treatment selection and sequencing for CLL. Following discontinuation of a non-covalent Bruton tyrosine kinase inhibitor (BTKi), venetoclax is clinically active in patients with CLL or Richter transformation who have not received it in the past. CAR-T therapy may also be an option, but this requires further study.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract: Outcomes of Therapies and Resistance Mutations Following Non-Covalent Bruton’s Tyrosine Kinase Inhibitor Treatment for Patients with Chronic Lymphocytic Leukemia and Richter Transformation.
Take care of yourself first.
Ann Liu, PhD