Susan O’Brien, 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.

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

Exciting novel-based treatment strategies being investigated in chronic lymphocytic leukemia.

Implications for treating chronic lymphocytic leukemia with small molecule combination regimens in the frontline setting.

The rationale for investigating and using PI3K inhibitors to treat chronic lymphocytic leukemia.

Susan O’Brien, MD, and Anthony Mato, MD, MSCE, describe their preferences for treating newly diagnosed chronic lymphocytic leukemia based on disease presentation and patient variables.

The rationale for integrating CD20 monoclonal antibody therapy into the frontline setting of chronic lymphocytic leukemia.

Frontline therapies available to treat newly diagnosed high-risk chronic lymphocytic leukemia, and the rationale for selecting a targeted therapy versus chemoimmunotherapy as initial treatment.

Reactions to an atypical diagnosis of high-risk chronic lymphocytic leukemia in a 61-year-old man.