Novel Therapies and Their Impact on Treatment Pathways for Chronic Lymphocytic Leukemia

In this interview, Seema A. Bhat, MD, discusses the evolving treatment landscape for chronic lymphocytic leukemia, including strategies for treatment selection, sequencing, addressing diagnostic gaps, and exploring novel therapies to improve patient outcomes.

Please introduce yourself by stating your name, title, and any relevant clinical experience you’d like to share.

Seema A. Bhat, MD: I'm Seema A. Bhat, MD, a hematologist/medical oncologist and an associate professor of medicine at The Ohio State University, Columbus Ohio. I specialize in treating patients with lymphoid malignancies, particularly focusing on chronic lymphocytic leukemia (CLL).

How do you approach treatment selection in CLL, particularly balancing targeted therapies such as Bruton’s tyrosine kinase (BTK) inhibitors and venetoclax-based regimens?

Dr Bhat: The treatment landscape for CLL has changed over the past decade. Chemoimmunotherapy has been replaced both in frontline and relapsed/refractory settings by targeted agents, including covalent BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and the BCL-2 inhibitor venetoclax, which is often combined with an anti-CD20 monoclonal antibody (mab). Treatment selection for an individual patient should consider disease-specific and patient-specific characteristics such as comorbidities and personal preferences.

We have the choice of using continuous, indefinite BTK inhibitor treatment or a 1-year, time-limited venetoclax-based regimen, with obinutuzumab added for the first 6 months. From the disease standpoint, attention needs to be paid to the genomic profile of the disease, for example, for high-risk patients with presence of del17p or TP53 mutation, data suggest that continuous BTK inhibitor therapy is superior to time-limited venetoclax-based therapy. For standard-risk patients, either treatment modality can be chosen, and attention needs to be paid to patient-specific factors.

Continuous BTK inhibitor therapy has the advantage of being easy to administer and does not require rigorous monitoring, while the venetoclax plus obinutuzumab involves frequent monitoring for tumor lysis syndrome (TLS) initially and patients need to come to the clinic every 4 weeks for the first 6 months for obinutuzumab infusions. Side effect profile for these 2 treatments differ. Arrhythmias (eg, atrial fibrillation), bleeding, and hypertension are some adverse effects unique to BTK inhibitors and require careful patient selection. If a patient has cardiac risks, such as atrial fibrillation, hypertension, or if they are receiving anticoagulation, then it may be better to avoid a BTK inhibitor-based treatment. Besides the risk of TLS, venetoclax can also increase the risk of neutropenia and gastrointestinal symptoms such as nausea and diarrhea.

Having discussed all pros and cons, patient preference is an important factor in choosing treatment. Some patients have a strong preference for a time-limited treatment, while others prefer avoiding infusions or do not mind indefinite oral therapy. These considerations are important when choosing treatment for patients with CLL.

Can you discuss how treatment sequencing is determined for patients with relapsed or refractory CLL?

Dr Bhat: For patients with relapsed/refractory CLL, when they meet criteria for treatment, the choice of therapy is largely based on their frontline regimen. One important thing to remember is that chemoimmunotherapy is no longer recommended for treatment of CLL in frontline or in the relapsed or refractory setting.

For patients previously treated chemoimmunotherapy, both covalent BTK inhibitors and venetoclax with an anti-CD20 mAb are viable options, with treatment selection mirroring the considerations used in frontline therapy.

For patients on a covalent BTK inhibitor, it is important to know whether the change of treatment is needed due to adverse effects or disease progression. In cases of intolerance, switching between covalent BTK inhibitors (eg, from ibrutinib to acalabrutinib or Zanubrutinib) is possible. For progression on a covalent BTK inhibitor, venetoclax and an anti-CD20 mAb is the next-line therapy. However, based on the results from the BRUIN-321 study, presented at ASH 2024, pirtobrutinib, a noncovalent BTK inhibitor, can also be considered.

For patients who progress after frontline fixed-duration venetoclax plus obinutuzumab, covalent BTK inhibitors are logical next steps. Retreatment with venetoclax plus an anti-CD20 mAb may be considered if relapse occurs after a long duration (eg, >2-3 years). Currently, data on sequencing pirtobrutinib before a covalent BTK inhibitor is lacking; clinical trials are ongoing and are even looking at introducing pirtobrutinib in the frontline setting. We may see evolution of sequencing in future.

Patients who have relapsed on both a covalent BTK inhibitor and venetoclax-based therapy are called dual-refractory and face a guarded prognosis. Recently approved treatments for this population include pirobrutinib and CAR T-cell therapy. Pirtobrutinib can work for patients who have developed resistance mutations while on the covalent BTK inhibitors, and was approved by the US Food and Drug Administration (FDA) for patients who progressed on prior covalent BTK inhibitors and venetoclax. It is an oral therapy and is very well tolerated. CAR T-cell therapy (liso-cel) was also recently approved for this group of patients, which is exciting and provides an additional option for these patients.

What are the current gaps in diagnostic pathways for CLL, and how might these be addressed to improve patient outcomes?

Dr Bhat: We define CLL by risk groups based on certain genomic factors, with IGHV mutation status and FISH panel results being the most important. However, fewer than one-third of patients undergo FISH testing done, and an even smaller proportion of patients have IGHV mutation status tested. While genetic testing is increasingly utilized, it is not yet routine for all patients. There also seems to be a knowledge gap regarding the use of comprehensive NGS panels, especially for identifying TP53 mutations. The absence of this information can directly impact treatment selection and prognosis assessment.

The lack of testing may reflect both knowledge gaps and limited access to advanced diagnostic tests. There is a need for continuing medical education to improve awareness of molecular testing for treatment decisions and the skills to select the therapies according to molecular test results. Improving access to these tests in community settings will also help broader utilization of these important tests, ultimately improving patient outcomes.

Are there specific challenges in managing treatment adherence or toxicities that affect the overall cost of care for patients with CLL?

Dr Bhat: Oral therapies have the advantage of being easy to administer and are preferred by our patients. However, adherence can be a challenge given that the responsibility is transferred from the physician to the patient. Patients may inconsistently take their medications due to forgetfulness, lack of understanding about adherence, polypharmacy—common in older patients—or complex dosing schedules.

Targeted therapies such as BTK inhibitors may cause side effects, including fatigue, diarrhea, bleeding, or arthralgias, which can also contribute to nonadherence. These side effects may also lead to hospitalizations, increasing health care utilization and costs. Poor adherence can result in disease progression, requiring more frequent visits to health care providers, additional diagnostic tests, and potential changes in treatment.

It is very important to provide patient education and support through their treatment journey. Patients must fully understand their treatment plans and the potential side effects from the treatment. Emphasizing the connection between adherence and cost management is essential. Pharmacists and patient education programs can play a significant role in providing detailed medication information, addressing side effects, and developing adherence strategies. Medication adherence interventions can be utilized, such as reminder systems (eg, smart phones and alarms), simplified dosing schedules, and patient-centered communication. Patient education for proactive monitoring and prompt intervention to manage side effects can prevent complications, reduce hospitalizations, and lower costs.

What novel therapies or combinations currently under investigation hold the most promise for CLL, and how might they impact existing treatment pathways?

Dr Bhat: Recently, at ASH 2024 data, from multiple trials was presented, which was very exciting. The AMPLIFY trial demonstrated superiority of the fixed-duration, all-oral combination therapy of acalabrutinib plus venetoclax versus chemoimmunotherapy. Hopefully, when this combination is approved, we will have another time-limited option available for our patients, especially those who want to avoid intravenous infusions. The same combination is being compared with venetoclax plus obinutuzumab in the MAJIC study. The results of this trial may further define the differences between these 2 fixed-duration regimens.

We are seeing encouraging data in the relapsed/refractory CLL setting. Emergence of resistance is a major mechanism of progression for patients treated with a covalent BTK inhibitor. To specifically address resistance, in addition to the recent approval of the noncovalent BTK inhibitor pirtobrutinib, there is significant interest in the clinical development of BTK degraders, which specifically target and destroy the BTK protein regardless of presence or absence of a resistance mutation. At ASH 2024, results for 2 BTK degraders, NX-5948 and BGB-16673, were presented, showing a response rate over 75% for both agents, which is very promising.

Bispecific antibodies are also being tested for CLL. Epcoritamab is a bispecific CD20-directed CD3 T-cell engager that activates T cells, directing them to kill malignant CD20+ B cells. In heavily pretreated patients with CLL, single-agent epcoritamab demonstrated a high overall response rate and a manageable safety profile. This trial is also investigating at combining epcoritamab with other agents, such as venetoclax or pirtobrutinib.

All these new treatments continue to make CLL research very exciting. We will hopefully see the approval of some of these agents in future, and others may shift to frontline setting as more data emerge. The treatment paradigm may be further refined which will also affect treatment sequencing for relapsed disease. Overall, it is always beneficial to have more options for our patients.