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Experts Address HCP Questions on Contemporary Treatment for CLL

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Deborah Stephens, DO

Associate Professor
Department of Hematology
Huntsman Cancer Center Institute
University of Utah
Salt Lake City, Utah

Deborah Stephens, DO: consultant/advisor/speaker: AbbVie/Genentech, AstraZeneca, BeiGene, Celgene/Bristol-Myers Squibb, Epizyme, Lilly, TG Therapeutics; researcher: Merck, Novartis.

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Jennifer Woyach, MD

Division of Hematology
Department of Internal Medicine
The Ohio State University
Columbus, Ohio

Jennifer Woyach, MD: consultant/advisor/speaker: AbbVie, AstraZeneca, BeiGene, Genentech, Janssen, Loxo, NewWave, Pharmacyclics; researcher: Schrödinger.

View ClinicalThoughts from this Author

Released: January 30, 2023

Key Takeaways

  • Arial fibrillation is a concern that physicians must manage when using BTK inhibitors to treat patients with chronic lymphocytic leukemia but does not preclude use of a BTK inhibitor.
  • Risk of tumor lysis syndrome should be considered with venetoclax-based therapies, but high risk should not preclude use of these regimens.
  • Noncovalent BTK inhibitors can overcome resistance to covalent BTK inhibitors.

In this commentary adapted from a discussion between Deborah Stephens, DO, and Jennifer Woyach, MD, at a live event at ASH 2022, the experts address important questions surrounding optimal use of contemporary therapies for chronic lymphocytic leukemia (CLL) and discuss key data on emerging treatment strategies.

What are your thoughts on the most recent National Comprehensive Cancer Network (NCCN) guideline updates for CLL?

Jennifer Woyach, MD:
In the current NCCN guidelines for CLL (v.1.2023), ibrutinib has been changed from a preferred regimen to an “other regimen” for patients with CLL requiring treatment in both the first-line and relapsed settings. Current preferred regimens include acalabrutinib (with or without obinutuzumab), venetoclax plus obinutuzumab, and zanubrutinib.

Deborah Stephens, DO:
I think these updates reflect clinical trial data that have been presented over the past few years, in particular those from the ELEVATE-RR and ALPINE trials. The good news is that all of the approved covalent BTK inhibitors are very effective, so we really can tailor our therapy to patients based on their comorbidity profiles and which adverse events we want to most avoid. 

Is there still a role for chemoimmunotherapy in the treatment of CLL?

Deborah Stephens, DO:
The role of chemoimmunotherapy for CLL is significantly diminished today. I cannot think of a patient to whom I would recommend chemoimmunotherapy. In older patients, I never recommend this approach unless they cannot access BTK inhibitors or venetoclax due to financial barriers. The one space in which I might consider chemoimmunotherapy is for young patients with low-risk disease featuring mutated IGHV and del(13q). But even for these patients, clinical trial data have shown progression-free survival (PFS) benefits for both BTK inhibitor‒based and venetoclax-based regimens vs fludarabine, cyclophosphamide, and rituximab (FCR). Dr Woyach, do you still recommend chemoimmunotherapy in your practice?

Jennifer Woyach, MD:
I have not given chemoimmunotherapy for CLL for a long time, particularly given results from the phase III ALLIANCE and ECOG trials in 2018, which showed the benefit of frontline ibrutinib over bendamustine plus rituximab and ibrutinib plus rituximab over fludarabine, cyclophosphamide, rituximab (FCR), respectively. There is an academic discussion of whether there is still a role for FCR in young patients with CLL with an IGHV mutation who potentially could be cured. But in practice, those patients do very well with venetoclax plus obinutuzumab or a BTK inhibitor. For the most part, I think chemoimmunotherapy should no longer be used to treat CLL.

For patients with CLL at high risk for tumor lysis syndrome (TLS) with venetoclax, do you consider treatment with venetoclax-based regimens?

Deborah Stephens, DO:
I do. Although TLS is a concern with venetoclax, this risk does not change my treatment recommendations if I am considering venetoclax. Often in the relapsed setting, I will use 3 weeks of obinutuzumab as a lead-in therapy. After that, patients usually are at low risk for TLS and do not have to be admitted.

Jennifer Woyach, MD:
I agree. I think physicians have started to not include a TLS risk assessment prior to starting obinutuzumab, as it is now understood that it lowers white blood cell count for nearly everyone. This means that most patients will no longer be at high risk for TLS with venetoclax after the obinutuzumab lead-in. Instead, I perform CT scans after 2-3 weeks of obinutuzumab and base my TLS assessment on those.

How can community hematologists best manage the risk of TLS with limited hospital resources and fewer opportunities for referral?

Jennifer Woyach, MD:
I think this is the issue that leads to less venetoclax use in community cancer clinics because the logistics can be difficult. One point, as mentioned previously, is that obinutuzumab can be used to effectively debulk many patients, so the number of patients at high risk for TLS is decreased considerably after a few doses of obinutuzumab. One thing we do at our institution for select patients for whom logistics are an issue is admit to the hospital for a rapid escalation of venetoclax with close TLS monitoring.  If you have an academic center nearby, most CLL specialists would be very happy to ramp up the venetoclax and then return the patient, so this is something that can be considered. 

Is there a risk of sudden ventricular arrythmias with BTK inhibitors?

Jennifer Woyach, MD:
With both acalabrutinib and ibrutinib, there is a small but real risk of ventricular arrythmias and associated sudden death. Atrial fibrillation is a risk factor that has been identified to predict sudden death with ibrutinib. The development of hypertension appears to increase the risk of atrial fibrillation, suggesting it may be an initiating event.

The risk of ventricular arrythmias appears to be lower with acalabrutinib vs ibrutinib in retrospective analyses but remains a concern. Less is known about the risk with zanubrutinib. Zanubrutinib has been associated with a very low risk of atrial fibrillation, and sudden deaths have not been reported to my knowledge. However, there is a fairly high risk of hypertension, similar to ibrutinib, and it remains possible that zanubrutinib does carry some risk of arrhythmogenic cardiac toxicities.

Can BTK inhibitors be used in patients with preexisting atrial fibrillation?

Deborah Stevens, MD:
Personally, I am not afraid to use BTK inhibitors in patients with CLL and atrial fibrillation. I prefer to have a good working relationship with a patient’s cardiologist and/or primary care physician to help manage the risk. Physicians should take care regarding drug–drug interactions, such as with calcium channel blockers. Blood thinners also should be used with caution in this largely older patient population, who often meet the CHADS2 score for atrial fibrillation stroke risk, indicating need for an anticoagulant. Patients with atrial fibrillation should not receive warfarin; early studies showed that using warfarin with ibrutinib can lead to severe, life-threatening bleeding. With the newer anticoagulants, patients simply need to be monitored for bleeding and bruising.

I have recently started referring some patients with CLL for the “Watchman” device, which cardiologists use to seal off the left atrial appendage for 45 days, then look for a thrombus in the atria. If no thrombus is present, the patient is taken off anticoagulation and put on a blood thinner.

For some patients, however, control of atrial fibrillation will not be possible. In this situation, a patient may need to switch from BTK inhibitors to a new drug class (eg, BCL-2 inhibitors) or may be able to stop therapy if they already have achieved a remission for 2-3 years.

How often do you have patients receiving BTK inhibitors monitor their blood pressure?

Jennifer Woyach, MD:
Given the risk of hypertension, patients receiving BTK inhibitors will need to have their blood pressure checked regularly. If a patient’s blood pressure is elevated in the office, I send them home with a blood pressure cuff for a few weeks of daily monitoring before I consider treatment. If I see a patient only every 3-6 months, I ask them to get their blood pressure checked between visits, as well.

For relapsed/refractory CLL, could obinutuzumab be used with venetoclax vs rituximab plus venetoclax (ie, the MURANO regimen)?

Jennifer Woyach, MD:
Increasingly, it has become clear that obinutuzumab is a more effective CD20 antibody in CLL than rituximab. However, rituximab plus venetoclax is approved in this setting (although venetoclax plus obinutuzumab is approved in the newly diagnosed setting). Both are effective regimens.

Deborah Stephens, DO:
I try to use obinutuzumab when I can for my relapsed patients. One question is, if a patient with CLL received frontline venetoclax plus obinutuzumab, completed therapy, and then relapsed, is it reasonable to treat them with the same combination again?

Jennifer Woyach, MD:
Unfortunately, there are no data to help answer this question, but limited data suggest that venetoclax retreatment can provoke another remission. That said, I would consider retreatment with venetoclax plus obinutuzumab if a patient relapsed after a long remission.

Should venetoclax ever be used in CLL therapy for longer than 1-2 years?

Jennifer Woyach, MD:
This is a great question, and few data exist to answer it. Based on data from CLL14 and MURANO, venetoclax is recommended (in combination with obinutuzumab or rituximab) to be administered for 1 or 2 years. A small study from Australia examined patients with CLL who had been receiving venetoclax for a median of 29 months. At approximately 6 years of follow-up, these patients showed higher rates of clonal hematopoiesis and even myelodysplastic syndromes. This suggests to me that indefinite venetoclax is not desirable in CLL. In my practice, I try to treat to undetectable measurable residual disease (MRD) status, especially in the post‒BTK inhibitor setting. In general for these patients, I will treat for 2 years, then continue on in 6-month increments, assessing MRD status. I then stop once undetectable MRD status is achieved. For patients who have not had a prior BTK inhibitor, I treat for 1 or 2 years depending on whether they are treatment-naive or relapsed/refractory, and then consider discontinuation regardless of MRD status.

Deborah Stephens, DO:
There are many facets to this question, and the right answers are not yet clear. Sequential monitoring is needed to understand the kinetics of MRD. For example, some patients may be MRD positive but on a steady decline and likely to decline further toward undetectable MRD. These patients likely would benefit from continuing venetoclax. Conversely, increasing MRD over time shows developing resistance to venetoclax.

The randomized phase III MAJIC study is comparing acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab in previously untreated CLL/small lymphocytic lymphoma and will use MRD to guide therapy duration (maximum 2 years); patients who become MRD negative can stop treatment. The PFS results from this study may help answer the question of optimal venetoclax duration.

If a patient receiving continuous BTK inhibitor monotherapy achieves undetectable MRD, do they need to continue the BTK inhibitor?

Jennifer Woyach, MD:
The answer to this is not yet clear. Achieving undetectable MRD with a BTK inhibitor has not been shown to be a meaningful endpoint yet. However, if I had a patient with undetectable MRD who wanted to stop therapy, I would give them that option, although this is not the standard of care approach. This is still a very highly debatable question—whether MRD with a BTK inhibitor‒based regimen means anything. 

Which patients with CLL are best suited for venetoclax plus a BTK inhibitor?

Jennifer Woyach, MD:
Right now, it is hard to say that there are any patients who would do better with venetoclax plus a BTK inhibitor than either of the standard options. It may be that higher-risk patients could benefit from a time-limited course of venetoclax plus a BTK inhibitor. It is possible that PFS could be improved by using a BTK inhibitor with venetoclax instead of obinutuzumab, but there are not enough data to know yet.

Deborah Stephens, DO:
When I think about these studies, I always think, “Is this regimen able to cure patient?” If the regimen was curing people, then I think it makes sense to give it all up front and try to cure people, especially the younger patients. But I am not convinced that these BTK inhibitor plus venetoclax combination regimens are curing people, so I think we still are stuck with having to figure out how to sequence these therapies over a lifetime.

I have a young patient with high-risk disease and massive lymphadenopathy who lives 7 hours from our clinic. She would be a candidate for venetoclax plus a BTK inhibitor, in my opinion. Three months of a debulking therapy with a BTK inhibitor could be followed by venetoclax to decrease the risk of TLS.

Can noncovalent BTK inhibitors overcome resistance to covalent BTK inhibitors?

Deborah Stephens, DO:
The covalent BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—all require wild-type BTK C481 for good activity. The noncovalent BTK inhibitors—eg, pirtobrutinib and nemtabrutinib—bind a different BTK site and do not require the C481 moiety for activity. The phase I/II BRUIN study has shown us the efficacy of pirtobrutinib in CLL. This trial enrolled patients with CLL who had at least 2 prior therapies including a BTK inhibitor. The overall response rate was approximately 70%, which is impressive in this highly refractory population.

Of importance, PFS was improved in patients with 5 or more prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor. Median PFS in this study was 19 months, significantly longer than that seen in retrospective analyses of treatment with PI3K inhibitors. Also, the PFS curves overlap in patients with and without a C481S mutation, emphasizing that a C481S mutation should not preclude using pirtobrutinib.

Your Thoughts?
What are your thoughts and questions on current and novel management approaches for patients with CLL? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc.

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