 There’s another category of drugs that we haven’t talked about much but that we have available…are drugs that inhibit PI3 kinase. Idelalisib was the first drug available. That drug had adverse effects and toxicity associated with it. Perhaps some of the subsequent PI3 kinase inhibitors were better tolerated. Idelalisib is approved, and so is duvelisib, for the treatment of relapsed CLL [chronic lymphocytic leukemia]. Umbralisib is not approved, but I’m anticipating we’ll hear something about approval soon from the FDA. Debbie, can you summarize where we’re at with PI3 kinase inhibitors and how they fit into our treatment algorithm. I know Anthony’s group reported out their work with umbralisib. Perhaps you can summarize us that abstract. We can also have Anthony comment on it.

 Umbralisib is the newest drug in this class of PI3 kinase inhibitors, and it’s different because it also inhibits something called casein kinase 1 epsilon. There are multiple mechanisms of action, but it also prevents translation of oncoproteins and helps slow and control growth of lymphoma cells. There haven’t been any head-to-head comparisons of umbralisib vs idelalisib or duvelisib. To anyone who’s used all those drugs, it’s pretty clear that umbralisib does have a better toxicity profile. You don’t see as many of those autoimmune adverse effects that were seen early with idelalisib. There’s a large study, called UNITY-CLL, that looks at umbralisib paired with another anti-CD20 monoclonal antibody, ublituximab, that was given in both relapsed and refractory but also in the front line. That’s notable because frontline use of idelalisib or duvelisib would result in severe autoimmune toxicities. However, the umbralisib combination seemed to be very well tolerated in these patients.

The interesting question you ask is where should we use these drugs? At this minute, as far as standard of care using umbralisib, it’s at least a third-line therapy. I would give preference to using a BTK inhibitor and venetoclax over umbralisib unless there’s some major contraindication—we’ve gotten great at managing these toxicities and with different comorbidities. Anthony and Callie just talked about these third-generation BTK inhibitors, which are even more tolerable and probably more efficacious. Does that push them to fourth-line therapy? Where to use them is interesting. Umbralisib is a great drug, and it probably will get approved in the frontline and relapsed settings based on the UNITY study.

Anthony’s group had an interesting concept in that using umbralisib in combination with the anti-CD20 ublituximab as a way to solidify remissions in patients who have been continuously on ibrutinib but still have residual disease. They gave this combination continuously until the patients achieved MRD [minimal residual disease] undetectable status and then confirmed it again a month later. This study is still a little early, but they presented 24 patients, and two-thirds of those patients were able to reach MRD undetectability. The median time off therapy is around 8 months. That’s meaningful clinically, especially if patients are having adverse effects to these drugs. At the time of analysis, they reported about three-quarters of these patients were still MRD undetectable.

It’s an interesting concept, but it’s unclear to me if it’s necessary to add the potential toxicity of these drugs. Both ublituximab and umbralisib were used, and we’ve talked a lot about how CD20s can induce MRD-undetectable remissions. How much of the work was done by umbralisib? How much was done by ublituximab? Do you need both? Do you need it at all? In patients who are tolerating ibrutinib well, maybe it’s just as good to continue on them even though they don’t have MRD undetectability.

Videos

A comparison of 3 PI3K inhibitors—idelalisib, duvelisib, and umbralisib—as treatment for chronic lymphocytic leukemia.

PI3K Inhibitors for CLL

 We’re going to turn to new treatments that we’re excited about and some of the updates we saw at ASH [American Society of Hematology] 2021 meeting. Before we do that, Jackie, touch on COVID-19. There were a couple of abstracts presented at ASH on COVID-19. One was an antibody response that was presented by the French group. The other was the Israeli group that reported on cell responses to vaccination against COVID-19. Jackie, could you summarize those abstracts for us? What were the take-home messages?

One abstract shows that in our patients with CLL [chronic lymphocytic leukemia], there’s decreased responses to the vaccination. The NIH [National Institutes of Health] also had a group of patients, I think 57, who were treated. They found that they needed about 45 days after their last vaccine dose to have an antibody response. In treatment-naїve patients, 71% were able to achieve that antibody response. For patients on a BTK inhibitor, it was 57%. For patients on venetoclax-obinutuzumab therapy, it was 0%, but the numbers were very small. It’s hard to know whether it was just the monoclonal antibody. The titers were higher on patients treated with Moderna, as we’re seeing in other patients who are immunocompetent.

The other trial showed patients who had been treated before with anti-CD20 monoclonal antibodies. Even with a third booster shot, they had issues getting the vaccine response. This is the group from France. Unfortunately, we know that because of their immunocompromised state, patients with CLL or lymphoma are at high risk for not developing antibodies despite vaccinations and boosters. Because many haven’t received an anti-CD20 monoclonal antibody, they have issues maintaining any response.

I remind my patients that even with the booster, if they get exposed to COVID-19, they should let us know so we can refer them to infusion of monoclonal antibodies. I don’t know how this will change in the era the omicron variant, which is 3 of 4 cases in the United States. We understand from emerging data that these monoclonal antibodies do not work as well because of the level and degree of mutations to the spike protein. This is an evolving treatment strategy for our patients with CLL. We recently got approval of this. It was shelved by AstraZeneca. We still don’t have access to the drug because it’s being distributed to every state, and every state is determining how they’re going to prioritize our patients. As of right now, we’re still waiting to hear that.

What to know in terms of COVID-19 vaccine responses in patients with chronic lymphocytic leukemia on novel targeted therapies.

Novel Therapies for CLL in the Context of COVID-19

 Nicole, I’m going to give you the task of introducing and reviewing large randomized trials that the German CLL [Chronic Lymphocytic Leukemia] Study Group has been doing, and the first report was this ASH (American Society of Hematology) meeting on the CLL13 trial that was done by the German CLL Study Group. Can you review that and the highlights of what was found with that study?

This was a nice study, although I wanted 1 more arm.

You did too, right? Glad I’m not the only 1.

 That [second arm] is in CLL17. It’s coming.

Excellent. This is looking at fixed duration with venetoclax-based combinations vs chemoimmunotherapy in previously untreated patients with CLL. The combinations were randomized to 4 different arms, so you had either FCR (fludarabine, cyclophosphamide, rituximab) or BR (bendamustine, rituximab) depending upon your age and comorbidities, vs venetoclax-rituximab as an arm vs venetoclax-obinutuzumab as an arm, and then the fourth arm of venetoclax-ibrutinib and obinutuzumab. A nice randomization. The arm that I’m assuming all of you also wanted was monotherapy with a BTK [Bruton tyrosine kinase] inhibitor, correct?

I wouldn’t mind I plus V (ibrutinib- venetoclax).

Monotherapy, maybe. I’m greedy, but I would take both.

But a nice, large, randomized study, of course. One of the things was to look at not just response but levels of undetectable MRD (minimal residual disease) between the arms, as well as adverse effects and toxicities over time. And in terms of the undetectable MRD, looking at both peripheral blood and bone marrow, believe it or not, not surprisingly, the arms that had venetoclax with obinutuzumab or venetoclax with ibrutinib and obinutuzumab had a higher level of undetectable MRD in the peripheral blood compared to traditional chemoimmunotherapy, upwards anywhere from 87% to 92% vs 50% in the chemoimmunotherapy arms.

The venetoclax-rituximab vs chemoimmunotherapy were more similar: in the 50% range for peripheral blood undetectable MRD. In the obinutuzumab arms, we saw a difference between that with the combination of venetoclax vs rituximab and venetoclax. Similarly, the adverse events and toxicities between all the treatment arms were much more similar to neutropenia, thrombocytopenia—all the things we see with chemoimmunotherapy. But obviously, with the combinations with the antibodies and venetoclax, cytopenias were also observed. The toxicities and adverse events were more similar in all the treatment arms. There were slightly higher hematologic malignancies in the chemoimmunotherapy arms but nonhematologic malignancies in the other arms; a little bit of [an outlier] in terms of that.

Obviously exciting data….We’re going to need longer follow-up to see how things settle out between the arms, but certainly there’s no doubt that we saw greater depth of undetectable MRD with the obinutuzumab-venetoclax–treated arms compared to chemoimmunotherapy. And we just need to stay tuned for that.

May I add 1 comment just in terms of arms? Instead of thinking I wanted 1 more arm, I was thinking I wanted 1 less arm. The chemoimmunotherapy arm was—I don’t know—I would have rather seen either of the arms you guys proposed for a 1000-patient study. One of the clever things about CAPTIVATE, [although] I sometimes criticize GLOW or CAPTIVATE, but the CAPTIVATE fixed-duration arm where they bothered to use the CLL, it was the data from CLL10 for FCR as a historical control; I think it was so clever to spare patients the randomization vs FCR. The primary comparison were CR [complete response] rates of FCR with I plus V. If they did that for CAPTIVATE, it would have been wise to do it again to spare patients chemoimmunotherapy in this setting.

I bet you’re not the only 1. You saw that there were patients that decided to get off the trial once they were randomized to chemotherapy.

Yes, I’m with them. I probably wouldn’t have been on board for that.

Key takeaways of the CLL13 (GAIA) clinical trial based on highlights presented at ASH 2021.

Chemotherapy-Free Regimens as Frontline Therapy in CLL

 We also studied ibrutinib-venetoclax in the relapsed setting, and the UK group also studied a similar regimen in the CLARITY study. At ASH [American Society of Hematology Annual Meeting], the HOVON 141 group [VISION trial] reported an abstract. Jackie, could you comment on the abstract that Carsten Niemann presented with regard to the trial with ibrutinib-venetoclax?

This was a phase 2 study for relapsed/refractory patients with CLL [chronic lymphocytic leukemia] combining ibrutinib with venetoclax. Similar to other trials, like CAPTIVATE and GLOW, this included ibrutinib leading for the first 2 cycles and then the ramp-up dosing schema for venetoclax. From cycles 4 to 15, you did a combination of ibrutinib and venetoclax. The trial was designed to measure progression-free survival at 12 months after cessation with the option to restart if there was any evidence of detectable MRD [minimal residual disease]. Investigators assessed for MRD by flow cytometry. The MRD was detected at 10-4. It was a trial that included 225 patients.

The majority had mutated disease at 64%. With group-enriched 

 mutation. Eighty-six percent of patients were able to complete the planned treatment, but 8 patients were taken off trial early on during the initiation because of toxicity during the ibrutinib part. There were some events of bleeding.

The study was complicated in the sense that there were 2 arms, and 1 was not randomized. If you achieved undetectable MRD at the end of therapy, determined as no evidence of disease at 10-4 in the peripheral blood and in the bone marrow, you were randomized 2:1 to receive ibrutinib maintenance or observation. The observation arm had 48 patients; ibrutinib maintenance had 24 patients. Patients who didn’t achieve undetectable MRD weren’t randomized, and they were to continue ibrutinib until progression of disease. Patients who had been on observation at the time of presence of detectable MRD at 10-2 were allowed to restart ibrutinib and venetoclax similar to the way it was initially.

The presenters determined that, upon the rechallenge, these patients were able to go into remission again, saying that you could potentially intervene before full progression where patients have symptoms and just intervene at the time of the MRD showing up again or MRD positivity.

That brings us to the question of whether this is something we should embrace, because by IWCLL [International Workshop on CLL] Guidelines, we essentially wait to re-treat until patients they have symptoms or some other IWCLL criteria that determines that the patients need therapy. I wanted to know how you guys feel about this study in that sense, whether starting therapy again at 10-2 might be good, something that we should strive for in future trials or we should wait until the patients have a full relapse.

That’s exactly the question we need to get at from some of these studies. Bill, you mentioned earlier about intervening early for evidence of minimal residual disease to intervene. Depending on the disease characteristics of those patients, would some benefit from early intervention? For our high-risk patients, we’re concerned that intervening earlier may potentially be better. Other individuals who still have disease evident—forget MRD positivity—can go many years without needing re-treatment because they have good-risk features to their disease. [We need to] understand how to utilize MRD and personalize that based on somebody’s disease characteristics. That’s going to be important for us to learn from these studies, whether intervening early based on MRD. As we see time to next treatment, their response duration, and so on, it’s important.

 I agree. We need clinical trial data to support those types of decisions. If they’re different from what our standard has been, we need to show some clinical benefit to that. I’ve had patients relapsing, and I won’t usually treat them. I don’t re-treat them. I don’t always wait until they fulfill the criteria because my thought is, “This patient’s disease is growing. Maybe their hemoglobin isn’t 10 g/dL, yet or their platelet count isn’t 100 per mm3 yet, or they’re not having drenching night sweats yet but it’s coming. If there’s less disease to treat, you’re more likely to get a better response. I might not wait technically to start re-treatment until they fulfill the criteria. I wait until I feel there’s clinical benefit to starting them on re-treatment. Does anybody else have a thought in terms of those approaches, intervening at MRD relapse, etc?

Hard to know. From a trial design perspective, it’s impossible to understand response rates before patients progress. That’s 1 issue. It’s hard to understand what progression is to re-treatment. It requires a new way of thinking about patients if that’s going to be the paradigm. We have a lot of stopping trials where we follow MRD sequentially. It’s incredible how long a patient can go from time of MRD conversion to clinical progression. If you watch enough of these patients, years go by before they become clinically symptomatic, and then it makes me question whether it makes sense to do these interventions based on a number or as percentage of MRD crossing some threshold.

 With chemoimmunotherapy and FCR [fludarabine, cyclophosphamide, rituximab], we reported a median time to progression from MRD relapse of 2 years. We see a spectrum of kinetics of disease and relapse, and there can be patients who go for extended periods of time and don’t need re-treatment even after chemoimmunotherapy.

Considerations for treating patients with relapsed/refractory chronic lymphocytic leukemia with the combination of ibrutinib and venetoclax.

Fixed-Duration Therapy in Relapsed/Refractory CLL: Ibrutinib Plus Venetoclax

 We’ve talked about 3 irreversible inhibitor options for our patients if we’ve chosen to put a patient on a BTK [Bruton tyrosine kinase] inhibitor. Can you walk us through some things you think about in terms of which 1 you select among those 3? How do you make that decision, that choice of treatment, for your patient who you’ve decided to treat with a BTK inhibitor?

Based on the ELEVATE-RR trial that compared acalabrutinib [Calquence] against ibrutinib [Imbruvica] in high-risk patients in relapsed/refractory disease, I’m extrapolating the data to the front line. Similarly, with the data we have coming out of second-generation zanubrutinib [Brukinsa] against ibrutinib, I’m also extrapolating that in terms of considerations for my patients. For the most part, in my practice, I’m using second-generation BTK inhibitors because of the tolerability issues. This is based on data from these clinical trials, but also what I see in my clinical practice is that patients end up having much more toxicities—adverse effects like arthralgias, rashes, and similarly bleeding events. They have more events of grade 1 ecchymosis, and it becomes concerning.

Overall, I look at the patient’s characteristics and profile. If they have any issues with a PPI [proton- pump inhibitor], I may choose or select zanubrutinib because the drug acalabrutinib may have an interaction and may not be well observed if you’re on a PPI. This might be overcome in the future because data are also coming out with a tablet, not only with a capsule. But as of right now, a PPI is an issue because many patients are taking a PPI. If the patients develop a toxicity such as intolerable headache with the use of acalabrutinib, which usually happens within the first 3 months, then I might select zanubrutinib. For the most part, the insurance will cover this even though it’s not fully approved for the use in patients with CLL [chronic lymphocytic leukemia]. But based on the data coming out and abstract, we can appeal.

For which patients do I consider using ibrutinib? I’ve used it in patients that have a coexisting solid cancer, because the use of the ibrutinib may have better outcome for these patients. But I recently had a patient present with CLL who had a large renal cell cancer. For him to have surgical resection, the surgeon asked me to debulk him as fast as possible, and I felt that ibrutinib might be better based on data from the trial comparing ibrutinib and acalabrutinib. Short of that, most of my patients are being treated with a second-generation BTK inhibitor at this time.

 Anthony, 1 question I’m asked by my patients is, “I’m starting on acalabrutinib. How long am I going to be on this treatment?” I’m sure you’ve heard that question before. How do you usually answer?

For starting the drug based on the standard of care, it’s a treat-to-progression strategy. Of course, we’re looking at excellent frontline data from the ELEVATE-TN, but we don’t have a median. I’m thankful that I can’t quote a median progression-free survival [PFS] for them, but I can quote a low discontinuation rate due to adverse events. And I comment that in our practice, most patients we’re treating with acalabrutinib in the frontline setting receive it with obinutuzumab in the context of an MRD [minimal residual disease]–driven, time-limited approach. That’s probably the future for BTK [Bruton tyrosine kinase] inhibitor–based combination therapies with CD20s. But for standard of care, we start it with the intent to stop it only with clinical progression or intolerance, both of which are relatively rare events.

 You have a lot of experience with real-world data. I’m sure you’ve reviewed data that indicate that patients are still getting first-line chemoimmunotherapy. In the United States, we have a ton of data favoring improved outcomes, at the very least progression-free survival, and in a couple of trials overall survival with frontline BTK inhibitor–based therapy. We didn’t talk at all about it, but venetoclax and BCL2 inhibitor–targeted therapy is also an option. What are the things that you think about when you’re thinking about first-line therapy as a standard treatment? How do you make a recommendation and discuss those options with your patients?

The conversation about chemoimmunotherapy is, for the most part, off the table in our practice. Outside the minority of these ideal candidates for FCR [fludarabine, cyclophosphamide, rituximab]—I don’t need to tell you who they are because you guys have defined that population—we offer that. But most of the time patients favor targeted therapies, given the great data we have from the ECOG trial, for example, vs FCR [fludarabine, cyclophosphamide, rituximab]. We have a couple of options: continuous BTK inhibitor–based therapy vs time-limited venetoclax- obinutuzumab. For the most part, my practice has narrowed down to use of acalabrutinib as the BTK inhibitor of choice and based on the standard of care, mostly monotherapy. I told you about the trial.

The hard part—and we all know this—is that there are very few comparative trials of note in the frontline setting comparing modern targeted therapies. None of us can quote data to support 1 strategy over another, so it’s about age, comorbidities, molecular genetic profile, patient preference. You go down this list, and then the patient and you usually end up with the same conclusion about which choice is better. But I don’t have any profile where I absolutely favor venetoclax over acalabrutinib or acalabrutinib over venetoclax. It’s on the table in all circumstances.

 Debbie, what are your must-have factors when you’re starting a patient on treatment? What do you need to know about any patient in terms of the prognostic factors we’ve had available over the years?

This comes up time and again. For me, the original decision point that needs to be made on treating patients comes from their immunoglobulin heavy chain variable [IGHV] status. For example, if a patient has a mutated 

 status, they still have all therapy options open. They might be patients who can benefit from chemoimmunotherapy. For patients with an unmutated 

, it’s been shown time and again that standard chemoimmunotherapy results in much shorter progression-free survival and less durable responses in that population.

If I had to pick only 1, that would be the 1 that I would ask for. The nice thing is it never changes. You can order it once on a patient and never have to reorder it throughout the course of their CLL. It provides important prognostic information too, about the pace of their disease and how quickly they’ll probably progress to needing therapy. The second most important thing is knowing their del(17p) status or 

 mutational status. There aren’t as much data on these patients because there aren’t as many of these patients. In the frontline setting, this is about 10% of the patient population. It becomes more prevalent in the relapsed setting, maybe 25% or higher.

There are limited data, but based on the data available, I would favor using a BTK inhibitor in these patients because the most data is there, the longest progression-free survival for these patients. It’s still a decision point for young patients with del(17p) or 

, whether you want to consider getting them prepared for the possible need of an allogeneic stem cell transplant if they’ve relapsed after multiple therapies. Those are the 2 must-haves for me.

 mutation status, del(17) by FISH [fluorescence in situ hybridization], and mutation status for 

 Any others? Does anybody else have any other must-haves? Jackie, could there was an abstract presented at ASH [American Society of Hematology Annual Meeting] with regard to 17p front line in the longer-term follow-up with the ALLIANCE A041202 trial that Dr Jennifer Woyach provided and outcomes for the 17p patients in the ibrutinib arms vs the non-17p patients and how they were similar. Do you want to comment on that data that were updated?

The data are looking very good. We had originally seen some of this progression-free survival that seemed very encouraging from the smaller group treated at the NIH [National Institutes of Health] in the front line in about 30-plus patients, where the PFS seemed to be similar to patients with less-risk disease. When Dr Woyach gave her updates on these patients with del(17p), they saw the same: these patients have better PFS compared with prior historical cohorts treated with any other treatment regimen. For these patients with 17p by FISH or 

-mutated disease, BTK inhibitors on continuous dosing continues to be my first-line choice.

 You mentioned earlier the availability of a new formulation of acalabrutinib, so we’ll be able to give and not be concerned about coadministration with PPI.

Yes. An abstract was presented at this year’s ASH [American Society of Hematology Annual Meeting], finding that the drug was safe and tolerated, was able to be absorbed without having a concomitant PPI in use. I’m looking forward to that. I don’t know when the FDA will give the approval, but I understand that the company is moving forward with this formulation, and the patients on PPIs won’t have to choose a different drug if acalabrutinib is the drug to be selected.

 I frequently find myself switching, and most of the time it’s not a problem. Occasionally, but uncommonly, stopping their PPI is a problem for some patients. That will be helpful for our patients.

Variables that impact which Bruton tyrosine kinase inhibitor is most appropriate as frontline therapy for patients with newly diagnosed chronic lymphocytic leukemia and the role of patient and disease factors in treatment selection.

Frontline Therapy for CLL: Treatment Selection Based on Patient and Treatment Factors

: Let’s start with the updates that we’ve had available over the last year. Jackie, we can start with you and if you could sort of give us your thoughts and comments around recent updates over the last data about ibrutinib [Imbruvica®]-based therapy.

At ASCO 2021 [American Society of Clinical Oncology annual meeting 2021], we had the 7-year follow-up for the RESONATE-2 study of first-line ibrutinib treatment for patients with chronic lymphocytic leukemia [CLL]. As you may remember, this was a registrational phase 3 trial that led to the approval for the drug for frontline treatment of patients with treatment-naive CLL. And it randomized patients to receive either ibrutinib or chlorambucil as monotherapy. Patients had to be over age 65 and with longer follow-up at 6.5 years, the PFS [progression-free survival] was 61% in patients with ibrutinib, whereas patients treated with chlorambucil was only 9%. It was interesting to see that the response rate was very high and reported as 92% for ibrutinib-treated patients with a number that we have never seen before for complete remission, which ended up being 34% at this follow-up. Meaning the longer that you’re on the drug, the higher rates of complete remissions that you can achieve. The ongoing rates of grade 3, or adverse events of interest, remained low, and these were hypertension and atrial fibrillation with no grade 3 or higher major hemorrhage.

The other study that was important to discuss was the longer follow-up for patients treated in the ALLIANCE trial; the outcomes were given and reported by Dr Jennifer Woyach [Jennifer A. Woyach, MD] at ASH 2021 [American Society of Hematology annual meeting 2021]. She discussed longer follow-up of, as you remember, the ALLIANCE trial that led to the finding of ibrutinib-treated patients doing better when compared against BR, or bendamustine [Treanda®] and rituximab [Rituxan®]. The trial initially was presented in the first interim analysis, and it showed superiority in terms of PFS for patients randomized to any of the ibrutinib-treated arms. And what we see here with the longer follow-up is that the all-grade rate events of atrial fibrillation is 19% and all-grade rate events of hypertension in patients with ibrutinib was 73%.

Now, something that I don’t think anyone was surprised about was the fact that patients that had high-risk disease did have a much better benefit compared to the patients that were randomized to BR [bendamustine, rituximab]. Ibrutinib continues to be the best drug for patients with high-risk disease, including patients with unmutated IgHV [immunoglobulin heavy chain variable] gene or deletion (17p). The median PFS for patients treated with BR was 44 months, and patients treated with ibrutinib or ibrutinib in combination with rituximab, the median PFS has not been reached. The other thing we saw on this abstract is that essentially the addition of rituximab does not correlate with an improved PFS. And, as such at this moment, we still believe that ibrutinib monotherapy might be a good treatment.

: Very active treatment, highly effective drug, a drug that gets a response in most all the patients but they’re not deep remissions. As we know, patients remain on treatment and are on treatment for an extended period. Let’s about adverse effects and toxicities. What are the adverse effects and toxicities that you think about and talk to your patients about prior to starting them on ibrutinib-based therapy, Nicole?

When we talk about the class in general, we obviously think about cardiovascular toxicities, such as atrial fibrillation or atrial flutter. You can also see ventricular arrhythmias, hypertension, bleeding issues, mostly minor bruising and petechiae. Certainly, there could be serious bleeding but that’s relatively rare. Arthralgias and fatigue, those tend to be, sometimes some GI [gastrointestinal] issues as well, but those are the more serious issues that we consider when we talk about initiating BTK [Bruton tyrosine kinase] inhibitors in general. And certainly, when we look at deciding between treatment options for patients depending upon if they have severe cardiac risk factors, are on anticoagulation or antiplatelet agents, those are things we’ll take into consideration when starting, let’s say, ibrutinib. Of course, we have the second-generation. We could talk about the other BTK inhibitors versus alternative therapy as well.

: Are there any patients you would not give a BTK inhibitor to or ibrutinib to as a first-line therapy?

Now that we have multiple options, I mean back in the day when ibrutinib was the first to market, clearly for our multiple relapsed patients regardless of what their comorbidities were, certainly if they’re CLL, if they were going to succumb to their CLL, we were putting them on ibrutinib and managing their comorbidities along with the drug. Now that we have multiple options, of course a consideration is if you’re concerned about if there are poorly controlled hypertension, severe cardiovascular disease, not very well controlled, on anticoagulation, you know if you think that a BTK inhibitor or ibrutinib might be a concern to give them potential toxicities, you might choose an alternative therapy like venetoclax [Venclexta®]. But certainly, you weigh the risk-benefit ratio and certainly if there’s a concern, you might want to choose a second generation, such as acalabrutinib [Calquence®], and we can talk more about that. Certainly, we have more options, and we can have those discussions with our patients accordingly.

Reactions to longer-term follow-up data presented in 2021 on the use of ibrutinib as frontline treatment for patients with chronic lymphocytic leukemia.

Ibrutinib Therapy for CLL: Long-Term Data

 entitled, “Recent Advances in the Treatment of Chronic Lymphocytic Leukemia.”

I’m Dr William Wierda, professor of medicine in the Department of Leukemia and section head for chronic lymphocytic leukemia [CLL] at The University of Texas MD Anderson Cancer Center in Houston, Texas.

I’m joined today by a panel of experts in CLL and I would like to welcome them and invite each of them to introduce themselves. We’ll start with Jackie Barrientos.

Hi, my name is Jacqueline Barrientos, and I am professor of medicine at the Zucker School of Medicine at Hofstra/Northwell [New Hyde Park, New York]. I do work at the CLL Research and Treatment Program in Long Island, New York.

Hi there, I’m Callie Coombs. I’m at the University of North Carolina [Chapel Hill, North Carolina], where I work as an assistant professor of medicine within the Department of Hematology mostly caring for patients with CLL.

Hi, my name is Nicole Lamanna. I’m at Columbia Universality Medical Center [New York, New York] on the Leukemia Service and director of the CLL Program here.

Hi everybody, Anthony Mato from Memorial Sloan Kettering Cancer Center [New York, New York], director of the CLL Program and very happy to be here today.

Hi, I’m Debbie Stephens. I’m at the Huntsman Cancer Institute at the University of Utah [Salt Lake City, Utah], and I direct the CLL Program here.

: Great. Welcome everybody and thank you for joining me today. We’re going to discuss a number of recent updates in the treatment of CLL that were presented at conferences over 2021, particularly focusing on the ASH [American Society of Hematology meeting] 2021 updates. We’ll discuss the data in the context of standards of care and guidelines for treatment and how these updates impact on our management of our patients with CLL.

We’ll start with targeted therapy, which began with [the] Bruton tyrosine kinase [BTK] inhibitor, ibrutinib [Imbruvica®], which has been available for several years now. We’ve learned over the years that CLL cells are dependent on the kinase activity of Bruton tyrosine kinase for survival, and ibrutinib was the first small molecule inhibitor that was developed, first in the laboratory and then clinically in treatment of patients with CLL. This is an irreversible inhibitor, meaning that it binds covalently to BTK at the cysteine 481 moiety and in doing so it blocks the ATP [adenosine-triphosphate]-binding pocket and inactivates BTK irreversibly. And the only way to replace functional BTK would be resynthesis.

The rationale for using Bruton tyrosine kinase inhibitors, such as the first-generation option, ibrutinib, as first-line treatment for chronic lymphocytic leukemia.

Jacqueline Barrientos, MD, MS

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