 If somebody asked me the most important things to do with a newly diagnosed patient with CLL [chronic lymphocytic leukemia], first and foremost—I can’t say this enough—it’s so important to check all the different genomic aberrations. You need to know. We’re always used to, “13q, they’ve got great disease, they’re never going to need treatment.” But that’s a knee-jerk reaction. It’s important to know that, but there are so many other molecular aberrations that we need to know about, specifically 17p, 

 mutational status. We need to know that. Looking back, when I’ve picked up patients who may have been seen by another provider, those weren’t checked. We could have potentially done them a disservice in the past if we gave FCR [fludarabine, cyclophosphamide, rituximab] to a patient who had an unmutated 

. They have a really poor response to chemotherapy-immunotherapy, but we didn’t always know that. That wasn’t always being tested routinely.

In a practice, it’s really important to adopt a uniform way of testing so that those key elements don’t get missed. I can’t say that enough. I built an order set in my own practice for established patients with CLL and for newly diagnosed, so the boxes are already clicked. Unless you unclick them, those things should be getting done. That way you don’t have to worry about which color tube is being done and drawn. The right things are being done. You need that. As I said, we’re in the day and age of personalized medicine, so why not give your patient the best benefit of their therapy by picking the right drug for their mutational status?

We’re lucky enough that a lot of our targeted agents are doing great in a high-risk patient vs a standard-risk patient. It’s not hurting anybody, but we need to know that because that’s how we’re going to be able to predict how many years they can go until they might need therapy. Patients are reading and looking into this. They know these things now. They’re coming in and saying, “I know someone who had this tested. What’s my IPI [International Prognostic Index] score? When am I going to need treatment? Am I ever going to need treatment?” We can’t always predict that, but they want numbers. By having that information and plugging those mutations into the CLL-IPI [International Prognostic Index for Chronic Lymphocytic Leukemia] calculation, we can give them some statistical evidence of what they may be looking at in terms of their disease, which makes them and their families feel better.

At the end of the day, it makes our jobs easier, because we’re giving them reassurance that we’re doing right by them. That’s my biggest take-home suggestion point. We need to be testing for the genomic aberrations, mutations, or whatever you’d like to call them, in all our newly diagnosed patients and again at relapse. Before you start any treatment on a relapsed patient, you need to recheck. The 

 does not need to be rechecked, but with all the other ones, you need to make sure a new clone hasn’t emerged, and that you’re treating your patient appropriately.

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An expert hematologist/oncologist highlights key takeaways for the future management of chronic lymphocytic leukemia given an evolving therapeutic landscape.

Looking Toward the Future of CLL Management

 When selecting a BTK [Bruton tyrosine kinase] inhibitor, a lot of our patients are older. The median age of diagnosis for CLL [chronic lymphocytic leukemia] is 70 years old, which means most of those patients are going to have at least 1 cardiovascular risk factor, whether it’s controlled atrial fibrillation, high blood pressure, or peripheral vascular disease. It’s really important to know that going in. If they have controlled atrial fibrillation, that’s 1 thing. But if a patient starts treatment with 1 blood pressure medication and suddenly is on 2 and then 3, that’s a big deal. We need to know our patients and their medications and compliance.

The study from ASCO [American Society of Clinical Oncology Annual Meeting] has shown that we may be able to look for different genes that are associated with higher risk of cardiovascular adverse effects. By looking at what’s called single nucleotide polymorphisms, or SNPs, we can predict if a patient has a higher likelihood of having a cardiovascular event vs another patient. That’s not something that’s being used mainstream, but that might be something that helps design our treatment plan for a patient. If we know they’re going to have a higher risk right out of the gate, then maybe we avoid drug X.

This study was done specifically with ibrutinib. By looking at the number of the SNPs involved, you could predict their risk for cardiovascular adverse effects. It’s personalized medicine. We’re moving into that day and age where you’re able to almost predict adverse effects, how a patient is going to respond, and if they’re going to be resistant to a drug. It’s a good marker to know the risk of cardiovascular adverse effects.

In terms of therapeutic sequencing strategies for CLL, that’s a good question because there are several options. When you go to the NCCN [National Comprehensive Cancer Network] Guidelines for a patient who has relapse disease, there are different options. When someone has been on 1 drug and has relapsed, it’s very important to recheck their genomic mutations because different clones can emerge, especially 17p and the 

 mutation. It’s very important to check for those again. The 

 mutational status doesn’t change. You check that only once. But the 17p should be rechecked because you want to know if a new clone has emerged. That’s the first thing I do.

Then I need to look at the patient. What has changed since their first line of therapy? Their age, other comorbidities, new comorbidities? Are they as robust as they were when they were first diagnosed? What did they receive first line? This might be a patient who received FCR [fludarabine, cyclophosphamide, rituximab] first line. In that case, I’d likely use a BTK inhibitor. But it depends on many different factors, not just choosing drug B because I had drug A before. As time goes on, especially with the targeted therapies, the BTK inhibitors and the BCL2 with venetoclax sequencing is going to evolve, and we’re going to see the best way to do it and if 1 treatment primes the microenvironment of the immune system for the next therapy. We don’t know that right now, but we will in time. In this day and age, aside from what they were on before, I have to really know the person and what’s going on with them to help guide my therapy.

Practical advice on optimal toxicity management and sequencing of therapy in patients with chronic lymphocytic leukemia.

Optimal Treatment Strategies for Chronic Lymphocytic Leukemia

 We were waiting for the head-to-head data on acalabrutinib vs ibrutinib for a really long time, especially since ibrutinib has been the drug of choice in a lot of practices for a really long time, partially because that’s what was around for a long time and old habits die hard. Having these data was really important. First, in terms of efficacy, they’re the same. Acalabrutinib is noninferior to ibrutinib in terms of PFS [progression-free survival]. Overall survival was not reached. In terms of efficacy, they’re both very good choices.

Where they really show their differences is with the cardiac ARs, or adverse reactions, specifically the hypertension and atrial fibrillation. We know they can happen in both drugs, but we continue to see that ibrutinib has higher percentages of atrial fibrillation and hypertension vs acalabrutinib. For instance, atrial fibrillation was 9.4% with acalabrutinib, and 16% in the patients with ibrutinib. For the hypertension, it was 9.4% for acalabrutinib, and 23.2% for patients with ibrutinib.

The discontinuation rate was a little higher with ibrutinib vs acalabrutinib. That holds true in practice, or at least in my practice. I’ve had patients who we’ve had to dose reduce when they’ve been on ibrutinib because of high blood pressure and uncontrolled atrial fibrillation. I’ve switched a few patients from ibrutinib to acalabrutinib who’ve had issues with hypertension and atrial fibrillation. Those are real adverse effects and concerns in mainstream practice. This trial showed they’re both great drugs in terms of PFS and overall survival. That was the first question. It was important to show that acalabrutinib is noninferior to ibrutinib. But then looking at the adverse events or reactions, we’re seeing atrial fibrillation and high blood pressure higher in the ibrutinib group vs acalabrutinib.

Tara Graff, DO, MS, reflects on the head-to-head comparison data of acalabrutinib vs ibrutinib in patients with previously treated CLL.

Acalabrutinib vs Ibrutinib: Head-to-Head Data in Previously Treated CLL

 How do we treat people? Do we treat them with monotherapy using acalabrutinib, or do we need the combination with an anti-CD20? In my practice, it’s patient specific. When we look at the ELEVATE-TN study, we see that both acalabrutinib monotherapy and acalabrutinib with obinutuzumab are very efficacious in terms of PFS [progression-free survival] and overall response rates. They maintain their efficacy across all the high-risk subgroups, including patients with bulky disease or who are older. They continue to do very well regardless of whether acalabrutinib was used as monotherapy or in combination.

It’s very patient specific. If I have an older patient, and even in some of my younger patients, depending on their burden of disease, I’ll just use acalabrutinib monotherapy, and they do very well. Especially in the day and age of COVID-19, adding in that anti-CD20 adds extra adverse effects and concerns with immunosuppression. It’s something to consider in the last year or so that maybe wouldn’t have been as big of a deal before.

Where I always use combination therapy is with my younger patients with high-risk disease and heavy disease burden. If they have a 10-cm lymph node that’s obstructing something, or if they’re really symptomatic, I’ll go ahead and use acalabrutinib plus obinutuzumab. I feel they do better having both agents on board. That’s traditionally how I’ve been making my decision. But it’s very patient specific. In the majority of them, I’m using acalabrutinib monotherapy, and they’re doing very well. The 4-year follow-up data show us that they’ve continued to do well in both the acalabrutinib-monotherapy group and the acalabrutinib-plus-obinutuzumab group in terms of PFS, overall survival, and overall response rate. As they were on it longer, the data were consistent. Patients continue to do very well. It’s very reassuring when making those decisions.

If I had a young patient, let’s say a 58-year-old man with a 17p deletion, and a 58-year-old woman without 17p deletion, as long as they didn’t have significant disease burden, I’d treat them the same. I’d give both acalabrutinib monotherapy because we know that acalabrutinib monotherapy has excellent PFS and overall response rate in both groups, whether the deletion 17p is present or not. The only time I would change my decision is if the disease burden were high, if they had a giant lymph node causing lymphedema, blockage of something important, or pain in general. Then I would I use combination therapy, but only if that circumstance was present.

As long as the patient doesn’t come in wanting fixed-duration therapy, I’d still use acalabrutinib because it’s very well tolerated. The data are excellent. The adverse-effect profile is great. Without that high disease burden, whether the patient is younger or older, I’d still use acalabrutinib monotherapy. If it was a patient who insisted on a fixed duration and didn’t want to have to be on something for the rest of their lives, only then would I consider using something different entirely. But in those 2 scenarios, as long as fixed duration isn’t an issue, I’d use acalabrutinib monotherapy, as long as there isn’t high disease burden or tumor burden.

Expert insight on the use of frontline BTK inhibitor monotherapy over combination therapy in CLL regarding the ELEVATE-TN trial’s readout.

Frontline BTKi Therapy in CLL: The ELEVATE-TN Study 4-Year Follow-up

 stands for Bruton tyrosine kinase. It’s critical for the propagation of B-cell-receptor signaling, and it’s upregulated, so it’s overexpressed in a CLL [chronic lymphocytic leukemia] cell compared with a normal cell. By blocking that signal, you’re decreasing B-cell proliferation and, essentially, cancer cell proliferation. This is where the target is for BTK inhibitors.

Ibrutinib was the first BTK inhibitor. It was the first generation. It targeted the BTK selectively, but it has more off-target inhibition as well. Then came acalabrutinib, which is a second-generation BTK inhibitor. It has very strong inhibition at the Bruton tyrosine kinase receptor, but also less off-target inhibition compared with ibrutinib. Therein lies what we see with certain adverse effects and things like that. We have those 2 drugs, and now we have zanubrutinib as well. That’s come into the fold. Those are the 3 drugs we’re using to inhibit the BTK.

We’re learning that there’s a sustained PFS [progression-free survival], overall survival, overall response rate, and tolerability as time goes on with the BTK inhibitors. The RESONATE-2 trial is looking at ibrutinib. It has the 7-year long-term follow-up data. It showed sustained PFS and overall survival; PFS was 61% at 7 years vs 9%. For chlorambucil, which it was compared with in that trial, overall survival was 78% and overall response rate remained 92%. Hypertension and atrial fibrillation—commonly seen as cardiovascular adverse effects with ibrutinib—persisted, but as time went on, they didn’t get worse. Patients actually appeared to tolerate the medication better. From 5 years on, patients did well. There was a low discontinuation rate from that point on. It continued to show efficacy and tolerability over time, which is impressive when you’re talking about an oral medication.

A comprehensive breakdown of the rationale behind targeting BTK signaling in CLL, as well as considerations for clinical experience with the available BTK inhibitors.

Rationale and Use of BTK Inhibitors as Initial Treatment for CLL

 In my practice and clinical practices all over [the United States], novel agents have completely changed the face of treatment and outcomes for our patients with CLL [chronic lymphocytic leukemia] to the point that chemotherapy-immunotherapy is hardly, if ever, used anymore. At times, immunotherapy, in terms of our anti-CD20 antibodies, aren’t even being used conventionally. That’s a big thing, especially in the time of COVID-19, where immunosuppression with vaccines and the risk of COVID-19 has been a concern, especially in our patients with CLL. But in mainstream, having these targeted agents, patients can take a pill, and in some cases, they can take a medication and have a fixed duration of therapy, knowing they’re going to be coming off in X number of months. That’s a big deal. It’s completely changed the treatment landscape for CLL in the last 18 months. It’s a whole new ballgame.

Molecular testing in any newly diagnosed patient with CLL is critical. We need to routinely be doing FISH [fluorescence in situ hybridization] testing for cytogenetics. We need to be looking at different genomic aberrations, specifically for deletion 17p, 

 mutational status. Too often, especially in community oncology, these are left out. They’re necessary to know if your patient has higher-risk disease, because that will determine their time to first treatment and possibly what medications you select. Patients who have higher-risk disease don’t conventionally respond to chemotherapy-immunotherapy. We stated that this isn’t really being used, but it’s important. The NCCN [National Comprehensive Cancer Network] Guidelines use those different genomic aberrations to dictate and help guide treatment. It’s very important that there’s some standardization for these different cytogenetics and mutations that are being routinely done in all practices.

By checking those markers, I’m going to go back to focusing on 17p deletion and 

 mutational status. We use a prognostic test called the CLL-IPI [International Prognostic Index for Chronic Lymphocytic Leukemia]. Conventionally, we always use the Rai and Binet staging systems, but now we take those 2 older staging systems and use them to calculate a risk score using the CLL-IPI looking at the different high-risk cytogenetics, age, and beta-2-microglobulin, and calculating how many points you have. It correlates to your overall risk, lets you know your overall survival, and also lets you predict when somebody might need treatment. Those are really important. It all starts with looking at those chromosomal abnormalities to help guide treatment, and then also fold over into the CLL-IPI. It’s crucial that we continue to educate people that we need to be checking for these genomic aberrations routinely on all patients newly diagnosed with CLL.

Tara Graff, DO, MS, outlines the current treatment paradigm for chronic lymphocytic leukemia by discussing the use of novel agents, molecular testing, and risk stratification.

Tara Graff, DO, MS, Mission Cancer + Blood

Articles

Looking Toward the Future of CLL Management

Optimal Treatment Strategies for Chronic Lymphocytic Leukemia

Acalabrutinib vs Ibrutinib: Head-to-Head Data in Previously Treated CLL

Frontline BTKi Therapy in CLL: The ELEVATE-TN Study 4-Year Follow-up

Rationale and Use of BTK Inhibitors as Initial Treatment for CLL

The Evolution of CLL Treatment