CLL Therapies: Novel Combinations

John Allen, MD, provides an overview of data looking at emerging combinations as initial therapy for chronic lymphocytic leukemia (CLL).

William Wierda, MD, PhD: Let's move on to the newer combinations that aren’t yet approved. One of the studies that was presented at EHA [European Hematology Association Congress] is the CAPTIVATE [NCT02910583] fixed-duration cohort. John, you presented that data. Can you give us a summary of that? Paolo Ghia, MD, PhD, also presented it at ASCO [American Society of Clinical Oncology Annual Meeting]. It was presented at both meetings. Perhaps give us a high-level view of what the outcomes were and your thoughts on fixed-duration combination targeted therapy.

John Allan, MD: Thank you. This was an encore abstract after Paolo presented it at ASCO. Just yesterday at EHA was the Q & A. Ultimately, CAPTIVATE is one of the largest phase 2 studies of ibrutinib-venetoclax. This obviously piggybacks off the work Nitin Jain, MD, at [The University of Texas] MD Anderson [Cancer Center]—who you and your group work closely with, Bill—had put out there with ibrutinib plus venetoclax. The first 80 patients showed really high rates of MRD [minimal residual disease] in really high-risk patients. CAPTIVATE built upon that. This is a large phase 2 study with 2 different cohorts. One is an MRD-guided, randomized, adapted approach which demonstrated a 1-year disease-free survival greater than 95% and no difference between ibrutinib continuation vs placebo.

What was presented more recently was the second part of this study looking at fixed duration, regardless of a response or an MRD attainment. All patients stop treatment, there’s 3 months of ibrutinib lead-in, tumor debulk, reduce tumor lysis, and then 12 months of ibrutinib plus venetoclax. Ultimately, 323 patients have been treated on CAPTIVATE, with 159 patients treated in this fixed-duration cohort. Ultimately, the results were very similar to what we saw in this response-adapted continuation type of treatment. The median follow-up is now about 28 months, about 2 years, or approaching about a year off of therapy with really high rates of complete remission. 56% of patients are obtaining complete remission; 96% of patients are obtaining a response with really high rates of MRD: 77% in the peripheral blood, and 60% in the bone marrow.

The estimated 2-year PFS [progression-free survival] was 95% across all studies. There were 27 patients enrolled who had high-risk 17p deletion and disrupted disease in this fixed-duration cohort, which had very similar outcomes in terms of response as well as MRD attainment, with maybe slightly lower numbers in the bone marrow. One of the big questions is how these high-risk patients will fare after stopping treatment. It remains to be seen whether we’ll see a similar story to what we see in CLL14. The CLL14 group has nicely shown that obtaining deep remissions and MRD negativity changes the biology and kinetics of these clones a little, so it'll be interesting to see if ibrutinib and venetoclax can alter that even more and maybe push out these relapses even further and cause these curves to come together. Ultimately, it provides a nice fixed-duration approach for young patients.

The other thing about this study is that it was in younger patients, and a unique approach that's different from venetoclax-obinutuzumab [VenG] because it's all oral. It was a once-a-day therapy. There's no anti-CD20 treatment. The tumor debulking is very effective, where 94% of patients are being debulked. The vast majority of these patients are not needing hospitalization, and it's a pill that you easily administer outpatient.

The venetoclax-obinutuzumab approach is 8 straight weeks with the obinutuzumab lead-in, then you start the venetoclax. There is a large commitment of patients needing to come in to initiate on a venetoclax-obinutuzumab approach. When patients have bulky disease and high white blood cell counts, obinutuzumab is not necessarily the most friendly drug to use. You can get into trouble with things like cytopenias and tumor lysis. If anything, the most unique approach about the ibrutinib plus venetoclax CAPTIVATE study, GLOW, and all these other things that were presented, is the advantages in the tumor lysis debulking. With very short follow-up, it remains to be seen if the biology changes or if these MRDs are somewhat different from what we see with VenG, but the vast majority of these patients are doing extraordinarily well. If you do attain MRD, what we see from the MRD cohorts as well as this is that patients are doing extraordinarily well going forward. There haven't been a lot of relapses.

We're now starting to see the patients who were retreated from the CAPTIVATE study. There are 8 patients now retreated with ibrutinib, depending on if they've had a really long remission. Mind you, most patients haven't progressed yet and can get ibrutinib plus venetoclax again. We'll start to see these patients come in over the next several years upon getting retreated and see what this new paradigm shift may be on these retreatment approaches. One of the things we don't know from venetoclax-obinutuzumab is this retreatment question. In the presentation, they show that vast majority of patients are still getting ibrutinib in the relapse setting and they're not necessarily getting retreated with venetoclax approaches. That may have to do with durability of the response.

As time goes on, more patients may be retreated if they relapse later on. But that's a big question to answer about the patients without IgHV mutations. To me, that will depend on if those patients will be retreated again and extend 1-year treatments into 10 years of their CLL [chronic lymphocytic leukemia] journey and so on. Those are big questions that remain answered. But the fixed-duration approaches with combination treatment have advantages of an all-oral therapy, effective tumor lysis debulking, 92% of patients complete the combination therapy, it's very easily administered outpatient, and it’s well tolerated. It now depends on sorting between older and younger patient populations. Is this a one-size-fits all approach that displaces VenG, or are there patients who may be better with a VenG approach? Are monotherapy approaches better, which comes from GLOW [clinical trial (NCT03462719)? I can let other people speak to that, but those are big questions on how broadly applicable an ibrutinib plus venetoclax approach might be for all patients with CLL.


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