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

Laura Zitella:

Welcome to part two of a Roundtable Discussion about BCL-2 inhibition in chronic lymphocytic leukemia. My name is Laura Zitella, and I'm back with my colleagues, Christina Russomanno and Leigh Ann Childress.

Christina and Leigh Ann, thank you for joining me again. In the first part of our discussion, we talked about first-line treatment options for CLL, with a focus on BCL-2 inhibition. Now, let's talk about second-line treatment for CLL, and the role of BCL-2 inhibition in second-line treatment with review of a case study.

To start off our discussion, just a brief review of the preferred regimens for CLL according to NCCN. we talked a little bit in the first section about our first-line options, which basically are a BTK inhibitor, or a fixed duration therapy with venetoclax and obinutuzumab. Now, in the relapsed and refractory setting, we can sequence these treatment options by using a BTK inhibitor, if we used venetoclax and obinutuzumab in the first-line, or if we used a BTK in the first-line, we could use venetoclax and rituximab in the second-line. It's also possible that patients were treated in the first-line and enjoyed many years of progression-free survival and were off therapy when they developed relapsed disease, is to consider using the same treatment that they received in the front-line.

We have a lot of different options, and we have a lot of different discussions with patients about sequencing therapy. One of the clinical trials that has been done for CLL is the MURANO trial, and that is the trial that serves as the basis for using venetoclax and rituximab in the relapsed and refractory setting.

Christina, can you talk to us a little bit about the MURANO trial and what it showed?

Christina Russomanno:

Of course. The MURANO trial was a randomized phase 3 trial in relapsed/refractory CLL, where patients were randomized to venetoclax with rituximab or bendamustine with rituximab. The venetoclax-rituximab was a 2-year regimen. Obviously, the rituximab was for 6 months, the venetoclax for a total of 2 years, as opposed to with CLL14, which we talked about in our last segment, where the venetoclax was only given for 1 year. And the bendamustine and rituximab was given for 6 months.

This study showed a survival benefit with venetoclax-rituximab vs BR. The 5-year median PFS, at least in the 5-year follow-up data, showed with venetoclax-rituximab 53.6 months with median PFS, vs bendamustine-Rituxan, which only had 17 months. And the overall survival rates at 5 years, 82.1% with the venetoclax-rituximab, vs 62.2% with the bendamustine-rituximab. Patients with high-risk cytogenetic markers did have worse outcomes than those without, but survival did remain superior with venetoclax-rituximab vs BR, regardless of the cytogenetic markers. Basically, this is just another study that was able to show that a novel agent in combination was better to treat CLL than chemoimmunotherapy.

Laura Zitella:

Thanks so much for that, Christina. The venetoclax-rituximab regimen, the treatment schema is a little bit different than venetoclax and obinutuzumab, and one of the big differences is that this regimen, the venetoclax is started first, prior to starting rituximab.

Leigh Ann, can you walk us through the treatment schema for venetoclax-rituximab?

Leigh Ann Childress:

Yes. You're still, again, there are many similarities in this particular treatment schema, but also some key differences, as you mentioned. We're still on a 28-day cycle, we're still using venetoclax and an anti-CD20 agent. The difference here, again, is the fixed duration of therapy, again, is 2 years, as compared to 1 in the venetoclax-obinutuzumab regimen that we've already discussed. This is, again, a 5-week ramp-up dose, where you increase the dose once weekly from 20 to 50 to 100 to 200 to 400 mg weeks 1 through 5, and then you're going to continue that venetoclax, 400 mg a day, as long as it's well-tolerated, for up to 2 years or until toxicity or disease progression, and that's from cycle 1, day 1. The rituximab actually starts after the ramp-up of the venetoclax, the anti-CD20 agent comes second in this particular treatment schema, and you're starting it at 375 mg/m² with cycle 1, and then you escalate that to 500 mg/m² on cycles 2 through 6 with that.

Laura Zitella:

Great, thank you. And then, once you are on the full dose venetoclax, we continue the venetoclax for 2 years. As you said, there are some similarities, but there are some key differences. We talked a little bit about the management of venetoclax in the first-line setting, but we didn't touch on all of the side effects. We talked a little bit about neutropenia, we don't need to repeat that here, but there are some gastrointestinal toxicities as well.

Leigh Ann, can you talk to us a little bit about what GI toxicities you see and how you manage them?

Leigh Ann Childress:

Sure. One point I want to make upfront about the GI toxicities, even though they were documented on clinical trials, what we see in most, with not only the BTK inhibitors but also with BCL-2 inhibition and things like rituximab and obinutuzumab, is normally the GI toxicities are very mild and manageable with all of these drugs that we use for CLL. And in my clinical practice, oftentimes what I see is we see more of these GI toxicities in, say, the first 6 or 8 weeks on therapy, and then it does tend to get better with time, whether that's just over time exposure to the drug or whether the patient has maybe identified some adequate coping strategies, I'm not really sure, but we do tend to see it improve. Encouraging your patients that you'll experience this at a certain level for probably the first month or two, but it will improve with supportive care.

With diarrhea, of course, encouraging your patient to hydrate if they're having loose stools, to make sure that they stay adequately hydrated in the setting of these agents that we're treating them with, but also using anti-diarrheals, loperamide is a great entry level option for this, and oftentimes is just enough to take care of the problem, but you do have other prescription agents that you can introduce if it's a persistent problem. Also, taking your venetoclax with a high-fat meal or snack in the evening or before bed, sometimes moving to that bedtime dose of your oral agent with a lot of different agents can improve the GI toxicities, or the patient's tolerability of those toxicities, so that's a consideration. There were also some events of nausea on this regimen, and it was, again, generally very mild and manageable with things like ondansetron or prochlorperazine.

Laura Zitella:

Thanks, Leigh Ann. I think you brought up an important point too, that it is important to take the venetoclax with a meal, so whether they're taking it in the morning or the evening, it's still important to make sure to remind them that they're taking it with a meal, and also that they're continuing to have good oral hydration of at least 1.5 to 2 liters per day. There's also some food-drug interactions, so we educate patients to avoid starfruit, grapefruit, and Seville oranges. And then, being an oral medication, there can be issues with adherence. 

Christina, how do you help patients come up with strategies to remember to take the medication every day?

Christina Russomanno:

It starts with a lot of education. The medication only works if you take it correctly. We encourage patients to keep a calendar, keep a diary. When you take that medication, whichever form you prefer, you check off a box, you move a switch, they have lots of options now for reminders for patients. But we really tell them, "If you stick with the schedule and you take it at the same time each day, you always take it with your breakfast, you always take it with your morning coffee, whatever it is, that really should be a trigger to remember." Writing it down, we try all little tricks, everyone's different, but we really do find that most CLL patients are very responsible, and thankfully, with venetoclax being a once-a-day drug, that makes it a little bit easier to ensure some compliance.

Laura Zitella:

Great, thanks. And what other side effects are you seeing with venetoclax?

Christina Russomanno:

Going back to GI a little, we actually see a lot of complaints of bloating and gassiness in patients, just because that one wasn't brought up, and that's something that's not specifically outlined in the literature, but a lot of patients do complain of that. I just wanted to bring that up a little, that we do recommend that they use a simethicone, Gas-X, which works really well.

But other than that, with the venetoclax, most of what we see is cytopenias, so we see thrombocytopenia and neutropenia very often with these drugs. And so, again, I know we had previously talked about it a little, but with the neutropenia, obviously, we do try to push our patients through, especially during a ramp-up, but there is, at any point in time, the ability to hold the drug and/or dose reduce the drug. And with thrombocytopenia, again, you might also have to hold the drug and/or dose reduce, especially patients who might be on anticoagulation or other things. You really have to be careful and monitor for these cytopenias.

Laura Zitella:

Yes, I agree. One other side effect that I have seen a bit of is cough, and anytime a patient has cough, obviously, we have to rule out infection, because people with CLL are at higher risk of having sinus and pulmonary infections, so I always do an infectious workup, and check COVID, and check a respiratory viral panel, consider the possibility of GERD.

But it's been very interesting, I have seen a number of patients that had not had an infection and truly just had a cough, and I know that it was the venetoclax, because in some of these patients, we had to hold the venetoclax for another reason, and the cough immediately went away the week they were off, and then when we restarted it, it came back again. I can think of one patient in particular that this persisted during the entire time he was on therapy, and I had him take guaifenesin, long-acting, twice a day, and that managed it so he was able to continue therapy. But I looked, and the incidence of it is pretty low, but I've seen it a bit in my practice, so I thought I would just mention that also.

Let's move on to a case study. Because the venetoclax-rituximab regimen is a little bit different, we talked earlier about how the risk of tumor lysis syndrome with venetoclax-obinutuzumab was greatest prior to starting obinutuzumab, and by the time that you came in with the venetoclax, the risk of tumor lysis is generally pretty low. But with venetoclax-rituximab, this is reversed. I'd like to talk to you about a patient that I had who I treated, and she was a 68-year-old female who initially was on acalabrutinib, but unfortunately had progressive disease. The plan was to start venetoclax and rituximab, and her white blood cell count was 140,000, and her lymphocyte count was 134,000, so she had very, very elevated lymphocyte counts, and on exam, she had palpable spleen, and she had 2–3-centimeter lymph nodes in her neck and her axilla. One of the first considerations before starting the venetoclax was, what is her risk of tumor lysis syndrome, and could she start venetoclax as an outpatient, and what precautions should be taken?

Christina, can I have you comment on the risk of tumor lysis syndrome in a patient who has an absolute lymphocyte count of 134,000 and lymph nodes that are about 2-3 centimeters in size?

Christina Russomanno:

Yes, the lymph nodes themselves are relatively small, but her absolute lymphocyte count is high, and so she falls, really, in my perspective, she would fall in the high tumor burden just because of that absolute lymphocyte count and the high white blood cell count. For this patient, if you are initiating therapy with venetoclax ramp-up, this is a patient you would watch super closely and/or consider possibly ramping up in the hospital setting.

Laura Zitella:

Yes. Well, we had quite a bit of a discussion about it, she also had a history of SVT, and we talked to her a lot about whether or not we should admit her for monitoring or whether we could do it outpatient. Now, technically, according to the tumor lysis risk stratification prophylaxis guidelines, she technically was medium tumor burden because the lymph nodes were all less than 5 centimeters, but as you pointed out, the lymphocyte count was really high, so I knew she was high-risk. But we talked about it together, and she wanted to try it as an outpatient. I said that would be okay, but in this situation, because she was so high-risk, I told her that she would need to be in the infusion center all day getting hydration, and making sure that we monitored the tumor lysis labs 6 hours after she started the venetoclax dose, and if there were any significant abnormalities, then she would need to go the hospital.

We arranged all of this, and, of course, started the allopurinol, I started it a week before the first dose, and she was really diligent about making sure she was drinking about 90 ounces of fluid. She was a very motivated patient. And so, she goes to the infusion center, and we do the pre-dose tumor lysis labs, and her potassium was 6, which is very high, and her phos was four, and her uric acid was 3.5, which is good, calcium was 9.8, creatinine was 0.9, so good kidney function, and she had an elevated LDH. The infusion nurse saw these labs and, of course, was appropriately concerned that there already was tumor lysis, and was wondering if I should admit the patient for monitoring and if it was safe to continue as an outpatient.

Leigh Ann, I will ask you, if you had a patient and you saw these labs, what about the potassium would concern you?

Leigh Ann Childress:

In the community-based setting, it's not often that we're going to see a patient with a white blood cell count of 140,000, so we're already alarmed when we see that. And then, these pre-dose labs, if the potassium comes back at elevated, and, as in this case, it's 6, you need to suspect that this patient may in fact have pseudo-hyperkalemia, simply because the white count is so high, because when you have a white count that is this high, oftentimes these white blood cells are very fragile, and when you put them into the centrifuge to spin the test, basically, those cells start to lyse, and you get release of potassium into that blood sample, which gives you a falsely elevated potassium.

Just like in many other aspects of practice, if you get an elevated potassium that you simply can't really explain, oftentimes one of the things that you want to do is repeat it, but in this case, you could actually get venous blood gas, or you could just repeat a serum potassium and look at that. But that's one consideration when you have a white count that's this high is to consider that as a possibility.

Laura Zitella:

Yes, thanks. That's exactly it. I think it's a really important clinical pearl to know that you can have a pseudo-hyperkalemia with a high white blood cell count. I had another patient that had a high white blood cell count, because in CLL, a high lymphocyte count is not an indication for treatment, so if someone doesn't have cytopenias or bulky lymphadenopathy, sometimes they are not undergoing treatment and their white count is a 100,000, 150,000, 200,000 even. And I had another patient that was being seen by cardiology and had an elevated potassium, and they sent him to the emergency room, and I had to call the emergency room and explain to them that they should check VBGs, and it turned out his potassium was normal, and it was just the pseudo-hyperkalemia. I think that's a really good clinical pearl for practitioners to know.

For this case, the potassium actually was normal when we checked the whole blood potassium, and it was 4.2. And so, we had her take her first dose of venetoclax there in the infusion center, we started IV fluids, and then we checked labs 6 hours after that dose, and fortunately, she did not have tumor lysis. The potassium was normal at 4, the phos was 3.7, the uric acid was 3.1, her creatinine was 0.9. Her LDH went up a little bit, but that's not a criterion for tumor lysis, but it did show us that there probably was some breakdown of the CLL cells, but no tumor lysis.

She came back the next day and we did 24-hour post-treatment labs, and again, there was no tumor lysis. And then, we did the same thing with day 8 for the ramp-up dose, is we had her check labs the day before, we had her come to the infusion center, take her 50 mg dose in the morning. We kept her in the infusion center all day for 6 hours of IV hydration, and then repeated the labs, and then the following 24 hours later. Fortunately, she did really well, and after that, she had weekly visits with labs until the ramp-up was completed. And then, she continued the venetoclax and had complete resolution of lymphadenopathy and splenomegaly. This patient has now completed 2 years of therapy.

And as I mentioned in our earlier segment, at my institution, we do check measurable residual disease testing using the clonoSEQ next generation sequencing platform, and her measurable residual disease after 2 years of venetoclax and rituximab was 0 in a million cells. That was really exciting news to be able to share with her, and to be able to tell her that that is associated with prolonged progression-free survival.

I'm curious, Christina, in your experience, after the patient has completed the venetoclax ramp-up and has completed Rituxan, in that period of time where they're only on the venetoclax, how often are you seeing the patients? How often are you checking labs?

Christina Russomanno:

Honestly, it depends on the patient, but there are periods of time where we will let them go up to 3 months. If they are doing well, they're stable, they're compliant, we check in on them here and there in 3 months, and we'll check labs every 3 months.

Laura Zitella:

And Leigh Ann, what's your practice?

Leigh Ann Childress:

It's pretty much the same with us. We typically check them monthly, up until they've reached that first year on therapy, and then, after that, depending upon, again, as Christina said, how stable the patient is, how well-tolerated the medications are, oftentimes we will go to a quarterly check at that point.

Laura Zitella:

Yes, same with us, monthly for the first year, and then if counts are really stable, we move to every 3 months.

Well, that was great. I really appreciate being able to talk to both of you about this and hearing about your clinical practice.

This brings us to the end of this part of the discussion. For more information and for the final chapter of this discussion, please visit JADPRO Online at JADPRO.com. Thank you very much.