Laura Zitella: Welcome to this virtual roundtable about managing the role of BCL2 inhibition in chronic lymphocytic leukemia and what advanced practitioners need to know. My name is Laura Zitella and I'm a nurse practitioner at the University of California San Francisco. And joining me today for this discussion are two of my fellow nurse practitioners, Christina Russomanno from Columbia University Irving Medical Center, and Lisa Nodzon from Moffitt Cancer Center. Thank you so much for joining me today. Christina's going to get us started with a new case study and discuss the use of time-defined therapy with a BTK inhibitor plus venetoclax. Chrissy?
Christina Russomanno: Hi, Laura. Thank you so much. So to start, let's review this case. Very simple case. So this is John. He is a 50-year-old gentleman with CLL, del 13q. He has a mutated IGHV, so good risk factors. He was diagnosed about 3 years ago and has been monitored. No significant past medical or surgical history. As a background, he works long hours as a financial advisor and has two young children at home. His disease has been progressing. Today his labs show a white blood cell count of 230,000, hemoglobin of 7.5, platelets of 50. Let's say that we did some CAT scans. No bulky disease. So we determine it is time for him to initiate therapy. And John's preference is to pursue time-limited therapy vs. continuous. So the first question I have for Laura and Lisa is, what do you think the treatment options are for John just knowing this information?
Laura Zitella: I'd be happy to start. If John is interested in time-defined treatment, there are 2 excellent options. One is venetoclax and obinutuzumab, venetoclax being an oral medication, obinutuzumab being an IV infusion. Or acalabrutinib and venetoclax, both being oral medications. And both of these options are time-limited. There is a third option that could be considered and that is a 3-drug regimen of acalabrutinib and venetoclax and obinutuzumab, which would be 2 oral medications and 1 IV medication. And so I think the issue of incorporating an IV infusion into a time-defined treatment regimen is something that has implications for patient preference and lifestyle.
Christina Russomanno: Yes, I agree. I think that for John, right now the world is his oyster. There's no wrong answer here. And unfortunately, John is young. So most likely John will see more than 1 regimen in his lifetime or more than 2. And so we know if he wanted to avoid IV-based therapy, maybe the right choice for him would be acalabrutinib with venetoclax. But I think that really to understand some of this background, we should really review some of the most recent studies that looked at some of these combinations. So I know in our last talk we focused on CLL14. So looking at these oral regimens or a combination with obinutuzumab, we can first look at the AMPLIFY data.
So AMPLIFY was a randomized phase III study in treatment-naive CLL, really focused on young and fit patients. There were no del(17p) or TP53 patients allowed. And this also was not an MRD-driven study. Primary endpoint was PFS, so it was fixed duration, acala-venetoclax, acala-venetoclax-obinutuzumab or investigator's choice FCR or BR depending on the patient. And patients received 14 cycles and then were stopped. There was lots of data that came out of this. I'm just going to highlight a few takeaways.
So we saw better PFS with AV and the AVO arms vs. the chemo-immunotherapy, and that was including the unmutated patients when the data was censored for COVID. So just to review what that means, this study was unfortunately done during the peak of COVID. There was a lot of infection noted and there were COVID-related deaths. Most of the COVID-related deaths unfortunately were due to those who were unvaccinated. And so some of the data was skewed because of that. So they did censor the data out and rerun the data. So that's why I say after we remove the COVID patients.
There was also less cardiac toxicity and TLS with the AV and AVO arms. There were more serious AEs in the AVO arm. And the neutropenia unfortunately was comparable to the chemo-immunotherapy arms. MRD was deeper in chemo arms vs. AV, but higher undetectable MRD rates in the AVO arm. Longest PFS was obviously noted in patients with undetectable MRD at end of treatment. But really the main results I liked out of this study was that unmutated and mutated patients had similar PFS results in the AVO arm. So unmutated derived benefit from the addition of the obinutuzumab vs. just the AV.
Moving on from that a little bit, it's important to look at other studies. So there's a complementary study that was done by Matt David's group out of Dana Farber with AVO. And so knowing that AMPLIFY didn't include these high-risk patients, this group did a study with TP53 and 17p deletion patients. And unlike AMPLIFY, this was also an MRD-driven study. So at cycle 25, 60% of TP53 patients had undetectable MRD and 70% did not progress at 4 years, which is great. So this AVO becomes a viable option for these high-risk patients.
And then, finally, the MAJIC study, which we're all waiting on the data to be presented on this. This is a really important study, phase III randomized upfront study of acala-venetoclax vs. venetoclax-obinutuzumab. This was also an MRD-guided study with the primary endpoint being PFS. It included patients with all cytogenetic and molecular findings, so good for all-comers. VO is obviously an approved upfront regimen. We know that AV is not FDA-approved yet, but it is still an NCCN category 1 preferred regimen plus or minus obinutuzumab in those with and without 17p and TP53. So the VO was given per standard of care guidelines. The AV arm had a 2-month lead-in with the acalabrutinib. And there was a max of 2 years on therapy with total time on study to be about 5 years.
There are no results yet, obviously. We are waiting on all of that. We're hoping to get more MRD-guided therapy as it correlates to PFS from this, as well as to see if doublet patients need more time to achieve undetectable MRD, as well as many other data points. So based on these studies, do you feel that there is a need for obinutuzumab in John's treatment regimen? I'll focus that one at Lisa.
Lisa Nodzon: I think that's an interesting point. As you had mentioned earlier, particularly in the setting of COVID, we know that obinutuzumab can really cause a lot of issues with lymphodepletion and our patients may not respond even to vaccines 6 months to a year at least after their last infusion. So it does bring up the topic of infection risk in our CLL patients. They already have hypogammaglobulinemia and we do encourage them to receive vaccines, but yet now giving them a therapy kind of negates all of that.
So it's a consideration I think when we are thinking about using obinutuzumab in a patient, combining it as we just discussed in the clinical trial using AVO vs. AV alone. I think that's going to have to be a very individualized approach with the patient, thinking about the safety with obinutuzumab, what is it really adding to the regimen of the patient. Of course, in the AMPLIFY, we saw a bit of a PFS benefit with the addition of obinutuzumab to acalabrutinib and venetoclax, but what’s the cost, right? The cost here being infection risk in that patient. So I think tailoring it to the patient is most important if you're considering adding it.
Laura Zitella: Yes, I completely agree with what you have said, Lisa, and with Chrissy. For someone who is young and is going to require sequential treatment over time, meaning you start with your initial treatment, achieve a remission for a certain number of years and then require additional treatment, I don't know if it makes sense to use 3 drugs upfront rather than saving 1 for later because the results with the acalabrutinib and the venetoclax as a doublet regimen are so good. In addition, the obinutuzumab adds extra toxicity. With the obinutuzumab, you can see more neutropenia, more infections, and also requires the added cost and inconvenience of IV infusions that would be required.
Christina Russomanno: Yes. I have to agree with you. Looking at the data, I mean, John is the perfect patient for any regimen really, but I think for him, and especially if he wants to avoid any IV portion, the AV is a really good option for him. And as you were saying, he doesn't really need the obinutuzumab based on the data we have thus far, and we can save a lot of possible issues and side effects, including risk of reaction, cytopenias, warranting drug holds, tumor lysis. And acalabrutinib would work to debulk the patient prior to adding the venetoclax, so less risk of tumor lysis there as well.
Laura Zitella: Yes. And you mentioned the MAJIC trial. The MAJIC trial is an incredibly important trial to be doing. Before acalabrutinib and venetoclax was included in the NCCN guidelines, if a patient wanted time-defined therapy, the option was really venetoclax and obinutuzumab. And I can't wait to see the data from the MAJIC trial because I think that's going to help us know which of the 2 time-defined treatments that we have now, acalabrutinib and venetoclax vs. venetoclax and obinutuzumab, is better for individual patients, especially based on their prognostic factors like mutated or unmutated IGHV or del(17p) or P53 mutation.
Christina Russomanno: And I like that they used acalabrutinib because we know that in Europe they're using ibrutinib, but we know that second generation have a better side effect profile. So it’s also great that they're using the acalabrutinib in that study.
Lisa Nodzon: Yes. And I think the benefit of looking at MRD as a directed therapy is important too because it kind of answers the question for us, "Well, how long should therapy be?" And if we're using MRD as the guiding factor for that, we can save our patients from having prolonged therapy, increased risk for mutations, increased toxicity, increased financial toxicity as well too. So I think that's going to be very important moving forward in the future.
Christina Russomanno: That's perfect because that was actually my next question. So that's great. Because obviously right now we have no firm guidelines on MRD testing. There's no consensus on how to do this. There's flow. There's NGS. There's clonoSEQ, 10-4, -5, -6. And in the community, there's absolutely no guidelines or recommendations. But I think we can all, as you were saying, see that there can be some benefits for this.
Lisa Nodzon: And even how long should the patient remain on therapy after their MRD negative? And then the other flip part is how often should we test after they come off therapy as well too?
Laura Zitella: Well, thank you so much, Christina and Lisa, for your expert opinions and discussion. This brings us to the end of the discussion. Please see our other two videos for further discussion on the role of BCL2 inhibition and CLL at jadpro.com.
