The combination of zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax (Venclexta) (BOVen) has demonstrated promising long-term responses in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 2 BOVen trial (NCT03824483) revealed that this triplet therapy induced high rates of undetectable minimal residual disease (uMRD) in both peripheral blood and bone marrow, suggesting the potential for an MRD-driven treatment approach.
High uMRD Rates and Treatment Discontinuation
In the study, 50 patients were evaluated for best end-of-treatment response. The results showed that 96% achieved uMRD in peripheral blood alone, while 92% achieved uMRD in both peripheral blood and bone marrow. All 46 patients who met the prespecified MRD endpoint discontinued treatment after a median of 10 months (interquartile range [IQR], 8-12).
According to Dr. Jacob Soumerai of Massachusetts General Hospital Cancer Center in Boston, the lead study author, "BOVen was well tolerated with no additional safety signals and durable PFS with long-term follow-up."
MRD Kinetics and Treatment Duration
The study also evaluated ΔMRD400, a measure of MRD kinetics quantifying at least a 400-fold reduction in MRD from baseline to cycle 5. Results indicated that 60% of patients achieved ΔMRD400, all of whom went on to display uMRD in bone marrow at 8 months. In contrast, only 21% of patients who did not achieve ΔMRD400 reached uMRD in bone marrow.
Notably, patients who achieved ΔMRD400 had a shorter median time on therapy (8 months) compared to those who did not (13 months, P < .001). Median MRD-free survival was not reached in patients who achieved ΔMRD400, versus 18.1 months in those who did not (HR, 4.02; 95% CI, 1.37-11.81; log-rank P =.003).
"ΔMRD400 at cycle 5 day 1 predicted early uMRD in the bone marrow and shorter duration of therapy," Dr. Soumerai noted, adding that ΔMRD400 did not correlate with traditional risk factors such as TP53/del(17p) or unmutated IGHV.
Safety Profile
Regarding safety, grade 3 or greater adverse events (AEs) included decreased neutrophil count (grade 3, 10%; grade 4, 13%), decreased platelet count (grade 3, 8%), lung infection (grade 3, 6%), and infusion-related reactions (grade 3, 2%; grade 4, 2%). Other common AEs included fatigue, diarrhea, bruising, and cough.
Future Directions
Based on these findings, a phase 2 study of BOVen with ΔMRD400-directed treatment duration has been initiated. Patients who fail to achieve ΔMRD400 will receive 24 months of therapy versus 10 months. The hypothesis is that a longer duration of therapy for these patients will further improve uMRD duration.
The BOVen regimen shows promise as a well-tolerated and effective treatment for previously untreated CLL/SLL, with the potential for MRD-driven treatment strategies to optimize patient outcomes.
