From Evidence to Practice: Integrating Alpine Zanubrutinib into CLL Treatment Pathways
Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous B-cell malignancy and is now treated in the context of disease related variables, patient related variables and therapeutic variables with increasingly substantiated targeted therapies. BTK inhibitors have become standard for the treatment of CLL, because BTK is an essential component of the B-cell receptor signaling pathway controlling the survival, proliferation, migration and tumor microenvironment interaction of the malignant B-cells.
The ALPINE trial was a Phase 3 clinical trial that compared Zanubrutinib to ibrutinib in patients with relapsed or refractory CLL/SLL. Information from this trial can assist health care providers in integrating Zanubrutinib into treatment algorithms for CLL.
Understanding the ALPINE Trial
The ALPINE study was a global, randomized, open-label Phase 3 study in 652 patients with R/R CLL/SLL, comparing Zanubrutinib with ibrutinib, another covalent BTK inhibitor. Patients were randomized in a 1:1 ratio to receive either Zanubrutinib or ibrutinib and were evaluated by investigators for assessment of the overall response rate (ORR), primary end point. Additional key secondary end points were PFS, OS and safety.
What Evidence Shows
The ALPINE trial reported ORR and PFS outcomes for Zanubrutinib and ibrutinib in multiple subgroups of CLL/SLL patients, including the ones with high-risk disease characteristics such as del(17p).
However, PFS from study end point assessment for Zanubrutinib has demonstrated continued clinical activity with near 50% of patients remaining on study in long-term follow-up up to 6 years, with responses observed in patients with del(17p) – a subgroup of patients with high-risk CLL. This information provides further information for clinicians as to the treatment’s effectiveness in relation to other BTK inhibitors and specifically the high risk CLL patients with del(17p).
Considering Safety Alongside Efficacy
Tolerability of treatment (disease control + side effects) plays a very important role in choosing an appropriate treatment for CLL patients. From cardiovascular safety comparison between Zanubrutinib and ibrutinib in ALPINE trial, there were significantly less incidence of atrial fibrillation and other related cardiac adverse events with Zanubrutinib versus ibrutinib. Importantly, there were fewer overall treatment emergent adverse events leading to discontinuation or dose reduction with Zanubrutinib.
The safety findings will be of particular interest when managing patients with a cardiovascular concern and can be considered in individual patient circumstances. Important factors to take into account are the patient’s current and past medication, their cardiac history, potential for bleeding and for infection, current or planned treatment with other medications that may interact with BTK inhibitors, laboratory test results, and the patient’s ability to take medication for long periods.
Positioning Zanubrutinib Within Treatment Pathways
The ALPINE evidence can be most readily applied to R/R CLL/SLL patients that were studied in ALPINE. Therefore, when considering the addition of alpine zanubrutinib to a treatment plan for CLL patients, it is helpful to determine the patient’s current disease status as well as their treatment history for targeted agents.
Information regarding resistance to BTK inhibitors in CLL is of growing importance to select appropriate subsequent treatments after relapse. Analyses of acquired mutations in patients from the ALPINE study with CLL relapsing on treatment with Zanubrutinib provide novel insights into mechanisms of resistance to this BTK inhibitor in patients with R/R CLL.
The design of CLL treatment pathways is a more complex matter. While the ALPINE trial provides additional information regarding the treatment of patients with R/R CLL/SLL, it is only one of several sources of information that must be taken into consideration when determining an optimal treatment strategy for individual patients with CLL.
Translating Trial Data into Clinical Practice
When assessing ALPINE for clinical relevance, consideration should be made for how trials define endpoints. While the results from ALPINE show higher ORR and PFS for Zanubrutinib versus ibrutinib in patients with R/R CLL/SLL, the evaluation of the results in the context of CLL treatment and management should also consider the duration of complete or partial response of participants and the overall treatment effects (disease control and harm) that occur over time for each group of study participants.
An additional dimension for evaluating Zanubrutinib versus ibrutinib was provided by the analysis of symptom-based PFS from patient reported data, which compared the symptoms deterioration outcomes of Zanubrutinib and ibrutinib.
The findings from ALPINE and other studies evaluating Zanubrutinib may contribute to treatment decisions on a case-by-case basis and based on all available evidence to assess all relevant factors, including the specific disease, previous treatment(s), comorbidities, other medications and general health of the individual patient.
Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.
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