John Allan, MD

Panelists discuss how CLL treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while addressing the management of BTKi class effects through dose-modification strategies and multidisciplinary care coordination, and anticipating future developments including BTK degraders that show excellent efficacy with improved safety profiles in highly refractory populations, bispecific antibodies for fixed-duration approaches, and results from the CLL17 trial comparing oral doublets to venetoclax-obinutuzumab that may further establish the role of time-limited combination therapies in transforming the treatment landscape.

Panelists discuss how CLL treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while addressing the management of BTKi class effects through dose-modification strategies that have become preferred over drug switching, emphasizing that intolerance is subjectively defined by patient acceptance and requires a multidisciplinary team approach including extensive patient education, close monitoring by nurses and pharmacists, and collaboration with cardio-oncology specialists to manage cardiovascular toxicities, with the notable exception that ventricular arrhythmias like PVCs warrant immediate consideration for drug discontinuation due to risk of sudden death.

Panelists discuss how chronic lymphocytic leukemia treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while addressing the management of BTKi class effects including cardiovascular events, hypertension, bleeding, diarrhea, and rash through dose-modification strategies that have become preferred over drug switching, particularly for ibrutinib, where robust long-term data support maintained efficacy with dose reductions from 420 mg to 280 mg daily, though similar dose reduction evidence is less established for second-generation BTKis like acalabrutinib and zanubrutinib.

Panelists discuss how CLL treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while addressing the management of BTKi class effects including cardiovascular events, hypertension, bleeding, diarrhea, and rash that typically occur early in treatment, noting that while second-generation BTKis may have slightly improved tolerability profiles compared with ibrutinib, most annoying adverse effects like arthralgias, cramps, and fatigue develop tachyphylaxis over time, with bleeding complications and late-onset dyskinesias being among the most challenging adverse events to manage across all BTKis.

Panelists discuss how CLL treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while addressing the management of BTKi class effects including cardiovascular events, hypertension, bleeding, diarrhea, and rash that typically occur early in treatment but can sometimes develop later, with dose-reduction strategies being effective for maintaining efficacy while managing tolerability across first- and second-generation BTKis.

Panelists discuss how CLL treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while noting that ibrutinib-venetoclax combinations may still have advantages due to increased venetoclax exposure and deeper responses, particularly as the field moves toward time-limited therapies that reduce long-term toxicities and financial burden.

Panelists discuss how treatment selection in CLL has evolved from universal single-agent BTKi use to a more personalized approach that considers patient-specific factors like IGHV mutation status, TP53 mutations, and 17p deletions, with growing excitement about emerging fixed-duration oral doublet therapies combining BTKis with BCL-2 inhibitors that may offer superior efficacy while reducing long-term toxicities and financial burden compared with continuous monotherapy approaches.

Panelists discuss how shared decision-making approaches in CLL treatment should balance BTKi selection with patient-specific risk features, particularly emphasizing the preference for BTKis over venetoclax-based therapy in high-risk patients with 17p deletion, while noting that approximately 20% of patients still receive outdated chemoimmunotherapy despite newer targeted treatments being available since 2016.

Panelists discuss how emerging therapies including BTK degraders, bispecific antibodies, and novel BCL-2 inhibitors represent exciting future treatment options for managing CLL patients across different lines of therapy.

Panelists discuss how bridging therapy with BTK inhibitors may optimize CAR T-cell outcomes by controlling bulky disease during manufacturing, with ibrutinib showing specific benefits for T-cell function enhancement.

Panelists discuss how lisocabtagene maraleucel (liso-cel) CAR T-cell therapy shows promise in heavily pretreated CLL patients, particularly younger patients with high-risk disease features who can achieve durable remissions.

Panelists discuss how the positive BRUIN CLL-321 phase 3 trial results support pirtobrutinib use after covalent BTK inhibitor exposure and consider its role in second-line versus third-line treatment sequencing.

Panelists discuss how clinical trial data supports switching between different covalent BTK inhibitors for intolerance management, with 60-70% of patients experiencing resolution of the original toxicity.

Panelists discuss how to define true BTK inhibitor intolerance versus manageable side effects and describe successful strategies for switching between covalent BTK inhibitors to maintain treatment efficacy.

Panelists discuss how retreatment with venetoclax may be appropriate in certain scenarios despite prior exposure, though continuous BTK inhibitor therapy is often preferred for patients with high-risk disease features.

Panelists discuss how to manage BTK inhibitor-related adverse events including atrial fibrillation, bleeding, and gastrointestinal toxicities through dose modifications, supportive care, and potential drug switching strategies.

Panelists discuss how sequencing therapies becomes challenging when using combination regimens like acalabrutinib-venetoclax in frontline treatment, requiring careful consideration of retreatment strategies and resistance mutation testing.

Panelists discuss how they approach prognostic marker testing at relapse, the importance of ruling out Richter's transformation, and timing of treatment initiation based on disease characteristics and progression patterns.

Panelists discuss how a patient with CLL with initially low-risk disease and mutated IGHV unexpectedly relapsed early after receiving venetoclax-obinutuzumab treatment with acquisition of high-risk features, presenting unique treatment challenges.

Closing out their discussion on novel treatment strategies in CLL, expert hematologist-oncologists address unmet needs and future directions in care.

An in-depth review of novel therapeutic targets making their way into clinical trials for patients with chronic lymphocytic leukemia.

Following their discussion on novel therapeutic agents in chronic lymphocytic leukemia, panelists consider how these agents might be sequenced for optimal efficacy.

Expert perspectives on the novel use of ant-CD20 therapy as first-line or combination treatment in chronic lymphocytic leukemia.

Key opinion leaders provide their perspective on the optimal management of high-risk chronic lymphocytic leukemia with novel therapeutic agents.

Clinical trial updates evaluating the combination of venetoclax with second-generation BTK inhibitors acalabrutinib and zanabrutinib, respectively.

Key updates from clinical trials evaluating the combination of venetoclax and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.

Centering focus on the relapsed/refractory setting of CLL, panelists consider the use of fixed-duration venetoclax following updated clinical trial data in this setting.

Expert perspectives on the role of non-covalent BTK inhibitors in managing patients diagnosed with chronic lymphocytic leukemia.

A panel of key opinion leaders elucidates real-world data with BTK inhibitors in CLL and considers the importance of patient-reported outcomes on quality of life.

Comprehensive perspectives on clinical factors that help to inform the selection of appropriate BTK inhibitor therapy for patients with chronic lymphocytic leukemia.