Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib have been wonderfully effective drugs for treating chronic lymphocytic leukemia (CLL). However, on their own, they must be taken continuously and do not produce deep enough remissions to warrant stopping treatment. Combining BTK inhibitors with other drugs may allow patients to get to undetectable minimal residual disease (uMRD) with time-limited treatment, meaning that once a patient reaches uMRD they could potentially stop treatment and just be monitored.
At the annual meeting of the American Society of Hematology (ASH) 2020, our own Dr. Brian Koffman interviewed Dr. Jennifer Woyach, a professor of medicine and hematologist at the James Cancer Center of the Ohio State University. They discussed a phase 1 clinical trial testing the safety of triple combination therapy consisting of:
- Acalabrutinib – a BTK inhibitor
- Venetoclax – a BCL2 inhibitor
- Obinutuzumab or rituximab – anti-CD20 antibodies
- Researchers had previously found that the combination of acalabrutinib plus obinutuzumab was safe and effective, but it didn’t get patients to uMRD.
- Venetoclax is well-known to produce deep remissions with time-limited treatment and seems to work well with BTK inhibitors.
- This study included 12 treatment-naïve patients and 12 patients with relapsed/refractory CLL.
- Treatment-naïve patients received obinutuzumab, and relapsed/refractory patients received rituximab
- Initially patients received acalabrutinib plus obinutuzumab/rituximab to “debulk” (i.e., reduce the number of cancer cells in the body) and decrease the risk of tumor lysis syndrome. After two cycles, venetoclax was added and triple combination therapy was continued for approximately two years.
- Thus far, the treatment combination has been well-tolerated, and no patients have discontinued due to toxicity.
- Patients have experienced side effects that are expected based on the safety profiles of the individual drugs.
- Some of the more common side effects patients experienced were headache, nausea, diarrhea, and infusion-related reactions.
- All patients responded to treatment, and the number of CLL cells in the blood decreased significantly.
- 2/3 of relapsed/refractory patients and 3/4 of treatment-naïve patients achieved uMRD in the peripheral blood by cycle 10.
- The results thus far from this small, early-stage trial are very promising, and the trial is ongoing.
Increasingly, researchers are studying combination therapies to treat CLL. By combining drugs that work through different mechanisms of action (i.e., BTK inhibitor plus BCL2 inhibitor plus anti-CD20 antibody), we can hopefully increase the chances of eliminating the disease. The thought behind this is that it is unlikely that cancer cells will be resistant to all of the agents in the combination. The results so far from this study seem to support this approach, and we continue to learn more and more about different drug combinations.
Please enjoy this brief interview with Dr. Woyach from the virtual ASH meeting which was held in December 2020.
If you are interested in learning about MRD testing, visit the CLL Society website here for additional information.
Take care of yourself first.
Ann Liu, PhD