An international view on the current approaches to frontline chronic lymphocytic leukemia therapy

Abstract

Abstract Background: The treatment landscape for chronic lymphocytic leukemia (CLL) has evolved significantly in recent years with the introduction of targeted therapies, including Bruton's tyrosine kinase inhibitors (BTKi) and BCL-2 inhibitors (BCL-2i), largely replacing traditional chemoimmunotherapy (CIT). However, in the absence of direct comparisons between these agents, selecting the most appropriate treatment for individual patients remains challenging. Aim: To provide practical recommendations for selection of frontline therapy for patients with CLL, focusing on patient risk stratification, the role of molecular testing, and the integration of individual patient preferences. Methods: These recommendations reflect the collective insights of 13 hematologists from Argentina, Australia, Brazil, China, Egypt, Kuwait, Mexico, Russia, Singapore, Taiwan, and Turkey. The panel members represent various global regions, including Latin America (LATAM), Middle East and Africa (MEA), Asia-Pacific (APAC), and Russia. Through an asynchronous online discussion followed by a virtual meeting, the panel evaluated CLL treatment strategies, focusing on targeted therapy selection, regimen duration (continuous vs. time-limited), molecular profiling, and patient-specific factors guiding therapy. Results: Therapy Selection: While acknowledging regional variability in access to novel agents, the consensus indicated that initial therapy selection is critically guided by disease-related factors (e.g., genetic risk profile) and patient characteristics (e.g., fitness, age, comorbidities), with strong emphasis on patient preferences and shared decision-making. Experts underscored the importance of molecular testing for 17p deletion (del(17p)), TP53 mutations and IGHV mutation status, particularly in settings where access to novel agents is dependent on these biomarkers for treatment approval or reimbursement. That said, in healthcare systems with broad access to novel agents, its direct influence on therapeutic decision-making may be less critical, serving primarily for prognostic value. First-Line Therapy Recommendations: CLL patients with del(17p)/TP53 mutations:For these high-risk patients, the panel strongly favoredcontinuous BTKi therapy, with second-generation BTKis (acalabrutinib, zanubrutinib) preferred due to their more favorable safety profiles. While a finite, BTKi and BCL2i combination was considered (acalabrutinib + venetoclax), especially for younger patients or those preferring time-limited treatment, its use in clinical practice was further restricted by regional availability and access. CIT was largely rejected in this specific patient group. IGHV-mutated CLL patients without del(17p)/TP53 mutations:For these lower-risk patients, the expert's recommendation favoured finite, BCL2i-based combinations with either a BTKi (venetoclax + acalabrutinib, or venetoclax + ibrutinib) or an anti-CD20 agent (venetoclax + obinutuzumab). For frail patients, continuous BTKi monotherapy was also considered. While CIT was acknowledged as an option in regions with limited access to novel agents, its use was recognized as a substandard approach and advised only after ruling out unmutated IGHV status and considering patient age, fitness, and comorbidities. IGHV-unmutated CLL patients without del(17p)/TP53 mutations:While the majority of experts considered patient fitness for this group, recommending continuous BTKi monotherapy for frail patients and venetoclax-based combinations with either a BTKi (acalabrutinib, ibrutinib) or obinutuzumab for fit patients, some emphasized the overall suitability for targeted agents regardless of a traditional fitness assessment, focusing instead on specific comorbidities that might impact tolerability (e.g., cardiac or renal conditions). There was a clear recommendation to avoid CIT in this patient group. Conclusions: This expert panel's insights address the evolving CLL treatment landscape and variable access to novel targeted therapies across LATAM, MEA, APAC, and Russia. It emphasizes that individualized patient care should integrate comprehensive molecular assessment, risk stratification, and critically, patient preferences, while also considering regional resource availability.