Andrew Zelenetz, Alexey Danilov, MD,
MD, PhD PhD
When it comes to treating chronic lymphocytic leukemia (CLL) for the first time, treatments fall into one of two categories: those that use a BTK inhibitor (BTKi) or those that use a BCL2 inhibitor. Each treatment has its upsides and drawbacks, and the physician must take those into consideration, as well as the patient’s preferences, when deciding which is the better treatment.
Three covalent BTKis have been approved to treat CLL: zanubrutinib, acalabrutinib, and ibrutinib. Treatment with BTKis continues indefinitely and involves risks, including developing atrial fibrillation (AF).1 When a patient’s CLL has a 17p deletion and a TP53 mutation, some advocate for the use of covalent BTKis.
The other treatment of choice is venetoclax (ven), a BCL2 inhibitor, and it is often combined with anti-CD20 monoclonal antibodies (obinutuzumab [obi] in frontline setting and rituximab in relapse).1 This is a time-limited treatment, which typically lasts for one year in frontline and two years in relapsed setting, and is thus attractive to some patients.2 Venetoclax also offers the chance of deep remission and undetectable residual disease.1
In this installment of “Drawing First Blood,” Andrew Zelenetz, MD, PhD, lymphoma specialist and medical director of quality informatics at Memorial Sloan Kettering Cancer Center in New York, and Alexey Danilov, MD, PhD, associate director of the Toni Stephenson Lymphoma Center at City of Hope in Duarte, California, discuss when each treatment should be used for a patient newly diagnosed with CLL, the nuances of using a BTKi, and whether continuous BTKi or time-limited ven-based therapy is preferred. Dr. Zelenetz was asked to argue for treatment with venetoclax and obinutuzumab, and Dr. Danilov was asked to argue for treatment with BTKis.
In which situations is it clear that one treatment should be used over the other?
Dr. Zelenetz: We know that all the agents, including the second-generation BTKis acalabrutinib and zanubrutinib, have a slightly higher risk of AF in patients who have a history of AF. For those patients, you might think about starting with ven-obi. One of the major reasons that people don’t start with ven-obi is resources. The venetoclax dose ramp-up still is quite onerous. There’s mandatory laboratory testing for tumor lysis syndrome before dosing, after dosing, and then the next day. The doctor then must obtain the laboratory results in real-time and act on the results, if necessary.
Dr. Danilov: I agree that it’s very difficult to define or describe a patient who is a clear candidate for one treatment versus another. I’d say the majority of patients in my clinic are good candidates for both types of therapy.
BTKis are easy to initiate, don’t require laboratory monitoring, and don’t require frequent follow-up. Because most patients diagnosed with CLL are older, this becomes a very practical treatment option. Furthermore, while BTKis are associated with risks of cardiac adverse events (AEs), such as AF and hypertension, the incidence of the former is in single percentages with selective drugs (acalabrutinib and zanubrutinib), and it is easy to monitor for the latter. Most of my patients tolerate BTKi therapy very well, without significant AEs, and we rarely need to reduce the dose or switch the agent. I agree that the presence of significant cardiac comorbidities may sway me from using BTKis. On the other hand, with ven-obi, feasibility may be an issue. Like Dr. Zelenetz mentioned, if somebody lives far and it’s cumbersome for them to come for laboratory checks, if I am to follow the package insert, then it becomes nearly impossible to offer that treatment. Furthermore, infusion reactions to obinutuzumab can be very unpleasant and may require hospital admissions, which complicate initial therapy.
Kidney dysfunction may confer a particularly high risk of tumor lysis syndrome, thus making this therapy riskier.
When using a BTKi, which is the preferred agent?
Dr. Danilov: In general, I prefer the second-generation or “selective” BTKis, acalabrutinib and zanubrutinib. I haven’t used ibrutinib in my practice for patients with CLL for some time because of the studies that have demonstrated improved safety of these drugs over ibrutinib. The notable findings the from the ALPINE trial, which randomized patients with relapsed or refractory (R/R) CLL to receive either ibrutinib or zanubrutinib, demonstrated improvement in progression-free survival (PFS) and tolerability.3 ELEVATE RR randomized patients with R/R high-risk CLL to acalabrutinib or ibrutinib and also demonstrated improved safety, particularly in terms of cardiovascular toxicities.4 However, I don’t have a strong preference between the two selective BTKis, acalabrutinib and zanubrutinib. I do believe they’re similar agents in terms of safety and efficacy, with some minor distinction in AE profiles. Occasional side effects include headaches, bruising, fatigue, and, of course, the rare cardiovascular toxicities we mentioned earlier.
Dr. Zelenetz: I actually use zanubrutinib a lot when I’m picking a BTKi. I find it extremely well-tolerated; however, I agree with Dr. Danilov that both drugs are very well-tolerated. Tolerance for acalabrutinib improved following the change in the formulation of acalabrutinib in 2022 (in the U.S.). This eliminated interaction with antacids and reduced the headache. Therefore, before the change in formulation, I became more comfortable using zanubrutinib. Today, I think both agents are appropriate for initial therapy.
When using a BTKi, should you add an anti-CD20 monoclonal antibody?
Dr. Danilov: In my practice, I typically don’t add a CD20 antibody to a BTKi. The ELEVATE-TN study demonstrated improved PFS with this combination over acalabrutinib alone.5 However, it also removes the conveniences and adds side effects.
Dr. Zelenetz: As an aside, I like to mention a potentially valuable therapy for pre-exposure prophylaxis (PrEP) for COVID-19, the monoclonal antibody pemivibart. During the COVID-19 pandemic, we tried multiple monoclonal antibodies for COVID-19 PrEP, but the target site would rapidly mutate. Pemivibart antibody is directed against an invariant part of the spike protein. It’s directed against the spike protein receptor binding domain, which is necessary for infection of human cells. If this were to mutate, the virus would not bind to human cells. So that’s a pretty good target. We use this now routinely in our patients with CLL. It’s not a perfect treatment because there is a 0.6% risk of anaphylaxis, requiring patients to be monitored after administration of the antibody for two hours, and it needs to be given every three months.
Is continuous BTKi or time-limited ven-based therapy preferred?
Dr. Zelenetz: Most patients, when asked if they would prefer a time-limited therapy or continuous therapy, generally opt for a time-limited treatment. However, the discussion isn’t that simple. Patients need to understand what is entailed with both options. Patients generally prefer intermitted treatment with gaps off therapy. They understand that with fixed-duration therapy, retreatment in the future is very likely. However, as was mentioned earlier, the logistics of venetoclax ramp-up can be a challenge for many providers.
Dr. Danilov: I haven’t seen the comparisons of financial costs of time-limited therapy versus continuous therapy. Dr. Zelenetz, maybe you’ve seen that?
Dr. Zelenetz: We tried to model it in our triple therapy versus monotherapy. It’s still a work in progress, but there’s a breaking point that happens. Being off a drug and needing to be retreated is more cost effective than being on a continuous drug. However, the cost effectiveness is tied to having a certain minimum median duration of benefit.
Dr. Danilov: Many patients do appreciate the idea of time-limited therapy. With continuous BTKis, the risks of cardiovascular toxicities don’t go away. AF and hypertension can develop at any time during treatment; so even though the frequency might be low, they hang as a threat, particularly for patients with cardiac history. For me, this often justifies the use of time-limited treatment. There is also an issue of bruising with BTKis. Some younger patients choose BTKis as their first-line therapy, and it turns out they play soccer and really don’t like the bruising. Every patient is very different, and quality of life is important. There are many individualized characteristics that go into these decisions.
Which are the optimal therapies for patients with CLL exhibiting TP53 aberrancy?
Dr. Zelenetz: Among the CLL expert community, there’s a tendency to say, “Use a BTKi as first line if there’s TP53 aberrancy,” but I’m not sure we have the definitive answer for that question because we’re lacking the clear retreatment data. There is no question that in the German CLL Study Group CLL14 trial of ven-obi versus obi-chlorambucil, we saw that the patients on both arms with TP53 aberrancy progressed sooner than the patients who had wild-type TP53. We really need longer-term follow-up of retreatment data to know that a BTKi is clearly the preferred approach. What do I do? I typically put those patients in a clinical trial where I use ven-obi and a BTKi with the goal of time-limited therapy.
Dr. Danilov: I agree that we are missing data. And I agree, in principle, with Dr. Zelenetz that either treatment is fully acceptable. Having said that, there are more emerging data that look really, really good, like zanubrutinib in the SEQUOIA study, which shows a three-year follow-up with more than 90% of patients still in remission.6 Those data are hard to ignore, and I wonder if BTKi-BCL2 doublets will find more use in this patient population in the future.
What weight do genetic factors carry with each treatment?
Dr. Zelenetz: There are some rare mutations that will affect treatment. The one thing that’s compelling is BTK resistance mutations. If they arise during treatment, pirtobrutinib is approved in the third line. Philosophically, though, if you started with a BTKi and then you end up with a cysteine 481 serine mutation, do you want to just go to pirtobrutinib as the second line instead of going to venetoclax with an anti-CD20 antibody in the second line, and then use protobutinib as third line?
Dr. Danilov: I agree, in general, there are no genetic factors that are compelling enough to say, “Only this or that treatment should be used for this particular genetic variant.” Having said that, if you look at the CLL14 data, CLL with TP53 mutations and unmutated IGHV seems to benefit somewhat less, with inferior PFS, compared with CLL with wild-type TP53 or mutated IGHV. With BTKis, we don’t see that for IGHV status — both groups of patients perform equally well — so I do check IGHV mutational status to clarify it’s the prognostic significance with venetoclax. It is a good point to bring up with patients to sometimes say, “You do have this risk feature, which might mean that this treatment will potentially be a little bit less effective.”
What are the sequencing options for each treatment? How are these considered alongside patient factors?
Dr. Danilov: If somebody is progressing on a BTKi, then you have very good data from the BRUIN study with pirtobrutinib, where PFS is roughly two years for patients who progressed on covalent BTKi.7 That same study demonstrated that patients who progressed on both venetocax and BTK inhibition have somewhat inferior PFS compared with those who haven’t seen venetoclax and transition to pirtobrutinib. That would be a point of argument to consider before going to venetoclax in a second line.
Dr. Zelenetz: The U.S. Food and Drug Administration label indication for pirtobrutinib is after two prior lines of therapy including a BTK and a BCL2 inhibitor. However, you can use it off label as you described. So, if a patient gets a BTKi in second line, then you can go to pirtobrutinib in third line without having to use a venetoclax treatment first.
What are the options with these two treatments if a patient’s CLL relapses?
Dr. Zelenetz: Dr. Danilov pointed out correctly that we have much better data about the effectiveness of ven-based treatments after BTKi-based treatments, and that’s because those treatments came after. So, in the R/R setting, we know that venetoclax is an effective treatment for patients who are either intolerant or progressing on BTKis. The data are less clear when the sequence is reversed. There are some who say, yes, you can use a BTKi after venetoclax, and it works, but the big question we’re all struggling with is, what happens when your patient is no longer responding to either a BTKi or a BH3 mimetic?
Dr. Danilov: Pirtobrutinib is something that’s approved in that setting. Now we have approval of lisocabtagene maraleucel (liso-cel), which is a chimeric antigen receptor (CAR) T-cell therapy in double refractory patients. Lisocabtagene is a very involved therapy with significant side effects. If choosing to go to pirtobrutinib or lisocabtagene, I would always go to pirtobrutinib first, because CAR T-cell therapy is associated with a somewhat underwhelming complete response rate (approximately 20%), PFS of about 12 months, and severe toxicities, both infectious and non-infectious (with the risk of cytokine release syndrome being greater than immune effector cell-associated neurotoxicity syndrome). Granted, the TRASCEND-004 study, which led to approval of liso-cel, enrolled patients who had received several lines of chemotherapy before going to CAR-T.8 They were all severely immunocompromised patients with disease that was very difficult to treat. It is indeed possible that we might see better results in the real world with CAR T cells, but we will have to see what the real-world studies show. I’m also excited about emerging tools, including BTK degraders and bispecific antibodies, where the early data look very impressive in CLL that is refractory to BTKi and venetoclax.
References
- Deng C. Dr Deng on BTK inhibitors vs venetoclax-based treatment regimens in CLL/SLL. OncLive. May 9, 2024. Accessed September 23, 2024. https://www.onclive.com/view/dr-deng-on-btk-inhibitors-vs-venetoclax-based-treatment-regimens-in-cll-sll.
- Ghosh N. Choosing BTK inhibitors versus venetoclax as first-line CLL therapy. Targeted Oncology. April 1, 2022. Accessed September 23, 2024. https://www.targetedonc.com/view/choosing-btk-inhibitors-versus-venetoclax-as-first-line-cll-therapy.
- ClinicalTrials.gov. NCT03734016. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia (ALPINE). April 1, 2024. Accessed September 23, 2024. https://clinicaltrials.gov/study/NCT03734016.
- ClinicalTrials.gov. NCT02477696. Study of acalabrutinib (ACP-196) versus ibrutinib in previously treated participants with high risk chronic lymphocytic leukemia (CLL). August 12, 2024. Accessed September 23, 2024. https://clinicaltrials.gov/study/NCT02477696.
- Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(Suppl 1):31.
- Tam C, Giannopoulos K, Jurczak W, et al. SEQUOIA: Results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab (BR) in patients with treatment-naïve (TN) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Blood. 2021;138(Suppl 1):396.
- Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44.
- Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study. Lancet. 2023;402(10402):641-654.
Disclaimer: The statements made by the participants do not necessarily reflect the opinions or stance of the American Society of Hematology.
Agree? Disagree? We want to hear from you! Send your thoughts and opinions on this controversial issue to [email protected].
