Roundtable Discussion: Pagel Walks Through Treatment Choices in Chronic Lymphocytic Leukemia

John M. Pagel, MD, PhD (Moderator)

Chief of Hematologic Malignancies

Center for Blood Disorders and Stem Cell Transplantation

Swedish Cancer Institute

Seattle, WA

SHIN: Could [this patient’s] presentation worry you in terms of transformation?

PAGEL: Absolutely. I would get a PET scan in this patient at the start. I don’t know if this patient transformed or not; however, if we’re seeing really high SUVs [standardized uptake values] or so, I’m going to biopsy that spot. You were more astute there than maybe I was. I wasn’t thinking about it, but I did suggest we should get scans, and a PET scan would absolutely be appropriate.

I will also say, I probably wouldn’t have done a bone marrow biopsy in this patient. I wouldn’t have seen a great need for it. We knew the marrow would have a lot of disease, and usually on the PET scans now they’re so good at telling us if we’ve got marrow involvement in this disease as well. So I think a PET scan would be appropriate here.

PAGEL: I’m going to ask…people’s thoughts about this poll and [their reasoning behind them]. Dr Chang…I’d love to hear your thoughts about what you would do [with] this patient, what you would choose, and why you would choose it.

CHANG: The reason I chose [acalabrutinib (Calquence) plus anti-CD20 monoclonal antibody] is that I thought that the patient has some risk factors, like chromosome 11 deletion, and I thought that [this option is] maybe slightly better than [the ibrutinib (Imbruvica) combination] in the sense that toxicity-wise, maybe its profile is better. I don’t know the data in terms of [the venetoclax (Venclexta) combination] and the risk factor group. Do we have enough data to show that is equally good in terms of that poor cytogenetics?

PAGEL: [It’s] important to recognize that the risk factors are [crucial] for figuring out what you’re going to treat patients with, so we’ll talk a little about that in a moment. But let me ask you, Dr Chang, you mentioned you thought acalabrutinib with the anti-CD20 antibody might be better tolerated, and I assume you’re comparing that to ibrutinib?

CHANG: Correct.

PAGEL: Has that been your clinical experience or are you basing that comment on data that you’re aware of?

CHANG: I think it’s based on data. I don’t have a lot of experience with acalabrutinib, but I [have used] ibrutinib a lot and I’m gradually switching.

PAGEL: A lot of us, of course, do use regimens that we’re familiar with [and that] have some safety, in our experience, but I will also agree with you that we have head-to-head data…comparing acalabrutinib to ibrutinib directly in a randomized setting. The adverse event [AE] profile is significantly more favorable for acalabrutinib than ibrutinib, with essentially the same efficacy.¹ I might ask someone who picked…acalabrutinib or ibrutinib as a monotherapy to give us an idea why you were thinking that might be what you would choose without the antibody therapy. Anybody willing to comment on that?

SHIN: I have always used BTK [Bruton tyrosine kinase] inhibitor monotherapy. I have never done the combination. I used to use ibrutinib as my go-to but acalabrutinib is just as effective and a little bit better tolerated, so I would just select acalabrutinib for this patient.

PAGEL: There’s more neutropenia when you add the antibody and there’s potential risk for more febrile neutropenia infections. Of course, you’ve got a couple of other factors that go along with the antibody. One is more significant B-cell depletion, and this is something to keep in mind in the COVID-19 era….I’ll also remind you that you can have infusion reactions when you get an infusion, whereas if you’re using a monotherapy oral agent, you don’t have to use [the antibody]. But it’s a plus or minus, give or take, whatever you think is right for that patient. I would guess that many of you who did choose adding the antibody like it because it would be potentially valuable in somebody with this kind of bulky disease; the big spleen, getting a quick nice response, all of that, and I think that’s reasonable.

SHIN: If you use an anti-CD20 antibody with a BTK inhibitor, would you continue to use it with venetoclax in the second-line setting?

PAGEL: That’s exactly what we’ve done. In the relapsed setting, if you’ve got acalabrutinib and an anti-CD20 antibody, like obinutuzumab [Gazyva], in the front line, what would you do in relapse? I’d go to venetoclax, and based on the MURANO [NCT02005471] data, it’s a combination with rituximab [Rituxan].² I have [to] tell you that I do that, but for me, it depends on the patient. There are many patients [who are] perfectly fine and [for whom it] may be appropriate to be getting venetoclax for prolonged periods of time, and then I wouldn’t add the antibody.

So I think it’s not one size fits all, but just because you’ve got an antibody early on doesn’t mean you couldn’t get it in relapse. Now, I want to say, I’ve come a little full circle on that in the COVID-19 era, in that I’ve learned— as we all have—that B-cell depletion from the anti-CD20 antibodies is significant. I do want to ask, for anybody who chose venetoclax and obinutuzumab, what are your thoughts on why you like that regimen for this patient?

CHARU: I chose that regimen because [the patient is 61 years, which is relatively young], so it’s a fixed duration of treatment. Moreover, because he has atrial fibrillation with the cardiac issues with ibrutinib and acalabrutinib, I thought that this may be a better option.

PAGEL: You have to remember that BTK inhibitors are associated with atrial fibrillation [and] hypertension, and those are dramatically lower with acalabrutinib than they are with ibrutinib. It’s valuable to keep that in mind, and I think that would be a reasonable choice too. We’ve had a good, well-balanced smattering of BTK inhibitors, like venetoclax, plus or minus anti-CD20 antibody therapy.

PAGEL: Our choice is largely between 2 different categories that are 2 different classes of therapy.³ There are the BTK inhibitors, and that’s either acalabrutinib or ibrutinib, or the BCL2 inhibitors…venetoclax and obinutuzumab.

We do know that ibrutinib is only appropriate in the front line by itself but there are no data showing any advantage to giving an anti-CD20 antibody with ibrutinib. Now, that’s because rituximab didn’t add anything to single-agent ibrutinib, [with which] you can use obinutuzumab with acalabrutinib if you want. It’s approved either with or without the anti-CD20 antibody.

The big difference, of course, with venetoclax and obinutuzumab is that it’s what we call finite therapy, which is 1 year of venetoclax with 6 months of the obinutuzumab, whereas the BTK inhibitors are delivered indefinitely until either progression or some intolerance.

Most patients with CLL in 2021 are going to see both classes of those drugs. Typically, most people in this country are using a BTK inhibitor in the front line, and venetoclax [has a strong response] in the relapsed/ refractory setting, but they can be reversed. We have less data doing it that way, but it can happen. What you can also notice is that in that front line, under preferred regimens, we don’t use chemoimmunotherapy anymore. We don’t [use it in particular, except for one small group of patients that are not well outlined here]. Those are the patients with the best risk factor, whereas those who have IGHV-mutated disease don’t have any high-risk features. They could still be eligible to get fludarabine, cyclophosphamide, and rituximab [FCR], with which there’s long-term functional cures in about 50% to 60% of those patients, but…if the patient is unmutated you would do much better with a BTK inhibitor or with venetoclax. So if [the patient is unmutated], there’s really no role for chemoimmunotherapy anymore. Consequently, we wouldn’t be using bendamustine plus rituximab anymore for most of these patients.

Right now, in 2021, what’s the standard-of-care front-line therapy for CLL? Would we say it’s a BTK inhibitor for all patients? I’m going to tell you right now, the answer is no, it’s not for all patients. You could easily understand that venetoclax and an anti-CD20 antibody could be reasonable in many patients in the front line. But what about high-risk patients? What about high-risk patients with 17p deletions or a TP53 mutation? Those patients absolutely should get a BTK inhibitor over venetoclax. The progression-free survival [PFS] in high-risk patients with 17p [deletions or] TP53 mutations is inferior with venetoclax compared [with] a BTK inhibitor such as acalabrutinib or ibrutinib.⁴

LIU: Do you combine a BTK inhibitor with venetoclax?

PAGEL: We have emerging data, [from] a trial that I was actively involved with called the CAPTIVATE trial [NCT02910583], which you’ll see in publication here soon; [they] come on the heels of some single-institution University of Texas MD Anderson Cancer Center data where they used ibrutinib and venetoclax together.⁵

I’ve also been actively involved in acalabrutinib plus venetoclax combinations as well. What we know from those regimens is that they are active, meaning they can give deep remissions. They can give…outstanding elimination of minimal residual disease [MRD], so patients can become undetectable for MRD, and that allows us to give those regimens as finite therapy.

I typically only do that in patients who have high-risk disease, [in those whom] I’m worried about emergence of an aggressive clone. Those are not uncommon to think about in people that have 17p deletions or TP53 aberrations, where you’re trying to keep the lid on the pot.

I will remind you all that we don’t have any data to say that combinations of therapy would be better than sequential use of these drugs. It is possible that if you give, let’s say, acalabrutinib [and] get some degree of PFS, and then you come back with venetoclax when the patient relapses and…get some degree of PFS, that that length of PFS, [when] they’re additive or sequential, could be much longer than if they were delivered concurrently, [when] you have just 1 PFS level.

I’m not ready to adopt that, and I have to remember [that] if a patient relapses after they’ve seen both classes of those drugs, I don’t have anything great in my back pocket to go to. I don’t feel great about that often. Plus, if they’re having AEs or problems, how do I know which drug [those are] due to? Do I hold 1 drug [or] both drugs? Which drug do I hold? Also…when the patient goes off therapy and relapses, which drug do I restart? Do I restart both?

I just don’t know. I have a lot of questions, and I would say…when you also factor in the cost of the therapies, it may be better for us in the long run to continue to do sequential therapies.

LORBER: Yes, about the issue about the 17p BTK inhibitor over venetoclax. Is that superiority just with the PFS, just because the BTK inhibitors continued for longer than venetoclax would? If we continued the venetoclax beyond 1 year to progression, do you think it would be equivalent?

PAGEL: I should have [explained] this…better. Remember, the frontline regimen of venetoclax and obinutuzumab is 1 year of therapy and then you stop. When we stop therapy with venetoclax in a [patient with] 17p deletion, they relapse quickly.

Now, if you were to start with venetoclax in the front line for that patient, then don’t stop the venetoclax. The data that we have, though, are in that finite therapy; we see the PFS curves fall off quickly once you stop treatment. That doesn’t happen, and you’re right that you’re staying on the BTK inhibitor. You’re keeping things under control and that’s important for those patients, whether they get a BTK inhibitor or a BCL2 inhibitor.

PAGEL: For me, it’s simple. Once you start using acalabrutinib, if you haven’t already, you will find that the patients have way fewer problems. They’re not in your office complaining of muscle aches, joint pains, rashes, brittle nails, losing their hair, ocular problems…it goes on and on with ibrutinib. You just don’t see those problems with acalabrutinib. I know that from my clinical experience, [as I have] a lot of…experience using all of these drugs. I choose acalabrutinib over ibrutinib every time because it’s a better tolerated therapy. I cannot see [having] a patient where I [would] still use ibrutinib. I wouldn’t fault anybody for using ibrutinib, but I’m just sharing my opinion and how I approach my patients.

The question if it’s better to add an anti-CD20 antibody we’ve already talked about…with the BTK inhibitor. I think in some patients it might be; in my practice, I typically don’t do it. The thing I’m trying to remember is that the beauty of these therapies in people who are a bit older— we’re not curing them—is that it’s an oral therapy; they don’t have to get IVs and they don’t have to be coming into the clinic, hopefully, as much.

And [as to whether] there’s still a role for chemoimmunotherapy—frankly, outside that small subset of younger, fit patients with mutated IGHV gene, who can get FCR, no. There’s no role for chemoimmunotherapy any more in people who have unmutated disease. And frankly, that means that we’re probably not giving bendamustine/rituximab anymore.

Now, I want to be clear: would people not benefit from chemoimmunotherapy? Sure they would. And I will say that we’re aggressive in the United States with these regimens. You go around the world and they still use chemoimmunotherapy and patients can do well. I wouldn’t fault anybody for using it. And when I say that there’s no role, I’m basing that on the data.

ZIARI: I have used both acalabrutinib and obinutuzumab in single treatment, not in combination in the past at all. [I have a little experience with acalabrutinib in CLL but I] have used it for [patients with] mantle cell [lymphoma] a lot in the past.

I currently have 2 patients on it for mantle cell, but in CLL…I have no patient on it. [Now, for] obinutuzumab as a single agent [there are quite a few patients]. But the data seem to be impressive, and when they’re combined, it makes sense.

CHARU: We must do dose reductions sometimes so [the patient still tolerates the treatment]. Do you escalate the dose again or do you just continue, in your practice, with the same low dose and still get the same results?

PAGEL: You’re going to have to make dose adjustments, or even discontinuations, much less frequently with acalabrutinib than you will with ibrutinib. The data are clear; …you have to discontinue ibrutinib due to an AE in at least 25% of patients. In that ELEVATE-TN trial, and many others we’ve seen, discontinuation rates with acalabrutinib due to an AE are only about 10%, which is dramatically less.⁵

In fact, [it’s] the same thing for dose reductions. Dose reductions with acalabrutinib are typically in the order of about 7% to 8%, and when you dose reduce acalabrutinib, by the way, you go from [twice-a-day] dosing to just once a day.

Dose reductions with ibrutinib are extremely common due to AEs and they happen in the vast majority of patients. In my experience, the dose reductions with ibrutinib don’t get us nearly as close to where we’d like to be to eliminate the problem that most people are having, as opposed to just switching them to acalabrutinib.

So instead of dose reduction on ibrutinib, I switch them to acalabrutinib. We have data that clearly show that at least three-fourths of patients who are intolerant to ibrutinib, if you switch them to acalabrutinib…will not have the same AEs come back. If they’re having muscle aches, joint pains, a rash, or whatever it is, and they’re bothered by it on ibrutinib, I switch them to acalabrutinib.

Then they’ll almost always do extremely well. Whereas if I dose reduce the ibrutinib, I don’t get the same benefit, at least in my clinical experience. It is also appropriate to try dose reduction in the right patients if you want. We know that over time, as the disease burden gets smaller and smaller, you don’t need as much of the drug. Simple, right? As you have less disease, you have less of those BTK binding sites, so you don’t need as much drug.

Now, if you’re seeing problems with an AE early, and you try to dose reduce, then you’re going to specifically lose efficacy. That’s another reason why I don’t like using ibrutinib, because I don’t want to have to try to dose reduce. I just switch [patients] to acalabrutinib, and frankly, I start them on acalabrutinib from the [outset].

_REFERENCES

1. _{Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210}
2. _{Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948}
3. _{NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia, version 4.2021. Accessed December 17, 2021. https://bit. ly/3JfKz1p}
4. _{Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2}
5. _{Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865. doi:10.1200/JCO.21.00807}