Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Patients with CLL who were able to rapidly clear measurable residual disease (MRD) needed less treatment and experienced longer remissions than patients who reached uMRD more gradually.
Who Performed the Research and Where Was it Presented:
Dr. Jacob Soumerai from Massachusetts General Hospital Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Combination treatments that combine a BTK inhibitor and a BCL2 inhibitor have been very successful in producing deep remissions in patients with chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The BOVen trial is a phase 2 clinical trial testing the triplet combination of zanubrutinib, venetoclax, and obinutuzumab for treatment-naïve CLL / SLL. As we previously reported, the combination successfully got patients to undetectable measurable residual disease (uMRD). However, researchers also wanted to look at how long they should be giving treatment and whether the speed of the MRD response (a.k.a. MRD kinetics) predicted future patient outcomes. At the most recent ASH meeting, Dr. Soumerai presented the 5-year follow-up results from this study.
Methods and Participants:
This phase 2 clinical trial enrolled patients with CLL / SLL who required first-line treatment. Patients received a combination of zanubrutinib, venetoclax, and obinutuzumab for up to 24 months. Treatment duration was determined by MRD status, which was measured every two months. Treatment was discontinued after confirmed uMRD (10-4) in both the peripheral blood and bone marrow.
Results:
- A total of 52 patients enrolled in the study, and the median follow-up is now 57 months.
- 96% of patients achieved uMRD in the blood, and 92% of patients achieved uMRD in the bone marrow.
- MRD-free survival was 34 months. Recurrence of MRD generally occurs about two years before clinical symptoms of recurrence, such as enlarged lymph nodes or increased white blood cell counts.
- There were two very distinct groups of patients. In one group (6 in 10 patients), their MRD dropped very quickly, and they reached uMRD in the bone marrow within 8 months of treatment.
- In the other group (4 in 10 patients), MRD decreased very gradually. Though most did reach uMRD by the end of the study, it took an average of 13 months of treatment to reach uMRD in the bone marrow.
- The patients with rapid drops in MRD (fast kinetics) were exposed to much less treatment, meaning fewer side effects, fewer appointments, and fewer expenses.
- Even though these fast-kinetic patients received significantly less treatment, they had a much longer MRD-free survival (51 months) than the slow-kinetic patients (23 months).
- Retreatment with zanubrutinib and venetoclax when needed was well-tolerated and effective.
Conclusions:
Patients who were able to clear MRD faster needed less treatment and experienced longer remissions than patients who cleared MRD more slowly. This appears to be a novel finding not correlated with typical risk biomarkers, such as TP53 mutation of IGHV status. However, more research is needed to understand the biology underlying these differences. Understanding what is causing these differences in MRD kinetics will be key to helping clinicians decide whether different approaches might be needed with patients with slow MRD kinetics. This finding is interesting considering the somewhat conflicting observation that patients with the more favorable biomarker of being IGHV mutated may respond more slowly to monotherapy with BTK inhibitors but have more durable responses. This suggests that what we can learn from disease kinetics is influenced not just by the nature of the disease, but also by the therapies being used to control the CLL / SLL. A phase 2 trial of BOVen using MRD kinetics to determine treatment duration is active now.
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract here: Multicenter Phase II Trial of Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen) in Treatment-Naïve Chronic Lymphocytic Leukemia: 5-Year Follow up, Retreatment Outcomes, and Impact of MRD Kinetics (ΔMRD400)
