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

Laura Zitella: Welcome to this virtual roundtable about managing the role of BCL-2 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.

Joining me today for this discussion are two of my fellow nurse practitioners, Lisa Nodzon from Moffitt Cancer Center, and Christina Russomanno from Columbia University Irving Medical Center. Thank you so much for joining me today.

First, Lisa's going to kick us off with a case study and discuss the use of venetoclax-obinutuzumab and the CLL-14 trial data. Lisa?

Lisa Nodzon: Sure, thank you.

The CLL-14 trial was a randomized phase III trial, looking at the efficacy as well as the safety of a fixed duration combination referred to as venetoclax and obinutuzumab compared to standard of care at the time, which was chlorambucil and obinutuzumab. This was in patients that were untreated and as well had co-existing comorbid conditions. The trial endpoint was looking at progression-free survival.

Let's move into a case study. Here we see the patient is 52 years old and he has del 13q as well as unmutated IGHV, which is conferring intermediate prognostic risk, but no significant mutations by next-generation sequencing or NGS. The case that we're going to talk about is going to highlight the application of the CLL-14 trial in a real-world setting. He's presenting with progressive symptoms. Looking at anemia, hemoglobin is less than 10 grams. Thrombocytopenia platelets are less than 90,000, as well as symptomatic splenomegaly.

We can see that he does meet iwCLL criteria for therapy. As I mentioned, he is intermediate risk. Despite being relatively young, he does have comorbid conditions that have coronary artery disease as well as diabetes. We know in our CLL patient population that treatment selection can be complex, right? We have to think about the comorbid conditions the patient comes into therapy with, as well as long-term safety, what we're going to give them. Could that be imparting any risk to the patient with regard to other factors in the safety of the drugs?

Moving on in our trial, again, he does meet iwCLL criteria for therapy. We do restaging studies. We do a bone marrow biopsy. We want to know the degree of CLL infiltration as well as looking at any other potential problems that we could encounter in the future. He, again, is intermediate risk. We still pick up the del 13q on the karyotype as well as the repeat FISH. With repeating of NGS, we do not find any adverse prognostic markers, particularly that of TP53 mutations.

We do a CT scan on him, a full one, to look at the size of the lymph nodes as well as the spleen. We do not see any bulky lymphadenopathy. Doing the CT here is really important because as part of our profiling for patients that we plan to put on venetoclax and obinutuzumab, we have to categorize them into low, medium, or high risk for tumor lysis, and that's going to again be based on the lymph node size as well as the lymphocyte count.

When it comes to shared decision-making in our patients with CLL, that's a very important topic, right? We have to take into consideration as the health-care provider the cytogenetics, what medications the patient may be on, as well as comorbid conditions. But it's important also to incorporate our patients into this, right? We have different therapies we can use in the frontline setting, so it's important to find out from the patient what were their goals of therapy may be and what's important for the patient in general.

Well, he is interested in time-limited therapy, so that brings us back to the venetoclax and obinutuzumab combination in the frontline setting. I think it's important here that we also discuss the CLL-14 trial data in terms of efficacy with the patient and also in terms of what comorbid conditions the patient may have. We know that based on the most recent CLL-14 trial update with the median follow-up of around 6 years, we saw that 40% of those patients did achieve an undetectable MRD, or otherwise what we refer to as minimal residual disease.

Well, what is that? That's a new important term that we throw out there for time-limited therapy, particularly patients on venetoclax, and that's really what disease is left over at the conclusion of therapy. Of course, we can do this with very sophisticated regimens that are flow cytometry, but more importantly, we use molecular-based regimens for this and defining this as less than 10^-4. Of course, some of these tests can go down to 10^-6, but in the CLL-14 trial, again, we saw that 40% of these patients attained undetectable MRD in the peripheral blood at the end of therapy, and that gave them equivalent of about a median follow up PFS of around 76 months. We can already begin to see here a really highly efficacious therapy with a pretty durable remission.

The next question our patients are going to have for us is, well, you're giving me therapy for a year. How does that translate into what if I need therapy for the future? A lot of our patients will ask us that and what we can tell them based on this long-term data is around 53% of these patients remained progression-free at 6 years. Most importantly, 65% of them had not required any second-line therapy in that timeframe. Again, reflecting a pretty prolonged treatment-free remission.

Important to point out as well even high-risk patients were allowed in this clinical trial, so they saw that those patients that did harbor TP53 aberrations, whether it be by or by del(17p), these patients had a median PFS of around 52 months on the venetoclax and obinutuzumab regimen compared to only 21 months with the chemoimmunotherapy. Again, we do see that high-risk patients did benefit. But as expected, we do see shorter remissions, which we knew to be expected.

Most important point I think on this particular regimen when we talk about patient education is that going to be of TLS risk, and how do we mitigate that? As I mentioned earlier, we do profile our patients based on the lymph node size, which is coming from your CT. We do know the lymphocyte count as well. With profiling of our patients, we can really tailor this risk mitigation.

With the lead-in the cycle on day 1 of obinutuzumab, we know that there is a very rapid tumor debulking that can occur, which can lead to an infusion-related reaction. This is just through cytokine release. It can cause hypotension in our patients. Most protocols are going to be center-specific, but basically they do have some inclusion for pre-medications out of a corticosteroid and antihistamine as well as acetaminophen. And then by the time that the venetoclax ramp-up happens, the patients are pretty much debulked, we'd have to say, with just that lead-in for the obinutuzumab.

One of the ways that we think about mitigation for our patients prior to starting venetoclax and obinutuzumab is really rather twofold. One, we have to think about the bulky lymphadenopathy, which could increase their TLS risk as well as the lymphocyte count. So, at our particular center, the protocol that we have is, one, we have a CTE. Obviously, we have the labs. But the regimen that we use is the combination of a corticosteroid, typically, again, Solu-Medrol. We might play around with dosing on this as well, too. If we're thinking about the risk of the patient, the higher the risk, we might increase the amount of steroid we give to the patient. Of course, on the flip side, we have to think about our patients with diabetes. This is going to cause some glucose problems for them. All patients are given an antihyperuricemic. We might consider the case for rasburicase in patients that have elevated uric acid levels as well. And then we think about acetaminophen or an antihistamine with our patients. So, we have a set protocol, but we can change this around if we need to, if we think the patient is lower risk or higher risk.

Laura, how about at your center? Do you do anything different?

Laura Zitella: We actually have recently changed how we're pre-medicating for obinutuzumab. We were seeing a lot of hypersensitivity reactions. And I think the CLL14 trial was really important because they recognized the incidence of hypersensitivity reactions and actually changed the dosing of the obinutuzumab from 1,000 milligrams on day 1 to 100 milligrams on day 1 and 900 milligrams on day 2 to split the dosing in order to minimize some of the reactions.

But even with that, we were seeing a lot of reactions. So, we started using montelukast for 7 days prior to starting obinutuzumab. We also have a five-medication pre-medication with acetaminophen, cetirizine, a glucocorticoid, famotidine, and the montelukast. And then recently we made an additional change for people who have a very high absolute lymphocyte count. I mean, you know, some of our patients start the obinutuzumab with an ALC of 100 or greater. And these patients are at the highest risk, the higher the lymphocyte count, the higher the risk of the hypersensitivity reaction. So, we started with a slow titration. We started the obinutuzumab at 6 milligrams per hour. And then increase every 30 minutes to the maximum rate. And we have tracked our data, and we found a significantly decreased incidence of serious hypersensitivity, but approximately the same amount of mild hypersensitivity. But of course, that could be managed with rescue medications and our biggest concern was preventing severe reactions that require admission.

Chrissy, what do you do at your center?

Christina Russomanno: So at our center, we do a lot more what Lisa does. I'm very intrigued, actually, by what you're doing. It definitely makes me think. But we do a lot more what of Lisa's doing at this point. Obviously, we tailor the premedications based on the patient. And sometimes actually patients that are at higher risk for infusion reactions will actually start some prednisone a couple days before. So maybe we'll put them on 50 milligrams of prednisone 2 days before they're scheduled to start their obinutuzumab In the hopes of mitigating some of these possible infusion reactions and praying there's no extra tumor lysis with the steroids.

Laura Zitella: That's another great strategy.

Lisa Nodzon: Of course, the next question is going to be, is there a role here for cardio-oncology? We know that cardio-oncology is a newer field, but really what their aim is after is looking at how can we mitigate some of the cardio-toxicity risks that our patients may experience, as well as thinking about the majority of our CLL patients coming in do have some underlying cardiovascular history. I think in selected patients, particularly those that have a pre-existing cardiovascular risk such as in our case example here, it's very important that we do reach out for multidisciplinary care. While these agents are not classically associated with direct cardio-toxicities, there's several considerations here that would justify involvement. I think very importantly we know that tumor lysis syndrome can be associated with cardiac strain. Why? This can induce electrolyte imbalances. Patients as well can have acute kidney injury.

There's the management of the infusion-related reaction itself. This could cause further decompensation in our patients that have congestive heart failure, so thinking about the fluids that we may need to give to our patients, as well thinking about polypharmacy or even drug interactions. We know that venetoclax is a CYP3A4 substrate, so caution would be advised here, particularly if you're co-ministering it with patients that are on other cardiac medications such as amiodarone or diltiazem or even certain statins. That's a really important factor when it comes to this medication. Why? These medications come out of specialty pharmacies, so the specialty pharmacist may not be aware of the routine medications that the patient is on.

We see here based on the CLL-14 trial data that it does support a fixed duration therapy even in the patients with unmutated IGHV, such as in our case. One, you have to employ appropriate risk stratification and mitigation to safely deliver this regimen. But as well, the importance of MRD. Looking at achieving an undetectable MRD does correlate with a prolonged remission duration, so this is starting to turn itself out to be a very important surrogate marker as well as endpoint in a lot of our clinical trials that we're utilizing venetoclax in for time-limited therapy. While we do see in the trial that patients who were MRD negative, that is less than 10^-4, at the conclusion of therapy had a significantly longer progression-free survival than those with higher MRD, we're still finding that, again, this can be a really important prognostic indicator.

In our case, the patient had IGHV unmutated. The trial did show that there was a difference in PFS between these two prognostic groups. IGHV-mutated patients had not reached a medium PFS at the 6-year time point, reflecting a very durable disease control. Compared to patients that were IGHV unmutated as in our case example here, medium PFS was around 55 to 60 months. Again, just really highlighting the importance of how we can utilize MRD in this particular setting.

I think some future implications are really important if we're thinking about venetoclax-based therapies in our patients with CLL. The case here does highlight that the time-limited venetoclax-obinutuzumab is very feasible. It's very effective as a frontline therapy with our patients with CLL. It does deliver a durable remission. It also highlights the feasibility of these regimens. If we're looking at an MRD-driven treatment strategy, these patients can have very prolonged treatment-free intervals, and that might be important. That's part of that shared decision-making that I just talked about. This patient was interested in a time-limited regimen.

Chris is going to talk about in an upcoming video looking at combining venetoclax with other regimens: BTK inhibitors and doublets, or even with triplets. I think future paradigms are going to use venetoclax as part of either sequential or combination therapies. It may even cause us to think about what about tailoring these regimens to our patients with adverse prognostic markers such as TP53 or IGHV unmutated. Where can we sequence time-limited therapies? Can we do it at all? Can we retreat our patients with venetoclax if they've had it previously?

But I think really overall it's leading us into optimizing how we look at therapy in our patients and incorporating what their desires may be as well, too.

Laura Zitella: Thank you, Lisa, for that excellent discussion. Please see our other two videos for further discussion on the role of BCL-2 inhibition in CLL at jadpro.com.