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

Laura Zitella:

Welcome to JADPRO's Roundtable Discussion on BCL-2 inhibition in chronic lymphocytic leukemia. My name is Laura Zitella and I'm a nurse practitioner at University of California San Francisco. Joining me today are two of my colleagues, Christina Russomanno and Leigh Ann Childress. Christina, can you please introduce yourself?

Christina Russomanno:

Yes. Hi, my name is Christina Russomanno. I am an adult nurse practitioner working almost entirely with CLL patients. I work at Columbia University Irving Medical Center in New York City.

Laura Zitella:

Welcome, Christina. And Leigh Ann, can you please introduce yourself?

Leigh Ann Childress:

Hi, I am Leigh Ann Childress. I am a nurse practitioner at Clearview Cancer Institute in Huntsville, Alabama. We are a truly community-based practice with 13 locations across the northern part of the state.

Laura Zitella:

Leigh Ann and Christina, thank you so much for joining me today. I thought we could start off this Roundtable series with a brief overview of CLL and then focus on using BCL-2 inhibition in the first-line treatment of CLL. So just briefly, I think most of our viewers are familiar with chronic lymphocytic leukemia, which is the most common adult leukemia. It's a chronic, incurable mature B-cell neoplasm, which is typically diagnosed on routine blood work and often patients are asymptomatic when they first present. They don't always require immediate treatment. In fact, for CLL, treatment is only required if there are symptoms such as bulky lymphadenopathy or cytopenias. And when a patient is first diagnosed and prior to initiating treatment, it's very important that they have certain diagnostic tests such as FISH testing, TP53 mutation testing and looking for the IGHV mutation. We know that deletion 13q, as a sole abnormality, is associated with a favorable prognosis. We also know that the presence of a mutated IGHV portends a favorable prognosis.

Now some of the higher risk genetic features are deletion 17p, deletion 11q, a TP53 mutation, and an unmutated IGHV mutation. Most patients with CLL are diagnosed at an older age and the median age is about 70 years. And fortunately, most of these patients enjoy very long overall survival and are more likely to die from something else rather than their CLL. But it is very heterogeneous, and some people unfortunately have a more aggressive disease course with CLL.

When we think about the possible treatments for CLL, a lot has changed over the landscape in the last few years and it's really moved away from chemotherapy and more toward targeted treatments. And these targeted treatments were developed through an understanding of the pathogenesis of CLL. CLL being a B-cell malignancy, has a B-cell receptor on its surface and this B-cell receptor is also triggered by other factors downstream. So this is critical for the growth and development of CLL.

There are targeted therapies that can target some of the downstream effects of the BCR receptor and block its function. So, for example, there's BTK and there are BTK inhibitors, acalabrutinib, ibrutinib, and zanubrutinib. And there's also P13K and we have the inhibitors, duvelisib and idelalisib. Now on the mitochondria, there is expression of a protein called BCL-2 and BCL-2 is critical for the survival of CLL cells because it inhibits cell death, so it promotes their survival by inhibiting cell death. And BCL-2 is over-expressed on CLL cells. We do have a BCL-2 inhibitor, venetoclax.

All three of these classes of drugs are targeted therapies that are possible to use for the treatment of CLL. The 2024 NCCN guidelines lists a few preferred regimens for CLL and at this time currently, there are three preferred regimens. One is acalabrutinib, which is a BTK inhibitor ± obinutuzumab, which is an anti-CD20 monoclonal antibody. Another is venetoclax and obinutuzumab. Venetoclax is a BCL-2 inhibitor, and obinutuzumab, of course, is an anti-CD20 monoclonal antibody. And lastly zanubrutinib as monotherapy, and that's a BTK inhibitor.

Now there are some differences in the logistics and treatment schema for these preferred regimens. Acalabrutinib and zanubrutinib as BTK inhibitors are for generally continuous therapy and they are available in pill form, whereas venetoclax and obinutuzumab is a time-limited therapy where patients receive 12 cycles of treatment and then they have time off of treatment.

For the remainder of this discussion, we're really going to be focusing on the logistics of using venetoclax and obinutuzumab as a fixed duration therapy in the first-line setting. And this was based on the CLL 14 trial, which showed that there was a significant progression-free survival benefit for patients who were treated with venetoclax and obinutuzumab vs chlorambucil and obinutuzumab.

The median overall survival in patients treated with venetoclax and obinutuzumab was more than 6 years, so that was a very significant outcome, and it also was highly effective even in patients who had some poor genetic features like the TP53 mutation or del(17p) or IGHV-unmutated CLL. The other observation with this study is they used MRD, or measurable residual disease testing, and found that many patients were able to achieve undetectable measurable residual disease and that this was associated with a longer progression-free survival, so a longer time with the CLL in remission and a longer overall survival. Some of the side effects that we're seeing included cytopenias, pneumonia, and infection-related reactions. And then there are also some other special considerations using this regimen that I'd like to talk about.

With the fixed duration treatment with venetoclax and obinutuzumab, there is a very detailed treatment schema. Christina, would you be able to review with us the logistics of the treatment schema for venetoclax and obinutuzumab?

Christina Russomanno:

Sure, absolutely. Looking at this, you could be a little confused at first, so this takes some time. But the way this regimen works is you would start with obinutuzumab in cycle 1. The first dose of obinutuzumab is split over days 1 and 2. The first day you would receive 100 mg, followed by 900 mg on day 2. Day 8, you would receive your full 1,000 mg and on day 15, 1,000 mg. At this point in time, you would most likely have very diminished blood counts. Hopefully some of your tumor burden would be down. So, then we start introducing the venetoclax ramp-up around day 22 of cycle 1.

The way the venetoclax ramp-up works is you increase the dose once a week for 5 straight weeks. You would start with 20 mg week 1, then you would move to 50 mg week 2, 100 mg on week 3, 200 mg on week 4, and 400 mg on week 5. Once you get to 400 mg, you'd continue that daily through cycle 12. And at the same time the obinutuzumab, the 1,000 mg dosing is continuing monthly through cycle 6.

Laura Zitella:

Thank you, Christina. One of the interesting aspects of the way that this regimen is administered is that there is a ramp-up for venetoclax, and the reason that venetoclax has ramp-up dosing is because of the risk of tumor lysis. One of the big considerations when we're starting patients on therapy is assessing for the risk of tumor lysis. Leigh Ann, can you tell us a little bit about how you approach preparing a patient for therapy with venetoclax and obinutuzumab in terms of tumor lysis prophylaxis?

Leigh Ann Childress:

Yes. One of the first things I think that I consider is who the patient is at baseline. What is their comorbidity situation? Do they have preexisting renal disease that may give them an increased propensity to have TLS with this drug regimen? I also consider that you have to know where your patient is with regard to their disease status. Do they have bulky lymphadenopathy? Do they have a high absolute lymphocyte count that will predispose them to higher rates of TLS? As far as the patient and their role in things, how well do you think that that patient may be able to hydrate for you? And then also, will that patient be able to logistically accomplish what is needed to monitor them for TLS, such as can they make it for laboratory? Do they understand the importance of the laboratory monitoring with the initiation of both of these drugs?

Laura Zitella:

Great, thank you. In addition to tumor lysis, which we're going to talk about a little bit, we also need to make sure that we do screening for hepatitis B serologies because there is a risk of reactivation of hepatitis B with obinutuzumab. And if the patient is a carrier of hepatitis B or has a history of hepatitis B, there is a very easy hepatitis B prophylaxis medication we can use. I typically use entecavir.

Tumor lysis syndrome was something that was seen in the initial phase 1 trials of venetoclax because these medications are so effective and rapidly reduce the tumor burden. And a few of those cases did result in renal failure or death, so prophylactic measures were instituted, the ramp-up dosing regimen was instituted. And now clinical tumor lysis syndrome is rare. We still do see some laboratory tumor lysis, which is fairly easy to manage.

But I think the other key thing with this regimen is that we need to also be managing tumor lysis syndrome prior to the obinutuzumab. And Christina, I wonder if you could comment on what you see in your patients in terms of their risk of tumor lysis before the obinutuzumab vs the venetoclax and comment on how effectively the obinutuzumab will cyto-reduce?

Christina Russomanno:

Sure, absolutely. Since we start this regimen out with the obinutuzumab, there is definitely a higher risk of tumor lysis before starting the obinutuzumab. So we have to prepare accordingly. These patients obviously we're going to risk-stratify based on their white blood cell count, based on their tumor burden. There's a whole schema to use to determine if your patient should be monitored in a hospital setting because of their risk of tumor lysis or if this can be done as an outpatient. Personally, I find that most of the patients who are initiating therapy fall into the medium-to-high risk category and wind up being hospitalized for initiation of obinutuzumab just because of that risk so that they can have constant hydration, frequent lab monitoring. Obviously we would start an anti-hyperuricemic, increased hydration before they start, and a lot of these patients will even start on some steroids beforehand to try to decrease the risk of a reaction to the obinutuzumab from the drug alone and from the high-risk disease that they have.

Some patients, after only the first 100 mg of the obinutuzumab, have a white count that drops from a 100,000 to 10,000. You can have very dramatic drops in your white count. You can have a very dramatic drop in your platelet count. Some of these patients actually become neutropenic, and so even one portion of cycle 1 and even days 8 and 15 might have to be held just because of the significant cytopenias that have incurred just from the beginning of obinutuzumab. Now, those patients then who start venetoclax later on have been debulked. So a lot of their risk for tumor lysis has significantly decreased if not been eliminated.

Laura Zitella:

Thanks, Christina. That's exactly what I'm seeing in my practice too, is that the risk of tumor lysis is the greatest when you're starting the obinutuzumab because the disease burden is so high at that time. And we are also seeing pretty significant infusion reactions to the obinutuzumab. Some of our patients are being admitted for monitoring if they have a high white count and a high risk for infusion reaction with obinutuzumab.

Leigh Ann, you work in a community setting. Is your experience similar or how are you managing the risk of tumor lysis and cytokine release syndrome with obinutuzumab?

Leigh Ann Childress:

So, of course, we're using uric acid lowering agents prophylactically, usually about at least 3 days prior to initiating the dose of either drug, depending upon what the situation is at that time. Also, counseling our patients to really do very good oral hydration in the 48 hours leading up to the dose we know is helpful. And then again, just knowing who your patient is, knowing if that white count is really high, if they're super bulky disease, if that's a situation where you anticipate that that patient is going to have an infusion reaction to the obinutuzumab. I think preparing that patient for that potential reaction is really important because many of our patients, if we really suspect that they're going to have a reaction and we prepare them for that, and the fact that this is not an allergic reaction per se, this is simply your drug doing what we want it to do, oftentimes they are able to navigate that infusion reaction much more easily knowing what actually is happening with that. I think that's one thing that we do to prepare them for the risk of TLS and preparing for that also, but the risk of cytokine release with the obinutuzumab and ultimately the infusion reactions.

Laura Zitella:

Yes, thank you. That's very similar. And upfront, I provide patients with a calendar outlining what to expect and explain to them that the first 6 weeks or so are pretty intensive with the frequency of visits and the amount of lab monitoring. But once you get through that initial month of obinutuzumab and the initial ramp-up of venetoclax, then ultimately they usually are only requiring monthly visits and the schedule gets a lot easier.

As both of you said, we assess for risk of tumor lysis prior to the obinutuzumab, and then we assess again prior to starting venetoclax. And most of the patients who are moderate or high risk before obinutuzumab end up being low risk prior to the venetoclax ramp-up, so it's a little bit easier to manage.

However, according to the package insert, we should be checking TLS labs the day before you start venetoclax, 6 hours after the first dose, and 24 hours later. That lab monitoring needs to be done with the first 20 mg dose and then the following week when they ramp up to the 50 mg dose. And I'm curious if, Christina, you have any clinical pearls on how you're getting those labs and how you're scheduling patients for those first two weeks?

Christina Russomanno:

Yes, so we try to schedule these patients as early in the morning in the clinic as possible. We obviously do their labs first. If everything looks okay, we dose them because they then have about a 6-hour wait time. We will actually at times, and again, this is not in the guidelines, but we will actually automatically hydrate them. They're going to be around, so we'll schedule them in the infusion center sometimes to at least get a couple of hours of hydration, a liter of fluid, just because they're there anyway, so we think this could possibly cut down. And then, of course, we do the 6-hour labs and then we always bring the patient back the next day, 24 hours later for re-lab assessment and possible hydration if they show any signs of tumor lysis. And despite the guidelines being for the first two dose escalations, there are some patients too who we wind up continuing to add that second day even at the 100, 200, or even 400 mg dosing just because some of their labs have been borderline.

Laura Zitella:

Yes, we have a similar practice. For my patients who are at low risk by then, I do have a number of patients that come to see us from hours away. You probably both have similar situations. So, sometimes to make it easier for a patient who lives 2 or 3 hours away, if they're truly low risk, I'll have them get their labs done locally the day before and then I'll tell them to take their venetoclax in the morning with breakfast and then their appointment with me will be 6 hours later. I'll tell them to take their venetoclax at 9:00 and then I'll have an appointment with them at 3 pm. So that will count for their 6-hour lab test.

And then the following day, I do usually have them come back to our institution because it's really hard to get the labs quickly if I'm having them go to an outside lab, the turnaround time isn't quite quick enough. And just in case they need something like hydration, it's better for them to be at the infusion center. But that's one way I've tried to make things a little bit easier in people who have very low-risk disease.

Christina Russomanno:

That's really interesting actually. I really like that idea of the labs the day before. That would save the patients a lot of time. It's a really great idea.

Laura Zitella:

Now, Leigh Ann, in the community setting, I bet you face some similar challenges in terms of lab turnaround time.

Leigh Ann Childress:

Well, we are fortunate in our particular centers that we have very quick turnaround time on our laboratories. But in working with local laboratories, sometimes we can experience delays in getting the results even if they're done the day before. So we try to keep our laboratory in-house as much as possible because we simply do have such a great turnaround time on our labs. We usually, same as Christina, try to get the patient in as early as possible. We are limited by the fact that in the community we don't oftentimes have access to extended hours for infusion centers, so we're more limited to more of an 8-to-5 schedule. So, we try to get the patient in by 8 am, of course, get lab draws first, seeing a provider at 9 am to review those baseline laboratories. We do have the patient dose while they're in clinic.

Depending upon how great they're doing with oral hydration, we also sometimes will send them back to the infusion chair to get additional IV fluids to help them along with that and then repeat the laboratory. Usually at 3:00 in the afternoon, some of our patients will leave and go grab lunch or do something else if they don't really need help with hydration. But we can typically get those laboratories back, both the chemistries and the CBC, if we do decide to repeat that, we can normally have those back within about 30 to 35 minutes. We're able to complete that in the context of an infusion day. We do also require them to come back at that 24-hour mark from the first dose and the first dose escalation so that we can again quickly assess those laboratories and determine are we seeing signs of tumor lysis at that point in time. And then again, assessing how well they were able to hydrate after they left our infusion center.

The one thing I would speak to as far as community-based practice, we actually have the luxury of having very fast lab turnaround time in our particular clinics. But many of the clinics that I know of that may be smaller than us in the community, oftentimes they are using labs that are not on site and sometimes it can take as much as 4 or 5 or 6 hours for them to get results back. So in those cases, if they have a patient that's very high risk, oftentimes that results in hospitalizing the patient simply so that the monitoring can take place, which that naturally drives up the cost of care for that patient and for their payers.

Laura Zitella:

Thank you for that. One of the other things that I wanted to talk about with the obinutuzumab and the venetoclax regimen is the risk of cytopenias. Obinutuzumab is associated with some cytopenias like neutropenia and thrombocytopenia, and venetoclax can also cause neutropenia. And sometimes we see that when we start the venetoclax, there is some neutropenia after starting it and we have to hold it and restart later. And what I've seen in my practice is that when you're getting the obinutuzumab upfront and more frequently, there's a higher incidence of neutropenia. But once you get to that monthly dosing, it's less likely. And so, I'm seeing less neutropenia with the combination as you get further along in the therapy.

Christina, is your experience similar and how are you managing neutropenia in your practice?

Christina Russomanno:

Yes, very similar. We are noticing intermittently through the ramp-up. It depends really how neutropenic they are, but there are times when we will push through, and we will give growth factor and we will continue the ramp-up. Obviously if they have sustained neutropenia, we will have to hold the dose. If we restart and they have again, sustained neutropenia, we will dose-reduce the venetoclax. And we do find that a lot of our patients, even those well-established, intermittently will have neutropenia and require some form of growth factor, even a year or two in depending on which regimen they're on.

Laura Zitella:

Yes, we have a similar practice. Especially early on, we do try to continue the ramp-up. We might hold a week, we definitely do give growth factor. And then once they're on the full dose, if there's any neutropenia, we'll give growth factor, we'll hold it, and then re-challenge at the same dose. But there are patients who develop recurrent neutropenia and then we end up dose-reducing the venetoclax to 300 mg a day.

Christina Russomanno:

Yes, very similar.

Laura Zitella:

We have a couple of more minutes and I think the last topic that I wanted to address was this measurable residual disease testing. With CLL, this venetoclax and obinutuzumab regimen is so effective that it can achieve undetectable, measurable residual disease in many patients. And that's associated with a superior duration of response and progression-free survival. So, it's defined as the blood or the marrow with less than 1 CLL cell per 10,000. That's a pretty significant remission. There’re a couple of ways of testing it. We usually, outside of a clinical trial, we're testing it on peripheral blood, but you can also test it on the bone marrow, and you can use PCR testing, flow cytometry, or next generation sequencing.

Christina, are you testing for measurable residual disease for your patients receiving venetoclax and obinutuzumab? And what tests are you using and when are you testing?

Christina Russomanno:

We are not routinely testing for MRD during the regimen. When they get close to the end of the regimen though, out of curiosity, we are sending off peripheral flow cytometry. That is usually how we measure. We don't do much next generation sequencing off clinical trial or patients who are a lot more complicated or further into treatment regimens. But yes, flow cytometry, usually when they're nearing the end of whichever regimen they're on, that involves the venetoclax.

Laura Zitella:

And Leigh Ann, are you testing for measurable residual disease?

Leigh Ann Childress:

We sort of have a mixed bag, so to speak, among all of our oncologists. We have some who are testing for MRD, but it tends to be at the end of the fixed duration regimen, if they do test for it. And we have others that are actually not utilizing it. And my understanding is that for those who do utilize it, I think we're usually doing it with peripheral blood flow cytometry.

Laura Zitella:

It's so interesting how practices are really different. This is an area of active research and at my institution, there is some variation between providers and what they do. But generally, we will obtain MRD testing prior to starting venetoclax and obinutuzumab because we use clonoSEQ MRD testing, which is a next generation sequencing that sequences the DNA and looks for a sequence that is specific only to the CLL cells and not in the healthy cells. So you have to have CLL cells present in order to identify these dominant sequences. And then in any given patient, let's say you have 3 dominant sequences, you can repeat the test and if those sequences have disappeared, then you have undetectable MRD. We're doing the ID prior to starting therapy. We're checking again after the 6 months of the combination venetoclax and obinutuzumab.

And then patients were taking venetoclax for another 6 months and we're testing at the end of therapy also, which sounds like a lot more testing than all of you are doing. But that's an area of active research, how and when and how do we use this information to inform ongoing therapy. And at this point, we are not using it to extend therapy in most situations, we would stop therapy no matter what the measurable residual disease testing showed. But we are obtaining that information.

All right, well, this brings us to the end of this part of the discussion. For more information in the next chapter where we focus on second-line therapy, please visit JADPRO online at JADPRO.com. Thank you so much.