Chronic lymphocytic leukemia (CLL) is a B-cell malignancy. Targeted therapies, in addition to newer therapeutic classes, have become fundamental to the treatment of CLL. BTK inhibitors were initially presented as an alternative to chemotherapy. Newer BTK inhibitors are entering the market, and consideration of previous therapies, the natural history of the patient’s disease, the patient’s overall health and specific safety features of each of the agents, are becoming increasingly important for optimal treatment sequencing.

Zanubrutinib is a next-generation BTK inhibitor that was investigated in the ALPINE study. In this study, Zanubrutinib was compared to Ibrutinib in 652 patients with relapsed or refractory CLL or SLL who had received at least one previous treatment. In this study, Zanubrutinib and Ibrutinib were compared with respect to several endpoints.

Understanding BTK Inhibition in CLL

CLL is a B-cell malignancy. For the most part, the tumor cells of CLL receive signals for their survival and growth from the B-cell receptor (BCR) pathway. BTK is a critical component of this signaling pathway. Thus, by specifically inhibiting BTK, it is possible to interfere with the signaling for the survival and growth of the CLL tumor cells.

Zanubrutinib is a next generation BTK inhibitor that is similar to other newer agents, such as acalabrutinib, and is a more selective BTK inhibitor compared to ibrutinib with less activity on other kinases and downstream pathways.

Where Zanubrutinib Fits

Zanubrutinib is approved by the U.S. Food and Drug Administration for the treatment of adults with CLL or SLL. This is a small molecule that is administered orally. Treatment is continued until disease progression or unacceptable toxicity. Zanubrutinib is given either twice daily at a dose of 160 mg or once daily at a dose of 320 mg.

Zanubrutinib is a next generation BTK inhibitor that is indicated for the treatment of CLL. Importantly, as with any treatment, for each patient, the decision to use Zanubrutinib, or any other BTK inhibitor, will be based on a number of factors, including the disease itself, prior therapy, concomitant medications and medical condition(s), and other important considerations.

What the ALPINE Trial Showed

The ALPINE study was a Phase 3 study comparing Zanubrutinib with ibrutinib in 652 patients with CLL/SLL that had received at least one prior therapy. With a median follow-up of 42.5 months, Zanubrutinib reported a progression-free survival hazard ratio of 0.68. Overall response rate was 85.6% for Zanubrutinib and 75.4% for ibrutinib.

There were 159 (24%) patients with del(17p) and 104 (16%) patients with TP53 mutations in the ALPINE study. In the final analysis of the ALPINE study, patients with relapsed or refractory CLL or SLL who had received at least one previous treatment were treated with either Zanubrutinib or ibrutinib. In this patient population, Zanubrutinib showed clinical activity against CLL in multiple patient groups, including those with high-risk del(17p) or TP53-mutated disease. These patients typically have a worse prognosis and were among the groups that were included in the trials of ibrutinib.

A limitation of this study is that it was a comparison of two different BTK inhibitors. Therefore, the results from this study cannot be applied to all patients with CLL, and other BTK inhibitors with different characteristics should also be investigated.

Considering Safety When Sequencing Treatment

Long-term CLL therapy requires a favorable safety profile and a favorable tolerability profile to allow for long-term treatment over extended periods of time. In the case of BTK inhibitors, this also extends to differences between individual drugs as well as between the effects on individual organs.

There were 247 cardiac events in patients treated with ibrutinib, including 106 (7.1%) events of atrial fibrillation or flutter (including 4 events of atrial fibrillation with rapid ventricular response), 4 events of syncope (considered to be cardiac in origin), 5 cardiac arrest events, 4 myocardial infarction events, 16 cardiac death events, and 103 other cardiac events. In contrast, there were 133 cardiac events in Zanubrutinib-treated patients, including 35 (7.1%) events of atrial fibrillation or flutter (including 2 events of atrial fibrillation with rapid ventricular response), 3 events of syncope, 2 cardiac arrest events, 1 myocardial infarction event, 2 cardiac death events, and 89 other cardiac events.

Adverse reactions can cause serious harm to a patient taking Zanubrutinib. Infections, hypoplasia or decreases in blood cell counts, bleeding events (hemorrhage), and cardiac arrhythmias (cardiac rhythm problems) can occur. With proper recognition of potential problems and the obtaining of follow-up information from patients as needed, these adverse reactions can be effectively managed.

Treatment Sequencing After Previous Therapy

For relapsed CLL, prior therapies given to the patient have to be taken into account for the treatment. For the second line of treatment, a different class of drugs than the one used for the first line of treatment should be chosen.

In summary, for patients with previously untreated CLL, Zanubrutinib or other BTK inhibitors may be evaluated as an option. For patients with previously treated CLL, Zanubrutinib or other BTK inhibitors may not be the right option for patients who failed prior BTK inhibitors.

New therapeutic agents including BCL2-directed therapy are becoming important for the treatment of CLL. Consequently, a sequential single-agent or even combination regimen approach for individual patients is most relevant for optimal treatment strategies.

High-Risk Disease Requires Careful Planning

Patients with higher risk CLL can require a different approach to treatment selection and sequencing. In the ALPINE study, patients with del(17p)/TP53 mutations were included and a progression free survival advantage for Zanubrutinib over ibrutinib was observed in this subgroup of higher risk patients.

The alpine zanubrutinib study included patients with these high-risk characteristics and demonstrated a progression-free survival advantage for Zanubrutinib over ibrutinib in the del(17p)/TP53-mutated subgroup. Thus, the assessment of a patient’s CLL, including his or her genetic and molecular characteristics, can form the basis of clinical decisions regarding that individual.

The Importance of Ongoing Assessment

Patients on a BTK inhibitor as a single agent for the treatment of CLL are to be assessed for treatment response and for possible treatment toxicities (e.g. infections, decreased blood counts, hemorrhage, etc.). In addition, possible drug interactions with other medications the patient is taking need to be taken into consideration.

In case of disease progression or increasing burden of side effects, other options of treatment are considered. Mostly BTK-inhibitors are used in combination with other drugs, and therefore also interactions with constant use medications have to be considered and discussed with the patient’s hematologist.

This communication will be especially relevant to patients with CLL who are currently on treatment for their disease and require their treatment to be changed from time to time.

Looking Ahead

The development of more selective BTK inhibitors for the treatment of CLL has provided multiple options for the treatment of CLL patients. In the ALPINE study, Zanubrutinib was evaluated in CLL patients and differences were observed in progression-free survival and cardiac safety outcomes compared to ibrutinib. As for the treatment of CLL with BTK inhibitors, there is more than choosing between individual BTK inhibitors. Rather, there is a sequence of different treatments, depending on previous treatment(s), the biological features of the CLL, response to previous treatment(s), and the patient’s situation and goals.

Decisions on the most suitable treatment for CLL are evolving as more data becomes available and novel therapeutic agents are developed. These decisions should be made on an individual basis taking into account the current disease and the evidence available. It is best to discuss these with the patient’s hematology team.

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