Ibrutinib and venetoclax are highly effective treatments for chronic lymphocytic leukemia (CLL) that work through different mechanisms of action. Phase 2 clinical trials have shown that combining these two drugs is a very effective first-line treatment for patients who have not been previously treated for CLL. In addition, it produces deep responses (meaning many cancer cells are eliminated by the treatment). However, for patients who achieve undetectable measurable residual disease (uMRD), continuing treatment does not appear to improve outcomes, which supports the idea of fixed-duration treatments. As a result, researchers are moving toward treatment decisions that are MRD-guided (i.e., treat until they reach undetectable MRD rather than based on a fixed time). However, clinical trial data is still needed to support this approach.
At the American Society of Hematology (ASH) 2021, our own Dr. Brian Koffman interviewed Dr. Jake Soumerai, a clinical investigator at Massachusetts General Hospital and an Assistant Professor at Harvard Medical School. They discussed MRD as a biomarker to direct treatment duration in a phase 2 clinical trial of triple combination venetoclax and obinutuzumab plus zanubrutinib.
- Venetoclax plus obinutuzumab is an approved therapy for CLL / SLL that produces durable remissions after one year of treatment.
- Zanubrutinib is a second-generation BTK inhibitor that may have a better safety profile than ibrutinib.
- This study tested the triple combination of venetoclax, obinutuzumab, and zanubrutinib (BOVen) and used measurable residual disease (MRD) to guide treatment duration.
- 89% of patients achieved undetectable MRD (uMRD) in both the peripheral blood and the bone marrow and were able to stop treatment after a median of ten months.
- 94% of patients remain at uMRD with a median follow-up time of 15 months after treatment.
- The combination treatment was well-tolerated.
- Researchers also looked at the speed of the MRD response by measuring the level of CLL in the blood before treatment and then four months into treatment (1 month after venetoclax reaches its target dose level).
- They calculated change in MRD over those four months and wanted to see if it predicted treatment outcomes like achieving uMRD or the durability of the response after treatment stops.
- 6 in 10 patients had rapid reductions in their CLL over the four months (> 400-fold reduction in CLL level), and these patients achieved uMRD within eight months of treatment and were more likely to remain at uMRD for longer.
- Next, researchers are planning another study to determine whether a change in MRD can be used to guide decisions about treatment duration.
Based on this study, it seems that patients who can clear their CLL more rapidly are more likely to reach uMRD and remain at uMRD for longer. This may give doctors additional insights into which patients are likely to respond to treatment and who might need longer treatment duration. MRD-guided treatment decisions are interesting to researchers, and more studies are underway to see if this concept can be validated in clinical practice.
Please enjoy this interview with Dr. Soumerai from the ASH meeting, held in December 2021 in Atlanta, GA, and virtually.
You can read the actual abstract here: Zanubrutinib, Obinutuzumab, and Venetoclax in Chronic Lymphocytic Leukemia: Early MRD Kinetics Define a High-Risk Patient Cohort with Delayed Bone Marrow Undetectable MRD and Earlier Post-Treatment MRD Recurrence
Take care of yourself first.
Ann Liu, PhD