Optimizing Testing Rates in CLL: Q&A


Drs Alexey Danilov and Anthony Mato respond to a variety of questions pertaining to the assessment and treatment of patients with chronic lymphocytic leukemia.

Alexey Danilov, MD, PhD: Should we move on to the Q&A session? We have close to a dozen questions there.

Anthony Mato, MD, MSCE: Sure.

Alexey Danilov, MD, PhD: It will give us an opportunity to discuss these topics a little more. Question No. 1 is, how are physicians testing for cytogenetic risk? How common is deletion 17p and TP53 testing done? We started the conversation with this. In our practices, we both seem to be testing for these abnormalities in every patient with CLL [chronic lymphocytic leukemia] whom we treat and often whom we diagnose. Deletion 17p and TP53 abnormality aren’t that uncommon. It comes up in 10% to 15% of previously untreated patients. In our practices, as referral centers, it’s probably even higher. The reality is it does impact treatment decisions. Particularly if you’re about to use chemoimmunotherapy in your practice, everybody should get tested, because you’ll be surprised how frequently this abnormality comes up.

It’s very important to also test for karyotyping, again, particularly in the context where you’re planning to use chemoimmunotherapy, which still has a significant market share in the United States. But even for targeted therapy, it’s highly prognostic. A recent publication from Ohio State [University] suggested that complex karyotype also predicts inferior outcomes on ibrutinib. All this testing is important for all patients.

Anthony Mato, MD, MSCE: Can you define a complex karyotype? Because every time we write a paper, we talk about 3 [abnormalities], and then there’s always a reviewer who insists that it’s 5. What is a complex karyotype? I’d love to know.

Alexey Danilov, MD, PhD: Right. It’s a bit of a moving target, but based on the amount of information that we have, I’d still define it as 3 abnormalities.

Anthony Mato, MD, MSCE: Me too. But I feel like there have been people pushing toward 5 or more abnormalities to define complexity, so I was curious where you stood on that.

Alexey Danilov, MD, PhD: Yes. That comes from the European data set, where there was an even worse prognosis with 5 abnormalities. But given the whole body of data, it’s reasonable to consider 3 abnormalities. We’re helped by next-generation sequencing, because I often find other high-risk mutations in these patients, such as NOTCH or SF3B1. It’s not just that, but for the purpose of complex karyotype, I always think of 3 abnormalities. Anthony, do you want to read the next question?

Anthony Mato, MD, MSCE: Absolutely. How do cytogenetic tests determine or influence treatment choice? Will the treatment choice be different for deletion 17p or TP53-mutated patients or [those with] a high-risk profile? I feel like we tackled this one already. We both completely agree to never choose chemoimmunotherapy for these patients. We could debate BTK [Bruton tyrosine kinase] inhibitors vs venetoclax, but there’s no comparative data set. Did you want to add anything to that, Alexey?

Alexey Danilov, MD, PhD: No. It’s clear that we wouldn’t use chemoimmunotherapy for these high-risk patients. But the choice between BTK inhibitors and venetoclax is still a valid choice. Both are good options, although many of our colleagues lean toward BTK inhibitors because of the volume of very encouraging data that we have with those drugs in this disease.

Let’s go to question No. 3. How high is the bleeding risk with BTK inhibitors when patients take NSAIDs [nonsteroidal anti-inflammatory drugs]? That’s a very good question. That has been studied. In fact, the risk of a major hemorrhage with BTK inhibitors is very low. Where that risk is particularly important to consider is around surgical procedures. That’s where problems arise. Of course, if it’s an emergent procedure, then all bets are off. But it’s very important to remember to hold BTK inhibitors for 3 to 7 days prior to minor or major surgical procedures and for the same period of time afterward, because that’s where problems arise.

There was a really interesting study from Virginia a few years ago where they found that bleeding risks were very high in those settings among our patients who inadvertently continued BTK inhibitors through surgery. In the meantime, in daily practice, those cases are still fairly rare, and I routinely combine BTK inhibitors with aspirin or NSAIDs. In fact, retrospective analysis and analysis of clinical trials suggest that combining antiplatelet agents with BTK inhibitors may somewhat raise minor bleeding risk, but doesn’t increase the major bleeding complications. Those are the ones we care about the most. Patients may bruise a little more. However, the likelihood of developing a CNS [central nervous system] bleed doesn’t seem to be that increased. It’s OK to combine these drugs.

Moreover, in my practice, I have combined BTK inhibitors with anticoagulants, like anti-DNA drugs. The reality is that BTK inhibitors are unfortunately associated with risk of atrial fibrillation. It’s higher for ibrutinib than acalabrutinib, but it’s there for both drugs. It seems to be a class effect. Invariably, these patients often require anticoagulation, so in my practice, I have also combined anticoagulants with BTK inhibitors. How about you, Anthony?

Anthony Mato, MD, MSCE: Yes. I completely agree with your answer. I’m comfortable with aspirin, NSAIDs, and combining BTK inhibitors with any anticoagulant except for warfarin. Of course, it always has to be taken into the context whether the patient is having bleeding or bruising issues before the BTK inhibitor was started, if they’re on those agents to begin with. I totally agree with you. The most dangerous situation is in the context of minor and major procedures. That’s where the risk is high, particularly if they’re on 1 or more of these agents combined with a BTK inhibitor. I don’t have much to add. We have a lot of experience combining these drugs, and I can’t think of the last patient who had a significant bleed on a BTK inhibitor.

How frequently is chemoimmunotherapy recommended for all patients with IGHV mutations? Or is the choice BTK inhibitor monotherapy? I already mentioned I’m using FCR [fludarabine, cyclophosphamide, rituximab] 0.7 times per year over the last 3 years, so I’m not using a lot of chemoimmunotherapy, even in my patients with IGHV mutations. But the choice for me is a targeted therapy, and it’s not necessarily mandated to be a BTK inhibitor. How about you, Alexey?

Alexey Danilov, MD, PhD: Yes, I agree. With chemoimmunotherapy, it’s not just patients with IGHV mutations. I would urge one to conduct next-generation sequencing in that setting. Because if I find NOTCH, SF3B1, any other high-risk mutations, I don’t do it anymore. I tailor it very carefully. BTK inhibitor monotherapy is still an appropriate choice there.

This is an exciting question: If zanubrutinib is approved, would it possibly replace acalabrutinib- obinutuzumab or ibrutinib-obinutuzumab? That’s an interesting question. It has multiple components to it. Do you want to start, Anthony? I was going to start with an easy answer.

Anthony Mato, MD, MSCE: You go first then.

Alexey Danilov, MD, PhD: Alright. The audience is probably aware of a recently reported analysis of the ALPINE study, where zanubrutinib was compared with ibrutinib with a slight improvement in overall response rates. However, it excluded partial response with lymphocytosis, so if you counted that, the overall response rates were similar. And there was maybe a slight improvement in PFS [progression-free survival]. But most importantly, there were lower rates of atrial fibrillation. In that context, zanubrutinib toxicities seem to be more aligned with acalabrutinib toxicities than with ibrutinib. If I have a choice between a second-generation and a first-generation BTK inhibitor, I’d go with the second-generation BTK inhibitor. In that context, the answer is probably yes. What do you think in terms of comparisons of zanubrutinib and acalabrutinib, which don’t exist today?

Anthony Mato, MD, MSCE: My decisions will be made based on how these drugs are studied. The one I’m going to choose is the one studied in a unique patient population, like deletion 17p, or in a unique combination, or compared with something that is clinically relevant. Those are what will go into how I’ll decide the winners and what I won’t be using. I’m fairly impressed with the SEQUOIA data set, because there was an initiative to study zanubrutinib in over 100 patients with deletion 17p in the frontline setting. That provides useful information for me. For me, the winner will be based on the patient population, a unique combination, and comparisons that are meaningful. That’s how I’ll make my decisions. If zanubrutinib does those things better than acalabrutinib, then I’ll likely use it. If not, then it will be a flip of a coin.

Alexey Danilov, MD, PhD: Yes. Very interesting. The issue that’s often raised is the use of proton pump inhibitors [PPIs] with acalabrutinib. We’re not supposed to use PPIs with acalabrutinib, but zanubrutinib doesn’t carry that restriction. I agree that with deletion 17p patients, the SEQUOIA data set with zanubrutinib is really impressive. One aspect of it that I still cannot get my head around is there were quite a few patients with IGHV mutations, which you don’t necessarily expect with deletion 17p. These patients usually have unmutated IGHV. I’m still not entirely sure what that means, but I agree, this is by far the largest data set with deletion 17p that we have.

Anthony Mato, MD, MSCE: Yes. Outside of the RESONATE-17, which was a relapsed/refractory data set.

Alexey Danilov, MD, PhD: Yes. Do you want to check out question No. 10?

Anthony Mato, MD, MSCE: Yes. No. 10 is about a patient’s case. This part will be easy. Do you treat patients with MBL [monoclonal B-cell lymphocytosis]? We’d both probably say no. But in this case, this has come up in my clinic a couple of times with fellows who have asked me this question. If a patient comes with a diagnosis of MBL, but you palpate 1 lymph node, or they get sent for extensive scanning and they happen to have 1 pathologically enlarged lymph node, are you changing that diagnosis to SLL [small lymphocytic lymphoma]? Another question I got asked just yesterday in the clinic—maybe you can answer it for me—is if a patient comes with a diagnosis of MBL, has every feature of MBL, but happens to have gotten a bone marrow biopsy that shows 75% involvement, do you still consider those patients to have MBL? What would you say to that?

Alexey Danilov, MD, PhD: MBL is an isolated finding in the blood. If a patient has bulky lymphadenopathy, I’d consider them as having CLL/SLL at that point. I still consider CLL/SLL as the same disease. CLL is really a lymphoma, rather than a leukemia. The disease originates from the lymph node and bone marrow. It’s the question of whether those cells come out to the blood or not, and for some rare patients, somehow they don’t. At that point, I’d consider the patient as having CLL and treat them as such.

In terms of doing a bone marrow biopsy on a patient with MBL, the diagnosis of MBL doesn’t require or presume that a bone marrow biopsy was done. I wonder what the reason is to do it, and if those patients have anemia or something where you’re looking for a reason for why they have anemia, thrombocytopenia, or symptoms. At that point, they also might have CLL. Is there a right answer? Did I blow it?

Anthony Mato, MD, MSCE: I don’t know the answer. I think you’re right. This particular patient I was being asked about had no reason to have a bone marrow biopsy. They had normal counts otherwise, but they happen to have one with this high percentage of CLL. I was being asked how to interpret that, in light of the fact that they only have 3% circulating lymphocytes and no palpable lymphadenopathy or spleen. To answer this question, if you have a patient with abnormal lymph nodes, this is SLL. But I agree with Alexey: There’s no difference. The question is, do they need treatment based on iwCLL [International Workshop on Chronic Lymphocytic Leukemia] criteria? Regardless of what name you assigned to the patient’s disease, that’s how you should decide if they meet any of those criteria. And if so, then you should think about treating them.

Alexey Danilov, MD, PhD: Yes. I’d reinforce that it’s a spectrum. When we talk about where MBL ends and CLL begins, it’s arbitrary. What’s to say that 5000 clonal cells is MBL and 5001 is CLL? It’s a very arbitrary cutoff. The good news is that patients who qualify for the criteria for MBL can have a very long time-to-treatment period, and the majority of them still won’t be treated. It’s important to consider that these patients have an increased risk of infections. That’s from the Mayo Clinic data. Even though those patients have MBL, they’re still immunocompromised. That’s particularly relevant in the age of COVID-19. I very much encourage these patients to get vaccinated and get their booster and follow all the guidelines.

Anthony Mato, MD, MSCE: The last comment I’ll make about that, you alluded to it with the term spectrum, is it’s an acknowledgment that the definitions aren’t perfect and there’s some room for gray zone in terms of trying to assign a patient a diagnosis. The question I’d throw out to you, which we don’t have time for, is what staging system are you using with your SLL types? There’s so much ambiguity that still needs to be worked out in the iwCLL criteria.

It’s 8 o’clock, and our conversation was supposed to end at that time. Speaking on my behalf, I had an amazing time and always enjoy having these conversations. We’re always open, we’re always unfiltered, and it’s great to hear East vs West Coast perceptions on how to manage CLL.

Transcript edited for clarity.

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