Managing Patients With CLL in the COVID Era: The Advanced Practitioner's Role

Lisa Nodzon: Welcome to this virtual roundtable, Managing Patients With CLL in the COVID Era: The Advanced Practitioner's Role. My name is Lisa Nodzon. I am a nurse practitioner in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida. Today I'm joined by my two colleagues, Jackie and Katie.

Jackie Broadway-Duren: Hello, I'm Jackie Broadway-Duren and I am a nurse practitioner at the MD Anderson Cancer Center in Houston in the Department of Leukemia.

Katie Tobin: Hi everyone, my name is Katie Tobin. I'm a clinical pharmacist in malignant hematology at Moffitt Cancer Center.

Lisa Nodzon: So, thank you ladies, for those introductions. In our fourth installment, we will focus on the current treatment paradigms in CLL, utilizing a real-world case study for relapse and refractory CLL. For those of us that follow CLL, we know that this world has completely exploded in recent years with the advent and the utilization of the novel targeted agents.

So going into our case study, Mr. W is a 69-year-old male who is diagnosed with Rai stage III B-cell CLL approximately four years ago. He's got higher risk prognostic factors of deletion 13q, deletion 17p as well as having an unmutated IgHV by NGS panel. He's got a TP53 mutation, as well as SF3B1. He presents with diffuse lymphadenopathy, persistent B symptoms, and he has the high-risk genetic features. At that time, he was treated with bendamustine and rituximab for four cycles and achieved a complete remission.

However, he relapsed approximately 15 months later by presenting back to the clinic again, and was placed on ibrutinib monotherapy, which he received for about a period of 18 months. Then, he developed some gradual disease progression. He now presents to the clinic again with swollen lymph nodes, significant fatigue, as well as increased frequency in his night sweats of two to three times per week. Looking at his labs on presentation, he's got a white blood cell count of 33,000, obviously with the predominance of lymphocytes at 26,000, hemoglobin of 11 gm, and platelets at 100,000, ANC of 2.2, an LVH of 335, beta-2 microglobulin at 5.7. On physical exam, he's got non-bulky lymphadenopathy. Lymph nodes are about 2 cm in the bilateral cervical region, as well as in the axillary region. He's got mild splenomegaly as well. He's got an excellent performance status.

And then again, just recapping on his therapy. He received four cycles of bendamustine and rituximab with an apparent complete remission, which he held onto for about 18 months, which would be consistent with his higher risk prognostic factors before he relapsed. And then recently he's been receiving monotherapy with ibrutinib. Important to note that he was dose reduced secondary to the adverse effect of arthralgia down to 140 mg before he started to progress again. So total time to progression was around 18 months. So, Jackie, thinking about a patient like this really good performance status, he's considerably failing ibrutinib with the higher risk features, what sort of treatments would you be thinking about in our current era of novel targeted agents and for patient like this considering high-risk features, good performance status, and being an ibrutinib failure?

Jackie Broadway-Duren: Well, at this point, if you sit down and look at what therapies are available, I would pretty much rule out acalabrutinib because that is still a BTK inhibitor. He's already progressed on a BTK inhibitor. So the next thing we would probably look at for this patient, considering his good performance status and that he's relatively young in his 60s, we will probably look at venetoclax maybe as single-agent therapy. But what would be important at this point is to sit down and explain to the patient that there is a process to starting this medication and the ramp up process and so forth. In some cases, there are other things that could be considered like the LOXO-305, which is still on clinical trial at this point. So, it would be a matter of whether the patient wants to go with a conventional treatment or whether they would be interested in enrolling in a clinical trial at this point.

Lisa Nodzon: Yeah, I think clinical trials are always an important option for our patients and, just like you, coming from an academic center and us at an academic center as well, it's something that we always offer to our patients. Standard of care will always be there for the patient. So if there's eligibility met for the clinical trial, absolutely. And how about thinking about COVID implications? Would that play a role at all into your therapy decision?

Jackie Broadway-Duren: Again, if the patient had been previously vaccinated, I would want to know when he was vaccinated, if he had both doses, and when was the second dose given. That is always a question that's pretty much standard now when patients come in, whether they're a new or returning patient. Depending on if the patient had been vaccinated three or four months ago, then I think we'll be good to go with therapy. If the patient told me they had just been vaccinated maybe a month ago, if we had considered that in a monoclonal antibody at that point, we probably wouldn't. So all those things would play into making the appropriate choice for the patient, but certainly it would be a consideration. We know that there's really good data by Seymour et al. published on venetoclax plus rituximab for relapsed/refractory patients. So certainly if the COVID vaccination does not present in the limitations, that actually may be a good option as well.

Lisa Nodzon: Yeah, absolutely. And having those higher risk features and failing ibrutinib, would you guys consider also referring him for consideration of transplant?

Jackie Broadway-Duren: Absolutely, he would definitely get a stem cell transplant and also consider possibilities in the future for maybe a CAR T or something.

Lisa Nodzon: Yeah, absolutely, absolutely, very, very much so. And Katie, how about any particular class effect in terms of adverse events? Do you consider incorporating into your teaching, whether it be for the BTK inhibitors or BCL-2 inhibitors, considering that these novel agents really are the hallmark at this point in time of our CLL therapy regimens?

Katie Tobin: Yeah, so first looking at BTK inhibitors. We definitely see myalgia—like this patient experienced—rash, hypertension, diarrhea. There are more serious adverse events like arrhythmias, serious bleeding. Now, if we look at the data that compared acalabrutinib and ibrutinib in the relapsed/refractory setting, so looking among all-grade side effects or adverse events that were greater than 20% of patients in either arm, acalabrutinib actually had lower incidence of hypertension. Acalabrutinib also had lower arthralgias and diarrhea. It did have a higher incidence of headache. And then adverse events that led to a treatment discontinuation occurred a little bit higher with ibrutinib as well. And then among any great events of clinical interest, the most, cardiac hypertension and those bleeding events that I mentioned, in general, they are much less frequent with acalabrutinib.

Then transitioning to our BCL-2 inhibitor of venetoclax. We definitely see tumor lysis, like Jackie had mentioned, the ramp up and how patients start venetoclax in CLL. It's a very time-involved process. We see my suppression in general, we see more neutropenia, but we also see anemia and thrombocytopenia still, can see diarrhea, definitely fatigue. You can see nausea, even though it's really not considered a moderate or high emetic potential. Now, we are seeing higher incidence of upper respiratory tract infections for cough, pain, and edema. I just want to touch on infections. We're seeing higher incidence of infections with both of these classes, with our BCL-2 inhibitors and our BTK inhibitors. So that's something to keep in mind. Pre-COVID, we were seeing higher incidence of infection, but keeping that in mind as we continue to go on in this new COVID world.

Lisa Nodzon: Yeah, absolutely. It's some of our patients think that just because they're taking an oral drug, it may be safer, but I have to explain to the patients as well, too, that, just because it's an oral drug, doesn't make it any safer. And particularly with our BTK inhibitors, it brings up the whole concept. At Moffitt Cancer Center, we're lucky we have cardio-oncology. Because, as you had mentioned, looking at the arrhythmias as well as the underlying hypertension that can be there, particularly with our BTK inhibitors. So we get extra vigilant and I think, probably like Jackie as well, they probably have cardio-oncology as well at their center.

Katie Tobin: Cardio-toxicity, it doesn't necessarily happen up front. You know, we definitely see patients on BTK inhibitors that they've done just fine for a month or two, even farther, but we're seeing uncontrolled hypertension, other cardiac events happening later on. So, another big education piece.

Jackie Broadway-Duren: The other thing with the BTKs is weight gain. We've had patients who are very concerned about weight gain. So you have to consider whether the patient is already a bit obese and that has been a cause for people to want to discontinue the therapy because of that.

Lisa Nodzon: Yeah, absolutely, and then having to be extra vigilant for, Katie, as you had mentioned, the neutropenia kind of across the trials, grade 3 could be around 60% or so. So, we get extra vigilant with the utilization of growth factor in our patients. And so between the higher risk for infection and then the neutropenia, these patients are almost in a higher risk category when we treat them. And so it does represent those challenges in the setting of COVID. I'm sure, Jackie, you guys see the same thing out there at MD Anderson when it comes to the management for the neutropenia.

Jackie Broadway-Duren: Yeah, I have to say, before venetoclax came on the market, so to speak, I don't recall us having so much of a problem with neutropenia with the BTKs, but we certainly do now. And we treat them in order to keep the patient on their current dose and to prevent those interruptions and try to prevent those reductions. So, the growth factors seem to work well. So that is definitely an implication with starting venetoclax as well.

Lisa Nodzon: Yeah, absolutely. It's such a good teaching point for our patients and also for our friends in the community practice as the utilization of growth factor to support our patients. Absolutely. Well, thank you for that nice discussion. So, as we can see, novel targeted agents, whether they're given as monotherapy or in combination, they've really led to improved outcomes, particularly in our CLL patients with these higher risk prognostic factors with data demonstrating improvements in progression-free survival, quality of life, as well as overall survival compared to the prior chemo immunotherapy regimens. Concomitant medication monitoring, as Katie had pointed out, is incredibly important in our patient populations as these drugs are coming from specialty pharmacies and our patients are already on other medications from other prescribers placing them in the middle. So these concomitant medication interactions are extremely important to be monitoring for.

And, as we can see, multidisciplinary approaches to patient adherence as well as adverse event management on these targeted therapies is extremely important. As we had just mentioned with the BTK inhibitors, particularly, with underlying cardiac risk factors that can now be exacerbated by the drug itself, it's really important that we are referring as necessary in providing that patient education. But through the multidisciplinary care, we can improve persistence by maintaining our patients on drugs through this collaborative care, particularly in our higher risk patients, where there are limited treatment options still for them.

This brings us to the end of our case discussion. Please see other segments for further discussion about the management of CLL patients in the COVID era or visit advancedpractitioner.com. Thank you for joining us.