Case Study: Treatment Options for the Newly Diagnosed Patient with CLL

Amber Koehler

Hi Josie, I'm excited to have our next installment of the CLL Expert Conversations! I’d like to start by talking about somebody who's newly diagnosed with CLL and what that looks like in terms of treatment options. How does that sound? 

Josie Montegaard

That sounds great. We get those patients coming into our clinic all the time. 

Amber Koehler

Yes, we do too. Let’s talk about Jim, a 60-year-old male. He works as an accountant, is married, and has a daughter in her senior year of high school, so he’s in a somewhat busy season of life. He has a past medical history of hypertension and is currently well-controlled on lisinopril. He has no prior surgeries or hospitalizations, and nothing else really to speak of from a medical comorbidity standpoint. He has CLL which was diagnosed about five years ago.  

His initial prognostic workup demonstrated mutated IGHV, no abnormalities on FISH testing or cytogenetics, and no evidence of TP53 mutation. 

So today when we see Jim, his white blood cell count is now 380,000, his hemoglobin is down to 8.7, and his platelets are about 100,000. He has some adenopathy on exam, the largest being around 2 cm. He denies any unintentional weight loss but does report occasional drenching night sweats. He has also noticed a little bit of increased shortness of breath at the gym, which is new for him. He's very active. So, what do you think? Do you think Jim needs treatment, or can we keep watching him? 

Josie Montegaard

We always make our treatment decisions based on the International Workshop on Chronic Lymphocytic Leukemia’s (iwCLL) criteria for treatment.¹ He fits the iwCLL criteria for treatment as he has significant anemia and some thrombocytopenia that are due to the CLL. This happens when the CLL becomes in such a large volume in the bone marrow that normal hematopoiesis cannot occur.  

Amber Koehler

I agree completely. A question I often get asked is, "Is there a certain number my white blood cell count has to be for me to need treatment? Is it 50,000? Is it 100,000?" And I think this gentleman's a good example of a case when there’s not necessarily an absolute value of the white blood cell count that triggers treatment in these patients. But to your point, we really rely on those iwCLL guidelines for when to initiate treatment. 

So, for Jim's treatment, there are two prevailing treatment options if you look at the evidence and the data that's been presented over the past five years that really supports novel agent-based therapy or oral targeted agent-based therapy in the frontline setting, as opposed to the more traditional chemo-immunotherapy. One option would be indefinite oral therapy with a BTK inhibitor. Ibrutinib, acalabrutinib, and zanubrutinib are currently approved. I'm sure you've seen the NCCN guideline updates in terms of preferred frontline therapy with respect to BTK inhibitors, Josie. 

Josie Montegaard

Yes. At this point, even though all three of those drugs are FDA-approved and included in the NCCN guidelines for frontline treatment, the recent update has removed ibrutinib from the preferred treatment list. So, at this point, I would pretty much only consider acalabrutinib and zanubrutinib for this patient, if I'm looking at BTK inhibitor therapy. 

Amber Koehler

That's typically our practice as well. The other thing to consider for him would be more of a time-limited treatment regimen. At 60 years old, he’s young. He's got good prognostic markers in terms of normal FISH, mutated IGHV, no evidence of TP53 mutation. He lives close to the clinic, so it's easy for him to come back and forth. So, a time-limited regimen with venetoclax and obinutuzumab in the frontline setting would be reasonable for him as well. What do you think? 

Josie Montegaard

I agree. And another factor that we sometimes use when we're considering which treatment road to go down is how bulky their lymphadenopathy is. BTK inhibitors really do an excellent job at debulking lymph nodes quite quickly, even within a few days, whereas obinutuzumab and venetoclax just don't quite reduce the lymph nodes as quickly and sometimes as thoroughly. For someone who had bulky lymph nodes, I may steer them a little bit away from obinutuzumab and venetoclax right at the get-go, if that was their primary indication for treatment. Fortunately, in his case, his lymph nodes are relatively small and we're really treating him for his cytopenias. I think either option for treatment would be great for him, but based on where he is in his life, I think starting venetoclax and obinutuzumab would perhaps be a preferred option based on his lifestyle. 

Amber Koehler

Do you want to talk a little bit about what that looks like in your practice? Because they get a couple of doses of obinutuzumab first, before starting the venetoclax. What does that look like with patients who have a high white blood cell count? 

Josie Montegaard

Sure. This patient had, like many patients with CLL, a very high white blood cell count at the time they needed to start this treatment. If we were to start them right away with the venetoclax escalation, they may be at high risk for tumor lysis. As such, for this regimen, the patients will start with obinutuzumab first. They will receive a split dose of obinutuzumab on cycle one, days 1 and 2. Then they'll receive a full dose on day 8 and then day 15. And then on day 22, they won't receive any obinutuzumab, but at that point we'll start the venetoclax escalation. And then moving forward, they'll receive obinutuzumab on cycle two, day 1, and then once every four weeks for a total of six cycles. Obinutuzumab does such a nice job at debulking the CLL burden in those first few weeks that often by the time a patient starts venetoclax, their white blood cell count is normal, and they are typically considered low risk for tumor lysis. 

However, one thing to keep in mind is just because we are not seeing much tumor lysis with venetoclax, we actually can see some laboratory tumor lysis with the first partial dose of obinutuzumab on cycle one day 1. And because of that, sometimes we do tumor lysis labs with our standard labs in the morning prior to receiving the infusion, but we'll repeat them at the end of the infusion as well before the patient leaves clinic, just to make sure that all the electrolytes are staying nice and stable. 

Amber Koehler

Something else I think about, especially with that day one obinutuzumab, is it's really important to counsel patients on the possibility of a reaction. I would say most of my patients probably have a reaction to day 1 obinutuzumab, despite the pre-medications that we give. So, I think a lot of counseling is needed, telling them that it's going to take some time, we'll stop the infusion, give them additional medications. And then once people get through day 1, generally they do pretty well through the rest of the obinutuzumab therapy, perhaps with the exception of some thrombocytopenia, especially if they have baseline low platelets. Is that your experience as well? 

Josie Montegaard

I agree. We often will see reactions in that first dose. We will premedicate with 80 mg of methylprednisolone and then the Benadryl and the Tylenol. Additionally, many of our physicians add some oral dexamethasone the night before their first dose and in the morning of their first infusion because we find that having some additional steroids in the patient’s system prior to day 1 infusion can be helpful at reducing the infusion reactions. But that's still something we're studying and gathering data on to fully implement as a standard practice. 

Amber Koehler

That's really interesting. You'll have to keep us posted. I know some patients, especially some of our older patients, really don't like steroids, but generally speaking I think a 60-year-old would probably do okay with them. 

Josie Montegaard

Yes, I think someone like Jim would do just fine. After the first couple doses of obinutuzumab, my patients do quite well and don't usually report any specific obinutuzumab-related symptoms. Sometimes they have a little fatigue in the beginning of the treatment, but as we can talk about a little later, fatigue is a little difficult to pinpoint one direct cause of. When your patients get to the first day of venetoclax, how are you typically monitoring them that day and then through the rest of the venetoclax escalation? 

Amber Koehler

Yes, I think this gets a little bit tricky. There are a lot of factors and there's a little bit of a gray area here. First of all, we're doing a tumor lysis risk assessment based on the package insert. We are primarily looking at the absolute lymphocyte count and the size of the largest lymph nodes, as well as the patient’s renal function Obviously, there are only so many lymph nodes you can feel on exam, so that's where imaging becomes really important in these patients. I know you and I have talked before that there can be some variation in when you do the scans. We typically will do the scans at day 1, prior to starting day 1 of treatment. But if I recall correctly, I think sometimes in your practice you will wait to scan until day 22. Is that correct? 

Josie Montegaard

That's correct. Sometimes, if we have not gotten a CT scan prior to starting treatment, we'll wait until closer to day 22, just to have a more accurate reflection of what their lymph node burden is. But often, a patient is coming to us with recent scans or we're getting scans prior to starting treatment anyway, and in that instance we're not re-scanning them about three weeks later. So there's some flexibility, of course. 

Amber Koehler

Right. For Jim, when we think about his risk assessment for tumor lysis syndrome, he has an ALC that is certainly above 25,000. He doesn’t have any particularly large nodes on exam or CT scans; they’re all less than 5 cm. So, he would be considered a medium risk for tumor lysis syndrome. Based on the package insert, we typically would not be admitting this patient, especially if he has adequate renal function.  Most of the time what I see with obinutuzumab is that the white count drops dramatically after those first couple of treatments, so I would suspect that his white count would be on the downtrend. For TLS monitoring for Jim, at the 20 mg and 50 mg doses, we are definitely getting baseline TLS labs (potassium, creatinine, phosphorous, calcium, uric acid) as well as the six-to-eight hour and the 24-hour tumor lysis lab monitoring. For the subsequent doses, the 100, 200, and 400 mg doses, we tend to be a little more conservative. If you look at the package inserts, technically all that is recommended is pre-dose tumor lysis labs. But in our practice, we've really stuck to this 24-hour tumor lysis monitoring, even at those 100, 200, and 400 mg doses. What does that look like for you? 

Josie Montegaard

We're very similar. I think that we are quite conservative in that we follow the package insert for the 20 and 50 mg escalation for all escalations. So that means we do the pre-dose tumor lysis labs, six-to-eight hours TLS labs, and then 24-hour TLS labs. 

The other thing that we do, and I think it is very important for all patients, is we hydrate them through each escalation. We do IV hydration because they'll be in our clinic anyway, and we do that for every week escalation. The package insert recommends oral or IV hydration. What are you doing at your clinic, Amber? 

Amber Koehler

We really help patients focus on pushing oral hydration. I love the water bottles they get sent with the starter pack. I think they're great. In general, I think as long as they're medium-to-low risk, we focus on that oral hydration. But certainly, even if there are some mild laboratory abnormalities that don't necessarily meet that criteria for clinical TLS, I'm going to have a very low threshold to give IV hydration that day.  

Josie, I think you said something really important about your experience and I think it reflects ours too, which is that even with this more intensive monitoring that we’re doing looking for tumor lysis syndrome outside of what the package insert recommends, we’re not really seeing laboratory tumor lysis and certainly not clinical TLS. I think that's reassuring, especially for our colleagues who practice outside of an academic medical center like we do, where these laboratory monitoring logistics can get really challenging. I think that's encouraging that perhaps, as we continue to move forward, that might make venetoclax-based regimens easier or more manageable for folks who practice in the community setting. 

Josie Montegaard

I agree. Once you get past the venetoclax dose escalation, we are no longer worried about TLS and the regimen is very well tolerated so the visit schedule becomes much less burdensome. What kind of side effects, once patients are on the full dose of venetoclax and getting monthly obinutuzumab, do you often encounter in your practice? 

Amber Koehler

I think probably the most common things I hear from patients are the loose stools and diarrhea. I also hear about a little bit of stomach upset, a little bit of nausea and then fatigue. We also, of course, are looking for things like neutropenia and infections. What about you? Is that pretty similar to what you see? 

Josie Montegaard

Yes, that’s pretty similar. And often, I feel like the gastrointestinal side effects can be pretty well prevented if patients are taking the venetoclax with food. If they’re still having some stomach upset or diarrhea post dosing, sometimes we’ll recommend antiemetics. Other times, we’ll recommend switching their dosing to the nighttime dosing because often they can sleep through any post-dose GI symptoms. What does your team typically do? 

Amber Koehler

I think that sounds pretty similar. We always make sure folks have Compazine on hand in case they need it. Sometimes taking it in the evening and/or changing what foods they take with it can help, so we walk people through what that looks like. In terms of the fatigue, that’s pretty tricky. I’m certainly ruling out other causes of fatigue. There are lots and lots of reasons people can be fatigued, whether it’s poor sleep, stress, depression, thyroid abnormalities, heart failure, or coronary artery disease. 

Josie Montegaard

Yes, I see that quite a bit in my practice as well. So going back to Jim, I think that he has tolerated this regimen very well with the venetoclax-obinutuzumab regimen. He's only on treatment for a full year. After that time point, he is able to come off all treatments, regardless of his response, which is based on the CLL14 trial², and then he can go back into a period of observation. Something that we do at the end of treatment to assess disease response and is somewhat helpful in determining and allowing us to predict how long he may have off treatment, is we perform a lab test called the minimal residual disease (MRD) test, which is a very sensitive test to detect CLL in the blood or in the bone marrow. 

There are a couple of different tests out there with different levels of sensitivity, but one of them is the clonoSEQ test and that can detect one CLL cell in a million cells. Are you using any minimal residual disease assays or tests? 

Amber Koehler

Yes, we are. Ours is an in-house one, so it's a little bit different. I think most places are still using the 10^-4 MRD by flow. If you look at most of the original venetoclax-based trials, much of that data on MRD negativity was presented at the 10^-4 level, so I tell patients that it’s not wrong to use that cutoff. There can be additional information and value with ClonoSeq, as we start to see some discrimination in outcomes at deeper levels of MRD. More to come on that I’m sure, but it’s not wrong to use the 10^-4 MRD by flow for CLL.  

Josie Montegaard

That’s a good point. This has been a great conversation, Amber. I look forward to chatting about CLL with you again soon.