What Advanced Practitioners Need to Know About BCL-2 Inhibition in CLL

Laura Zitella:

Welcome to part three of our Roundtable Discussion about BCL-2 inhibition in chronic lymphocytic leukemia. My name is Laura Zitella and I'm back for a final time with my colleagues Christina Russomanno and Leigh Ann Childress. Christina and Leigh Ann, thank you for joining me again.

In our previous discussions, we covered the first-line and second-line treatment of CLL using BCL-2 inhibition combinations. In this section, I want to briefly talk about the combination of BTK inhibitors and BCL inhibition, and then discuss with you how we employ shared decision-making with our patients to be able to choose among all of the different options of therapy that we have.

Starting with the combination of a BTK inhibitor and a BCL-2 inhibitor. The combination of venetoclax and ibrutinib is not currently FDA-approved, but it's now recommended in the NCCN guidelines for first-line, second-line, or third-line therapy as a category B recommendation. Keep in mind that a category B recommendation is based on lower-level evidence and it's based on NCCN consensus, but not uniform consensus. So that means that not all of the members agreed that this should be recommended in the NCCN guideline, but enough did that there was a consensus. The majority thought the intervention was appropriate.

Venetoclax and ibrutinib, that combination was studied in the CAPTIVATE trial. Christina, can you tell us about the treatment schema in the CAPTIVATE trial and a little bit about the results?

Christina Russomanno:

Sure. This trial is exciting, as all these combination trials are for us, because of the synergistic effect these two drugs can have on one another, and now we're kind of pinpointing two different targets, which is really exciting. CAPTIVATE, a fixed-duration oral ibrutinib and venetoclax, 3 cycles of ibrutinib lead-in. This is to de-bulk the patient, decrease the risk of tumor lysis syndrome once we add in the venetoclax. There are 12 cycles of ibrutinib at 420 mg daily, plus the venetoclax, the 5-week ramp up to 400 mg daily. This study really showed they achieved high rates of MRD. The 24-month PFS was 95% and overall survival was 98%. These are pretty amazing outcomes.

Laura Zitella:

Wow. Yes, it is. Again, there's a lot of interest in being able to come up with a fixed-duration therapy that allows patients a time off therapy. One of the considerations with using combination BCL-2 and inhibition and BTK inhibition is that you have the potential for side effects from the BCL-2 inhibitor, venetoclax, and you have the potential for side effects from the BTK inhibitor, whichever one of the approved inhibitors that is being used, and they're all being studied in combination. But I think one of the big advantages with a fixed-duration regimen is that there may be fewer side effects to the BTK inhibitors because you just are exposed to them for a shorter period of time, so there's a possibility of less toxicity. Is that what you've been seeing in your practice?

Christina Russomanno:

Yes. You have to consider that because there are, especially some of these longer term side effects to the BTK inhibitors, which increase with time on drug like arrhythmia, atrial fibrillation, or hypertension. You've kind of now given them a great chance of actually avoiding those toxicities, which when you talk to a patient about side effects of drugs, the cardiac side effects are always going to be the ones that scare them the most. They're always the ones they want to talk about. Yes, I do think that you do get away from some of those longer-term toxicities that are possible with the BTK inhibitors with limiting the time you're on the drugs. Absolutely.

Laura Zitella:

Yes. Now that we have all of these options, there are a lot of lengthy and extensive discussions, and one of our big roles is trying to help patients decide what is the best treatment for them is through using shared decision-making. With shared decision-making, we're seeking the patient's active participation and we're helping them explore and compare the treatment options. There’re a number of things to consider.

Leigh Ann, what are some of the considerations for your patients when you're trying to decide between the available therapies for CLL?

Leigh Ann Childress:

I think sometimes it's considering where they are in life. My young career professionals, oftentimes they want a fixed duration of therapy. They want a limited amount of perceived time off work, they want a limited amount of financial toxicities with copays, oftentimes on continuous therapy, those can actually get higher with time. Whereas I'll have an older adult that maybe cannot tolerate the logistics of a combination regimen, albeit fixed-duration, they would rather take a pill once or twice a day and be able to have monthly monitoring schedules because that's easier for them logistically.

Also, I think considering whether your patient is comfortable in the infusion suite. Sometimes when you talk about infusional reactions with agents like obinutuzumab and the fact that they may in fact end up being in the infusion suite all day, or with the combination regimen they might be in the infusion suite for prolonged periods of time waiting on laboratory, and there may be multiple days that they would have to travel or they would have to take off work or their spouse take off work. I think getting a preference for duration of therapy, fixed vs continuous, and what the patient has in mind, but also logistically what they can accomplish, whether that's them or their support system. And also considering financial toxicities in that. What do the co-pays look like?

Also, the financial toxicity of being away from work. If you have someone that is still a provider for their family taking multiple days off, if they're self-employed, they might lose income, which will impact them in a different type of toxicity. I think considering all of that and just meeting your patient where they are and what they feel like they can accomplish with you in a treatment regimen, because that is so important because you can have a gloriously effective treatment regimen and a very smart plan for the patient, but if you do not have the patient and caregivers buy-in, you've really gotten nowhere. Shared decision-making is super important in that situation.

Laura Zitella:

Yes, thank you for that. Those are similar discussions and similar considerations that I have in my practice as well. Christina, do you have anything to add?

Christina Russomanno:

Yes, I just think that the shared decision-making with the patient invests them more in their therapy and the commitment to their therapy, so that's super important. You'll always get those patients who will say, "Whatever you say, whatever you recommend, I'll do." But sometimes if you talk through it with them and they feel like they've been heard and every part of them has been considered when you make a treatment decision, they feel more like a human being and part of the team.

I think it's also important to stress to some of these patients that unless you're giving someone chemo immunotherapy, it's really hard to make the wrong decision because most of these patients will see a BTK inhibitor at some point in their therapy and a venetoclax-based regimen. Again, we might have our preferences and they might have their preferences, but in the long run, they most likely will see both. We can't say that they're going to make a wrong decision. Again, I only say if you give them a chemo immunotherapy, which we know is not traditionally used. Those are really the only real extras I wanted to throw in there about that.

Laura Zitella:

Yes, thank you. That is a really good point, and it is hard. It usually is a hard decision for patients, and they do rely on us a lot to help guide them in making that decision. I like what you said about reassuring them that you can't make the wrong decision. These are all appropriate treatment options, and if we don't use one in the first line, it's available to be used later on.

I think even with venetoclax and obinutuzumab, especially at centers that do this a lot, that have a high volume, we become very comfortable in administering this treatment to older patients. I have several patients who are in their late eighties that have done very well on venetoclax and obinutuzumab, so we don't necessarily need to use it in the front line. It can be used second line, and the same goes for the BTK inhibitors.

I think the last thing that I wanted to add is the importance of us being familiar with this data and being able to talk to patients about it. With most patients with CLL, they don't need to start treatment right away, and we have time. So, we start these discussions early on before they need treatment, and then every time we're seen, they talk about it again.

Just the other day in clinic, I had a patient that I was seeing who is not on any therapy and doesn't need therapy right now, but the plan was to do a BTK inhibitor based on his previous discussions with his hematologist. I reviewed the process of starting a BTK inhibitor, what to expect and side effect profile, and then I also mentioned using venetoclax and obinutuzumab. After our discussion, he was like, "Oh, wow, I didn't realize it was a time-defined therapy. I didn't know what that meant. I didn't realize that meant that there was going to be a period of time where I didn't have to take therapy." I know he's had at least 4 or 5 different discussions with his hematologist before, so that reinforced to me how much of this information is new and how much needs to be repeated and reinforced and our important role in reiterating the education every time we see the patient.

In conclusion, what we can say about sequencing of first-line therapy is that there's really no head-to-head comparisons of BTK inhibitors and venetoclax-based therapy in the frontline setting. We can look at the different trials, but those are comparing different patient populations. The longest follow-up that we have with the BTK inhibitor is with the ibrutinib, and at 7 years the progression-free survival has not been reached, so that's excellent. But that trial did exclude people who had CLL that carried the deletion 17p, so it was a group of patients with more favorable CLL. The 6-year follow-up for venetoclax and obinutuzumab, the progression-free survival was more than 6 years. Again, you can't really compare across trials, but both of these regimens have excellent outcomes.

I think as we go forward, it would be really important to have some perspective data, and that will help inform our shared decision-making a little bit better if we can see that one or other therapies have more of a progression-free survival. But in my experience with my patients, patients are very interested in being able to have some time off therapy. Christina, did you have anything else? Any other takeaways for our viewers today?

Christina Russomanno:

No. The biggest thing I stress being in nursing is just communication with the patient and frequent re-education, as Laura was just saying. There's constantly new information, new study results, there are new drugs coming down the pike, so it's really important that we stay educated, but that we also maintain education with the patients, and we keep the lines of communication open.

Laura Zitella:

Thank you so much. And Leigh Ann?

Leigh Ann Childress:

I think just continuing to make your patient a stakeholder in their treatment plan as well as the management of AEs, just including them, and as Christina said, educating them and also preparing them for next steps. Letting them know what is next after this duration of therapy or if you were to progress, what would be next, so that they're prepared, they're doing their research, and they come in to your visits ready to ask appropriate questions. They've been able to do their homework, and again, they feel like they are at the table where the decision is made. I think that's really important in this situation, especially when there's so many great options available to them.

Laura Zitella:

Thank you.

Well, this brings us to the end of our discussion on BCL-2 inhibition in chronic lymphocytic leukemia. Leigh Ann and Christina, thank you so much for sharing your expertise and your experience. For more information and to view more discussions on CLL and other topics, please visit JADPRO online at JADPRO.com.