CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 13, 2025
Expiration: September 12, 2025
Global Indications for Available BTK Inhibitors
As previously discussed, ibrutinib was the first-in-class BTK inhibitor available for the management of CLL and is currently approved as monotherapy in Europe and the United States for use in adult patients with CLL/SLL with or without del(17p), and in Europe in various combinations including with rituximab with or without bendamustine, or with obinutuzumab, or with venetoclax.50,55
Acalabrutinib is available in Europe and the United States as monotherapy for patients with previously untreated or relapsed CLL.56,57 In Europe, acalabrutinib can be used in combination with obinutuzumab in patients with previously untreated CLL.56
Zanubrutinib is approved in Europe and the United States as monotherapy for the treatment of patients with CLL.58,59
Pirtobrutinib is not yet approved in Europe for the treatment of CLL but is approved in the United States for adults with CLL/SLL who have received at least 2 previous lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.3 I anticipate the findings from the BRUIN CLL-321 trial might affect the approval status of pirtobrutinib in Europe.
It is worth mentioning that these agents are all approved for treating mantle cell lymphoma and some are approved for treating other B-cell malignancies. Zanubrutinib is the most broadly approved for these, including Waldenström’s macroglobulinemia, marginal zone lymphoma, and follicular lymphoma.
Treatment Algorithm for Newly Diagnosed CLL/SLL
The recommended treatment algorithm from the 2024 American Society of Hematology annual meeting’s educational program shows treatment options based on priority.27 Patient genetic information (eg, del[17p], TP53, and IGHV mutation status) is the most important factor to consider when selecting therapy for a patient with newly diagnosed CLL.
For patients with mutated IGHV status, time-limited treatments are preferred. Time-limited therapy with venetoclax-based regimens is preferred because the efficacy in patients with mutated IGHV status has been shown to be superior to continuous BTK inhibitor therapy. That said, continuous therapy is also an option.
For patients with unmutated IGHV, there is no preference between the 2 treatment types. For now, for patients with a del(17p) and/or TP53 mutation, our recommendation is for continuous BTK inhibitor treatment rather than time-limited treatment. Generally, acalabrutinib and zanubrutinib are preferred over ibrutinib because of a better safety profile with similar efficacy (acalabrutinib) or improved efficacy (zanubrutinib) in the R/R setting.39,41 We can extrapolate that this efficacy extends to the first-line setting as well, although head-to-head comparison data in this setting are not available.
Factors to Consider When Choosing Treatment
However, the optimal choice of treatment for individual patients may further change based on comorbidities, treatment toxicities, treatment logistics, comedications, and patient preferences.
The chart shown here displays the weighted pros and cons for each treatment based on efficacy and tolerability for genetic subgroups of patients on the left (as discussed in the previous section), as well as treatment-related logistics in the middle, and AEs, comorbidities, and comedications on the right.27
For example, the recommended treatment for a patient with no del(17p) or TP53 mutation and mutated IGHV would be obinutuzumab plus venetoclax or ibrutinib plus venetoclax. However, if the patient also has a history of cardiovascular events, this chart suggests that the obinutuzumab combination may be the preferred option of the 2.
In general, continuous BTK inhibitor therapy is more convenient to administer than venetoclax-based treatments because no intravenous infusions are involved and usually there is no need to monitor for TLS. By contrast, venetoclax regimens have a much lower risk for causing bleeding episodes and less accumulation of AEs because of the fixed-duration treatment.
Other factors to consider that are not shown in this chart are drug availability and cost. For instance, ibrutinib plus venetoclax is not approved by the FDA for use in the United States, but it can be used off-label.55,60 Other countries have approved only some of these BTK inhibitors for treating CLL. Also, the cost of continuous BTK inhibitor therapy is often much higher than the cost of fixed-duration venetoclax-based treatments.
Model of Overall Time to Treatment Failure For Typical Patients with CLL
This figure illustrates estimated treatment outcomes over time for patients in 3 genetic subgroups.27 This is an estimation because we do not have clinical trial data for this. Continuous BTK inhibitor treatment, shown in green, often achieves good outcomes, with time to treatment failure of approximately 8-10 years when second-line treatment is required. Time-limited BCL-2 inhibitor treatment is shown in the dark blue color followed by light blue between treatments. For the general patient population, we observe that the first PFS event after first-line BCL-2 inhibitor therapy occurs sooner than BTK inhibitor treatment, at approximately 6-7 years. However, we have the option of retreatment with BCL-2 inhibitor therapy, which can extend the time to a second PFS event for an additional 3-4 years.
As mentioned, treatment preference varies across the genetic subgroups, with a preference for BTK inhibitor for patients with a del(17p) and/or TP53 mutation. The 2 treatment options appear balanced regarding time to treatment failure for patients with unmutated IGHV. By contrast, patients with mutated IGHV tend to have longer times to progression with time-limited BCL-2 inhibitor-based treatment than with continuous BTK inhibitors.
Summary of CLL Treatment Sequencing With Example Algorithm
Now that I have reviewed treatment options in detail, it is important to discuss how to sequence these therapies. The recommended strategy is to alternate among therapies in the different treatment classes.60 In general, a poor response to venetoclax-based treatment should be followed by treatment with a covalent BTK inhibitor, and intolerance to a covalent BTK inhibitor should lead to a switch to a different agent in the same class. Noncovalent BTK inhibitors are typically the next treatment option after venetoclax-based regimens and covalent BTK inhibitors but before CAR T-cell therapy and clinical trials.
More specifically, if a patient has early progression during first-line therapy with obinutuzumab plus venetoclax, we can switch treatment to a continuous covalent BTK inhibitor. If there is intolerance to a particular BTK inhibitor, we could switch from to a different BTK inhibitor (ie, ibrutinib to acalabrutinib or zanubrutinib). If there is disease progression during treatment with a covalent BTK inhibitor we can switch treatment to a noncovalent BTK inhibitor. If there is a durable response to first-line obinutuzumab plus venetoclax, we can continue treatment with the same regimen until disease progression or intolerance leads us to switch to a covalent BTK inhibitor, or a noncovalent BTK inhibitor after further progression or intolerance.
If patients are first treated with a covalent BTK inhibitor, a treatment switch could be done when disease progression or intolerance occurs. If there is progression after a covalent BTK inhibitor therapy, we could switch to venetoclax-based treatment followed by noncovalent BTK inhibitors after further disease progression. If there is intolerance, we could consider noncovalent BTK inhibitors or venetoclax-based treatment.
AE Decision Support Tool for CLL
When treating patients with BTK inhibitors, it is important to be aware of potential AEs and how to manage them as they arise.
I am concerned that these valuable treatment options are often discontinued prematurely because of potentially minor AEs that have not been managed adequately.
To help prevent unnecessary or premature BTK inhibitor discontinuation, Clinical Care Options has developed a decision support tool to help healthcare professionals (HCPs) determine how to manage AEs. HCPs can enter the details of a patient case to receive recommendations based on EMA, FDA, and expert guidance.
Managing Bruising and Hemorrhage
General recommendations for managing the hemorrhagic AEs associated with the BTK inhibitor drug class include monitoring patients for signs of bleeding and, at the first occurrence of grade ≥3 hemorrhage, to withhold the dose until the AE resolves to grade 1 or baseline.3,50,55-59 For subsequent occurrences of a hemorrhagic AE, it is recommended to hold treatment and reduce the dose or permanently discontinue treatment after 4 occurrences or a long-lasting episode of neutropenia.
It is also important to note here that the pirtobrutinib safety profile data are from the R/R setting with patients who had received several previous treatments, whereas the safety data for the other agents are from patients in the first-line treatment setting.45
Managing Atrial Fibrillation and Cardiac Arrhythmias
Atrial fibrillation is also a known class-related AE with BTK inhibitors, but it does not necessarily require complete discontinuation of the BTK inhibitor drug class.3,50,55-59 As you may see in the AE decision support tool, experts recommend a cardiology consultation for patients experiencing atrial fibrillation. Low-grade occurrences can potentially be controlled with rate-control–directed therapeutic interventions without halting BTK inhibitor therapy. However, this should be managed on a case-by-case basis.
Managing Other Covalent BTK Inhibitor–Related AEs
For the management of other BTK inhibitor–related AEs, my general recommendation is to monitor patients for known AEs of interest and interrupt or reduce dosing as necessary before discontinuing BTK inhibitors.61 In addition, prophylaxis to reduce the incidence of infections may also be considered.
Patient and Caregiver Discussions: What AEs to Expect/Monitor During BTK Inhibitor Treatment
It is important to inform patients and their caregivers about what AEs they should expect and how to monitor for their occurrence.
I usually start discussing the potential for diarrhea, because it is one of the first AEs that patients notice. I make it clear to them that diarrhea can be of low grade and is usually temporary.
I also discuss the potential for bleeding and bruising, and that this is usually not very harmful, but that they should watch for serious or prolonged bleeding incidents.
I tell my patients that AEs like headache, arthralgia, diarrhea, and bleeding episodes may be low grade and do not require intervention, or can be managed without disrupting treatment. However, we also discuss options for screening patients for more serious AEs such as atrial fibrillation.
Understanding Challenges to Adherence and Persistence With Oral BKT Inhibitors
HCPs should also be aware of the challenges that patients face for adhering to BTK inhibitor treatment.
The cost of these agents can be a barrier for patients who have copayments for their medical care. We should discuss AE expectations with patients, ensuring they know that symptoms from their disease should improve soon after beginning treatment, but that AEs that make them feel worse can occur and need to be managed.
Patient education, shared decision-making regarding patient care, and involving an interdisciplinary team are critical to maximizing the benefit attained with BTK inhibitor treatment.
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