Monitoring, Treatment Decisions, and Managing Side Effects

Leigh Ann Childress

Welcome to our conversation about chronic lymphocytic leukemia or CLL. We know that CLL constitutes about 30% of adult leukemias, making it a very common diagnosis to see in patients in the community as well as the academic setting. These patients have survival that can be upwards of 15 or 20 years, therefore advanced practice providers play a frequent role in monitoring these patients for quite a long time.

Christina Russomanno

I’m glad we’re talking about this today, Leigh Ann. I think it's important that we start with the basics before we move into treatment. We really need to know the appropriate time to treat. There are recommended guidelines for this, but on paper it’s a lot different than in practice.

Leigh Ann Childress

It absolutely is. Often, these patients present incidentally with a primary care provider visit or perhaps as part of a pre-surgical workup. Most commonly, they will present asymptomatically with incidental lymphocytosis on the CBC or small palpable lymph nodes, and they are frequently referred to hematology/oncology at that point. Patients tend to be largely asymptomatic at the time of presentation, so if they have stable laboratories these patients can be monitored sometimes for years off treatment.

It's important that APPs following patients in the pre-treatment phase of CLL understand how to monitor symptom burden, as well as developing laboratory abnormalities, and give attention to risk stratification to set the pace of monitoring.

First-line treatment is indicated essentially when the CLL is causing problems. High white blood cell counts can often be stressful to monitor in the community setting, and many APPs are unsure at what point treatment is indicated. Chrissy, do you want to talk about what lab values and/or symptoms would lead us to pull the trigger for first-line treatment in the patients we’re monitoring for CLL?

Christina Russomanno

A lot of times, patients will present with very high white blood cell counts, which alarms many providers, especially those who are not familiar with oncology, specifically CLL. A lot of people assume that a high white blood cell count alone is a reason to treat a CLL patient. This white blood cell count of 300,000 or 400,000 absolutely terrifies them.

But in CLL, we know that it's more about what the crowding out of the bone marrow does to the other cell lines. For example, if there is less room for red blood cells to be made, you become more anemic, and per guidelines, they say a hemoglobin less than 10 is an indication for treatment. Or your platelet count drops and you develop thrombocytopenia, so you’re at a higher risk of bruising or bleeding. Per recommendations¹, an indication for treatment is a platelet count under 100,000. Now, those counts do matter, because if you're not able to make those cells, there will be symptoms such as fatigue, headaches, palpitations, shortness of breath, bruising, and bleeding. You might not be able to perform ADLs. It may impact multiple aspects of your life. 

Now, in practice, we don't stick exactly to a hemoglobin of 10 and platelet count of 100,000. Some patients may be stable for some time at numbers lower than those. But if those blood counts are starting to trend down into unsafe territory, that would be an indication for treatment. We want to make sure that we start treatment before someone is transfusion-dependent. Again, those counts really matter, not the white blood cell count alone.

A lot of these patients will live with lymphadenopathy and that's okay. They might not be overly happy with the their appearance, especially if others notice, but unless those lymph nodes are so large that they're impeding their ability to move or they're pressing on things inside the body and leading to side effects or discomfort, then lymphadenopathy alone wouldn't be an indication for therapy.

Other than that, you can look at lymphocyte doubling time as well as other factors such as frequent infections as indications or signs that the time for treatment may be near. Leigh Ann, Is there anything that you feel I'm forgetting as far as indications for initiation of therapy?

Leigh Ann Childress

I think the art of monitoring patients with CLL with regard to symptom burden involves knowing who your patient is at baseline. Combined with a thorough baseline assessment, regular physical examinations including a lymph node exam and assessment for splenomegaly as well as interview questions focused on B symptoms or significant changes in their overall well-being or health are essential. Sometimes these patients can also have symptom burden related to massive splenomegaly as their disease progresses. These assessments in the context of any change in lab results will help APPs identify when the right time to treat is.

Christina Russomanno

Yes, I completely agree.

Leigh Ann Childress

Chrissy, once we arrive at a level of symptom burden or laboratory abnormalities that indicate this patient needs to enter treatment for their CLL, what are the patient-specific or disease-related factors that you consider in selecting a first-line treatment for CLL?

Christina Russomanno

That's a very good question. If you look at cytogenetics, FISH, and molecular testing, there might be some results there that put the patient in a higher risk category that would make us lean toward one therapy or the other. For example, if they have a TP53 or 17p deletion, we might push toward continuous therapy with a BTK over time limited therapy with venetoclax and obinutuzumab in the upfront setting. 

We also look at a patient's comorbidities, what else they have going on that plays a role. We look at the patient themself, their lifestyle, their support system, what they can handle and take on. If there’s no specific medical reason for us to feel one option would be best over another, we discuss both time limited and continuous therapy with the patient. We provide the information and have a discussion with the patient, because it's important that the patient is part of that decision and they know why we are considering, maybe even pushing them toward, one option over another. Do you find the same in your practice?

Leigh Ann Childress

I do. Shared decision-making is so important with these patients, simply helping them understand and buy in to the therapy that we're recommending. But it’s also important to take into consideration their quality of life, and, as you said, the level of supportive care that impacts their ability to logistically complete the treatment that we're recommending.

I look at a patient's age as well, because you're looking at patients that oftentimes live with this disease for two or three decades. If they're diagnosed in their 50s, whether they're high risk or average risk, you may be thinking about the first line of therapy and then possibly time off therapy. So, that might guide my selection somewhat, whether that younger patient wants continuous therapy or periods without treatment. With an older patient who’s diagnosed in their 80s, however, their natural lifespan may extend only another 10 years or so. With those patients, it may be that continuous BTK inhibition as a monotherapy would be the most appropriate choice considering that therapy will likely control their disease for the duration.

Christina Russomanno

Do you think there are any specific medical comorbidities that might push you toward a certain type of treatment for a patient?

Leigh Ann Childress

Absolutely. In patients who have a significant comorbid disease burden, such as heart disease, renal disease, diabetes, I would take those comorbidities into consideration and potentially choose a less intensive therapy over a more intensive therapy. With BTK inhibition, for example, you want to consider a patient’s cardiac comorbidities due to the risk of cardiotoxicity. Do they have a history of uncontrolled hypertension or hypertensive heart disease? Do they have arrhythmias that may not be well-controlled?

With those patients, I would consider baseline cardiac clearance and enhanced cardiac monitoring for the duration of those therapies. Another thought is older patients may have poor renal function and an increased TLS risk with obinutuzumab or venetoclax. Also, consider that an older patient with significant comorbidities may have an increased risk of infection with immunosuppressive regimens.

Christina Russomanno

I agree. Looking at the patient's cardiac history and renal function are two important things. We know that there is a bleeding risk with the BTKs, so we may hesitate on a patient with a history of bleeding or a subdural hemorrhage. We may hesitate on a patient with a history of falls or who’s at a high risk for them. 

Recently, in our practice we needed to initiate treatment on an older patient who lived alone and was at a high risk for falls, with a history of them. We opted against a continuous BTK because we were so worried she would have a bleeding issue and there was no support at home with her. We made that decision based on safety, although otherwise a BTKi would have been a wonderful option for her. 

Leigh Ann, do you find that your patients come to you aware of and educated on the options for treatment, and do they know what they want? Or do you feel like they're pretty much open to whatever is suggested by the provider?

Leigh Ann Childress

My patient population ranges from people in blue collar jobs and/or farmers, up to engineers and PhDs. So, I think you base the discussion and the presentation of treatment options upon what their bandwidth is and level of health literacy. I do think most of my patients are open to the suggestions of their medical team. My patients who are better educated have usually done some of their own research and may come to the table with some options that they want to consider, whether it be more aggressive or more conservative types of treatment. How about you?

Christina Russomanno

I think it’s about 50/50. We have patients who have said, "I don't want to know anything about my disease. I'm not joining support groups. I'm not reading anything on any of these patient-centered sites." And then, we have people who literally can cite data from studies better than I can and know exactly what they want and why. So, you have these two extremes.

I think for the most part, patients have some thought in their head on whether they want time-limited therapy, with the current option being venetoclax with obinutuzumab, or continuous therapy with a BTKi. We know that in the beginning, time limited therapy can be more daunting. There are more office visits and lab checks, possible hospitalization to start if they are at a high risk for tumor lysis. But there is less financial toxicity in the long run, there is the potential for undetectable MRD, and there is time off treatment. Then there are others who already take daily meds, most likely indefinitely for issues with blood pressure or their thyroid. Their thought is that it is not a big deal to just swallow another pill, or pills, and they love the idea of fewer office visits and less monitoring. Plus, with the BTKis there is rapid reduction in their lymphadenopathy/splenomegaly. 

But again, there are certain patients we may need to push toward one therapy or the other. The good thing is that a lot of these patients, excluding patients who are ~80 and older, will probably see both therapies in their lifetime. So, if a patient receives, say, time-limited therapy with venetoclax and obinutuzumab upfront and then relapses and requires further treatment in the future, most likely they’ll receive some kind of BTK-based therapy next, and vice versa.

Knowing that, and again, with all things being equal, I try to instill in them that they can’t make a wrong choice, that patients respond to both of these core regimens. We know that in the future they’ll most likely see the other option and/or some other therapies coming down the pike. I feel this lessens some of the stress, as these patients already have to cope with the fact that they warrant therapy, how they will respond, side effects, etc.

Leigh Ann Childress

I love the way you said that, they’re not really making a wrong decision either way. That's a great way to frame that conversation for APPs who are learning to talk to patients about the therapies that are available, because the delivery of that information to the patients is so important in the shared decision-making process.

What I have seen most in my practice is the younger patients who are focused on career and family and often want the option for time-limited therapy. They’re usually willing to put in that up-front work in exchange for, hopefully, time off therapy later. My older patients are, to your point, the ones who say, "Hey, it's simple for me to take a pill every day and manage some common side effects.” There aren’t tons of grade 3 and 4 AEs associated with things like continuous BTK inhibitor therapy, making it easy to keep patients on therapy with minimal support as opposed to something that requires frequent visits to the clinic, lab checks, time in the infusion room, IVs, etc. Our older patients are often depending on children and grandchildren to take time off work and take them to appointments, so those logistics can certainly have an impact.

Christina Russomanno

I like that you brought up dealing with side effects because that's an important part of this as well. The patients are going to want to know, "Well, what could happen to me on these therapies?" The answer might push them in a certain direction. So in your practice, say a patient is on a BTK inhibitor, what are the most common side effects you see and do you have any pearls on how to best treat them?

Leigh Ann Childress

Sure. We're most commonly using second generation BTK inhibitors in our practice, like acalabrutinib, and one of the most common side effects that we see and hear about is headache. But the headache is usually well mitigated with a caffeinated beverage, like coffee or soda, or just a standard dose of acetaminophen.

The key there is letting your patient know that it can happen, that it's easily managed with interventions at home, and it’s a side effect that improves over time on therapy. I think that helps keeps them buckled in for the duration until they can get through that first 4-6 weeks of therapy when they see the side effects start to dissipate.

To a lesser extent, diarrhea is another one that we'll see on BTK inhibitors. It’s often managed very well by dietary modifications as well as things like loperamide. I seldom have to escalate to prescription-based therapy for control of the diarrhea. And again, this is something that tends to improve over time.

I think arthralgias is something also worth mentioning, especially in an older patient that already has issues like osteoarthritis at baseline. We tell them about as-needed dosing with pain relievers like acetaminophen, taking warm baths or soaks, and/or using warm compresses if they're having joint pain can often pretty well mitigate that. Encouraging the patient to stay active is key there too, just to keep those joints moving. When it comes to baseline osteoarthritis, getting them up and moving can frequently alleviate some of those symptoms as well.

Bruising is another thing worth mentioning because this is something the patient literally sees that they become concerned about, that maybe their laboratories are abnormal. So, telling them to anticipate some bruising or easy bruisability with BTK inhibitors can help lessen their concern.

Christina Russomanno

Knowledge is power, and I totally agree with what you're saying about making sure that they're able to identify common side effects. They've heard about them, so it's not a surprise. It’s important to let them know not to be a hero and to reach out if there’s anything they’re not sure about. They may wonder if something is an expected side effect of not. And there will be patients who have some kind of side effect that isn't overly common, something reported in less than 1% of patients.

I also really liked how you talked about pushing patients to be active, especially in the beginning, when patients often have some fatigue, their blood counts haven’t started to normalize, perhaps they're anemic. BTK inhibitors work great on the lymph nodes, working quickly to decrease lymph node burden and shrink the spleen, but they work less quickly on the bone marrow. So, it'll take some time for their blood counts to improve.

If the patient is already anemic, they might be very fatigued. They may be down-hearted and anxious. It's very important to push them to get up and move and go about their normal daily activities, exercise if they can, try to push through if possible. 

It is true that there are some side effects we know will happen in the first weeks to months of therapy that should get better. And then there are some that are, unfortunately, ongoing, like the risk of bleeding. Do your patients know to call first if they're going to have a procedure, or if they had any kind of injury, because of the bleeding risk?

Leigh Ann Childress

Yes, we educate patients to contact us well ahead of any invasive procedure, so that we can provide instructions on holding and restarting therapy afterward. BTKs specifically increase hemorrhage risk, and if the patient is also on a DOAC, the risk is even higher. Patients need to hold BTK inhibitors for 3-7 days pre- and post-surgery to minimize the risk of hemorrhage. For those on concurrent anticoagulation, the multidisciplinary team would need to consider the appropriate time off therapy based on the indication for the anticoagulation as well as the risk of thrombosis with the procedure.

Christina Russomanno

We cringe a little if a patient calls after experiencing any kind of head trauma because they can bleed easily in the head. Some of our patients are skiers or sometimes it's icy outside, so I tell them, "If you slip and hit your head in any capacity, you really need to be evaluated and have a CAT scan immediately."

Leigh Ann Childress

Absolutely. It’s very important to follow up on any kind of blow to the head.

Well, Chrissy, I really enjoyed this. We have so much more to talk about in our next two conversations.

Christina Russomanno

We really do. I look forward to chatting again next month.