International Experts Address HCP Questions on BTK Inhibitors for CLL and MCL

Key Takeaways:

• The decision of when to use BTK inhibitors and which BTK inhibitor to use depends on many factors and should be tailored to the individual patient.
• Atrial fibrillation can occur with BTK inhibitors, although it may not preclude their use; the second-generation covalent BTK inhibitors acalabrutinib and zanubrutinib are associated with lower rates of atrial fibrillation compared with ibrutinib.
• The noncovalent BTK inhibitor pirtobrutinib has demonstrated promising efficacy and safety results in clinical trials in chronic lymphocytic leukemia and mantle cell lymphoma.

In this commentary adapted from a discussion between Othman Al-Sawaf, MD, and Toby Eyre, MBChB, MD, the experts address important questions surrounding optimal use of approved BTK inhibitors and key data with emerging investigational BTK inhibitors in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

Does atrial fibrillation stop you from using approved BTK inhibitors?

Toby Eyre, MBChB, MD:
The second-generation BTK inhibitors zanubrutinib and acalabrutinib are associated with lower rates of atrial fibrillation compared with ibrutinib, a first-generation BTK inhibitor. That said, for patients with a history of atrial fibrillation and hypertension, I may prefer fixed-duration therapy with a venetoclax-based regimen vs continuous therapy with an approved BTK inhibitor. However, there is clearly a debate to be had about the pros and cons of venetoclax-based therapy vs second-generation BTK inhibitor therapy for these patients.

Do you refer new patients with CLL to a cardiologist to assess the risk of atrial fibrillation if they start a BTK inhibitor?

Toby Eyre, MBChB, MD: 
I don’t automatically refer all my patients to a cardiologist. I typically assess the patient’s cardiovascular risk and avoid BTK inhibitors if I think the patient is at particularly high risk. Whether I would use a BTK inhibitor also would depend on what treatment options were available for the specific patient.

If patients have specific cardiovascular issues (eg, hypertension that is difficult to manage), I will definitely perform an echocardiogram and an electrocardiogram to assess for ventricular hypertrophy and other conditions. Data from the phase III FLAIR trial have recently established that there are individuals who are higher risk for sudden cardiac events.     

In most patients with CLL, I prefer to prescribe second-generation BTK inhibitors vs ibrutinib due to the relatively better cardiovascular profile with the second-generation agents. However, I think it is important to consider patients individually when choosing a treatment option.

What are some of the mechanisms of resistance to covalent BTK inhibitors?

Toby Eyre, MBChB, MD:
The mechanisms of resistance to covalent BTK inhibitors are increasingly well understood. Mutation at the C481 binding site is frequently observed in patients who have developed covalent BTK inhibitor resistance (eg, to acalabrutinib, ibrutinib, and zanubrutinib). Because the C481 mutation contributes to resistance across all of the approved covalent BTK inhibitors, switching to a different covalent BTK inhibitor is generally ineffective.

Although covalent BTK inhibitors and noncovalent BTK inhibitors (eg, pirtobrutinib and nemtabrutinib) have the same target (ie, BTK), covalent BTK inhibitors form irreversible bonds with BTK, whereas noncovalent BTK inhibitors form reversible bonds. In addition, compared with covalent BTK inhibitors, noncovalent BTK inhibitors do not require the C481 residue as a binding site for their activity. Consequently, noncovalent BTK inhibitors are active in patients who have acquired C481 mutations that convey resistance.

What data are available with investigational noncovalent BTK inhibitors?

Toby Eyre, MBChB, MD: 
Of the noncovalent BTK inhibitors currently under investigation, pirtobrutinib is the furthest along in terms of clinical development.

Othman Al-Sawaf, MD:
Most of the clinical trial data we have on pirtobrutinib are derived from the BRUIN trial, which is an ongoing phase I/II trial examining continuous pirtobrutinib in patients with relapsed/refractory CLL or B-cell non-Hodgkin lymphoma.

Patients in the CLL cohort (n = 261) were heavily pretreated at baseline, with most having previously received another BTK inhibitor. Many also had a BTK C481 mutation. Although the patients in this trial had unfavorable disease characteristics, pirtobrutinib was associated with an overall response rate of 68% in patients pretreated with a BTK inhibitor. Median progression-free survival was not yet reached in patients with a median of 3 prior lines of therapy, including a BTK inhibitor, at a median follow-up of 9.4 months. This is important, because patients who are heavily pretreated and double refractory to BTK inhibitors and BCL-2 inhibitors can be very difficult to manage. These data show that noncovalent BTK inhibitors have a distinct efficacy profile that is quite promising.

The lack of head-to-head trials makes it difficult to compare the efficacy and safety profile of pirtobrutinib with those of other BTK inhibitors. However, data from the BRUIN trial suggest that cardiovascular toxicities are rare (any grade and grade ≥3 atrial fibrillation: 2% and <1% of patients, respectively; any grade and grade ≥3 hypertension: 7% and 2%). Ongoing comparative phase III trials should provide further information on the relative efficacy and safety of pirtobrutinib within the BTK inhibitor landscape.

Toby Eyre, MBChB, MD:
Data with pirtobrutinib in patients with previously treated MCL also come from the BRUIN trial. Patients in the MCL cohort (n = 134) had received a median of 3 prior lines of therapy, and almost all patients had received prior covalent BTK inhibitors, with most patients discontinuing prior BTK inhibitor therapy due to progression rather than toxicity.

Among patients in the MCL cohort with previous BTK inhibitor therapy, pirtobrutinib was associated with an overall response rate of 51% and complete response rate of 25% at a median follow-up of 8.2 months. Although data from the MCL cohort are derived from a very short follow-up period, it is intriguing that although most patients were resistant to covalent BTK inhibitors, more than one half still were sensitive to very selective BTK inhibition. The median duration of response was approximately 18 months, meaning that the observed responses were durable, which—given the high-risk profile of these patients—is impressive. It will be interesting to monitor results from the ongoing randomized phase III BRUIN-MCL-321 trial, which is a head-to-head trial examining pirtobrutinib compared with investigator’s choice of BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated MCL. This ambitious trial is currently recruiting patients and has a superiority design.

In patients with CLL with light-chain deposition in the kidneys, how would you manage treatment with a BTK inhibitor given that an overload of CLL can lead to kidney failure?

Toby Eyre, MBChB, MD: 
In patients with a paraneoplastic phenomenon, controlling the CLL clone at a moderate speed is important and, consequently, so is the time to deepest response. Although BTK inhibitors are highly effective, it can take a long time to achieve deep remission with these agents—in some cases, more than 1 year. In terms of response time, compared with BTK inhibitors, combinations of a BCL-2 inhibitor plus an anti-CD20 antibody are advantageous because they are associated with rapid, deep responses in patients who have not already been exposed to this combination. Assuming that a combination of BCL-2 inhibitor plus anti-CD20 antibody can be delivered safely, this combination would be my preferred approach in this case. Alternatively, if a BTK inhibitor is preferred, then adding an anti-CD20 antibody may be an option.

Othman Al-Sawaf, MD: 
I agree. Adding an anti-CD20 antibody to a BTK inhibitor can hasten the time to a complete remission, or at least a deeper remission. In addition, although it hasn’t been definitively established that the level of lymphocytosis has a prognostic impact on renal function, it is important to be mindful of lymphocytosis levels, particularly in patients with kidney problems and an overload of CLL.

Toby Eyre, MBChB, MD: 
I agree. In addition, I would probably monitor the light-chain ratio and light-chain load rather than the lymphocytosis. I think these measurements would probably be a better measure of potential response to treatment.

Do BTK inhibitors carry a risk of SC bleeding?

Othman Al-Sawaf, MD:
All BTK inhibitors are associated with some elevated risk of SC bleeding. However, the risk varies depending on the specific BTK inhibitor. The second-generation BTK inhibitors may have less relative bleeding risk than ibrutinib based on comparative data from the phase III ALPINE and ELEVATE-RR trials. For example, bleeding events were observed in 38% of patients who received acalabrutinib and 51% of patients who received ibrutinib in ELEVATE-RR. Bruising and hemorrhage were reported in 22% and 7% of patients who received pirtobrutinib in BRUIN, but larger randomized trials will provide more meaningful data with this agent.

What anti-infection prophylaxis do you recommend before starting a BTK inhibitor?

Othman Al-Sawaf, MD:
Data from retrospective cohort studies examining the incidence of opportunistic infections with BTK and BCL-2 inhibitors have shown that incidence associated with these agents is low. In most guidelines, there are no recommendations for prophylaxis for preventing opportunistic infections such as pneumocystis pneumonia (PCP). Similarly, there are no guidelines for antiviral prophylaxis.

Consequently, I don’t use anti-infection prophylaxis agents in my practice, nor do we recommend or mandate these therapies. The only opportunistic infections that concern me in patients receiving BTK inhibitors—particularly in those who are receiving high-dose steroids—are fungal infections.

Toby Eyre, MBChB, MD: 
I do not think it is a BTK inhibitor alone that influences risk of opportunistic infections, but more the context of use. There are other factors (eg, immune suppression resulting from autoimmune conditions or long-term steroid use) in addition to the BTK inhibitor itself that influence the risk of opportunistic infection. This is supported by data showing that when BTK inhibitors are administered as first-line therapy, PCP risk does not appear to increase. However, in heavily pretreated patients who have been profoundly immunosuppressed for several years, antifungals and PCP prophylaxis may be appropriate.

Can CLL bounce back quickly after stopping each of the BTK inhibitors?

Toby Eyre, MBChB, MD:
The covalent BTK inhibitors are associated with a risk of flare after discontinuation. It should be noted that when CLL is in deep remission, it does not tend to flare up after discontinuing BTK inhibitor therapy. Data from the ECOG 1912 trial—a randomized phase III trial comparing a combination of ibrutinib plus rituximab with fludarabine/cyclophosphamide/rituximab in treatment-naive patients with CLL—demonstrated that ibrutinib can be associated with durable remissions of up to 2 years. It is important, however, to consider what the next step in treatment will be before discontinuing a BTK inhibitor.

Othman Al-Sawaf, MD:
I agree. The data from the ECOG 1912 trial were surprising in that basically they showed that if a patient has a response to BTK inhibitor therapy and then discontinues it due to, for example, toxicity, there can be an extended time—more than a median of 20 months in the study—before symptomatic progression is observed.

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