The combination of ibrutinib plus venetoclax was found to eradicate minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to primary results from the phase 2 CAPTIVATE study. Further 1-year disease-free survival (DFS) data from the MRD cohort of the CAPTIVATE trial (NCT02910583), presented at the 2020 American Society of Hematology (ASH) Annual Meeting, also suggested that a fixed-duration therapy is feasible in patients who achieve undetectable MRD (uMRD) status.

The CAPTIVATE study enrolled 149 patients aged younger than 70 years with previously untreated CLL/SLL who received 3 cycles of frontline ibrutinib lead-in therapy followed by 12 cycles of combination ibrutinib and venetoclax.

uMRD, defined as 100% uMRD in peripheral blood and bone marrow serially over 3 or more treatment cycles, was found in 75% of patients’ peripheral blood and 72% of patients’ bone marrow.

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The 86 patients with confirmed uMRD were randomly assigned to receive ibrutinib monotherapy (n=43) or placebo (n=43). The 63 patients who did not achieve confirmed uMRD were assigned to receive either single-agent ibrutinib (n=31) or ibrutinib plus venetoclax (n=32).

In the confirmed uMRD group, there was no significant difference in the 1-year DFS rate between placebo (95.3%; 95% CI 82.7-98.8) and ibrutinib (100%; 95% CI 100.0-100; P =0.1475). This finding supports the use of a fixed-duration approach in patients who achieve uMRD, the study authors noted.

Among patients without confirmed uMRD, uMRD rates were found to increase to 57% in peripheral blood and 54% in bone marrow during the overall study period. At 30 months, progression-free survival rates exceeded 95% across all randomized arms.

In an interview with Cancer Therapy Advisor, John N. Allan, MD, a lead author of the CAPTIVATE study and an assistant professor of medicine in the division of hematology and medical oncology at Weill Cornell Medicine in New York, New York, discussed the findings from the uMRD cohort and their implications for the CLL/SLL paradigm moving forward.

Cancer Therapy Advisor: How does ibrutinib’s efficacy in the uMRD cohort compare with that of other therapeutic approaches to eradicate MRD in this disease setting?

Dr Allan: This study looked at the combination of ibrutinib and venetoclax and assessed its effect on achieving MRD negativity. An important part of this cohort was to then investigate how patients did when they were to receive ibrutinib vs placebo once they’d achieved an undetectable MRD state.

Early evidence has shown that ibrutinib and venetoclax work synergistically, and some of the earlier phase 2 studies have shown that also translated to clinical activity and synergy as well. Comparing ibrutinib monotherapy with combination treatments is somewhat difficult because 1 is a continuous therapy treatment. Ibrutinib or BTK inhibitors in general do not achieve MRD negativity alone in and of themselves. MRD’s role is in CLL and whether or not it is that important is still a little uncertain because you can be on drugs like ibrutinib continuously and have very good long-term outcomes without ever achieving MRD negativity.

With that setting the stage, this combination treatment has shown really high rates of MRD negativity, much more so comparatively with a venetoclax- and obinutuzumab-based regimen. No head-to-head studies have been performed yet, so it’s really hard to state if this combination is better than ibrutinib alone or is better than venetoclax-obinutuzumab, but when you look at the patient populations, they’re rather similar. And, when you look at rates of MRD negativity, the rates seem a little bit higher with this combination.

Follow-up for this study is still short, so it’s still hard to say whether stopping treatment for these patients is the right thing to do, but current evidence suggests that fixed-duration potentially has a role in CLL; it might be safe to stop when patients have achieved MRD negativity. But, we need longer-term follow-up still to truly determine that, and really that’s where the other side of this study comes into play: looking at patients who have undetectable MRD and seeing how they do on placebo vs continuous treatment with ibrutinib maintenance.