Overview

Although many patients with chronic lymphocytic leukemia (CLL) respond to initial therapy and the 5-year survival rate has improved, disease progression occurs. However, there is a lack of consensus on optimal treatment sequencing in CLL leading to uncertainty regarding the long-term effects of sequencing decisions on progression-free survival, overall survival, and the durability of responses in various patient subsets. Selecting the most appropriate therapy for relapsed/refractory (R/R) CLL in an individualized manner requires careful consideration of first-line therapy, disease characteristics, patient comorbidities, adverse event profiles, and goals of therapy.

Moreover, navigating the evolving R/R CLL therapeutic landscape requires a multidisciplinary team to engage and educate patients and effectively monitor and manage treatment-related adverse events (TRAEs) to improve treatment adherence.

To help clinicians mitigate barriers to adopting guideline-concordant use of novel therapies and formulate individualized, long-term treatment plans for patients with R/R CLL, this interactive practice guide interweaves education and practical guidance for easy integration of the latest evidence within daily clinical processes and workflows.

This activity is intended for community hematologists/oncologists, oncology APPs, oncology and clinical pharmacists, and other members of the multidisciplinary oncology team.

The treatment landscape for CLL has evolved considerably in the last decade, as an improved understanding of the underlying biology of CLL has led to the development and approval of novel targeted therapies, resulting in a therapeutic paradigm shift away from chemoimmunotherapy. Although there have been improved results with first-line therapy, CLL remains incurable, and a majority of patients relapse after primary treatment. Selecting the most appropriate therapy for R/R CLL in an individualized manner requires careful consideration of first-line therapy, disease characteristics, patient comorbidities, adverse event profile, and goals of therapy. The expanding number of therapy options and lack of data to guide treatment sequencing has further complicated clinical decision-making. These new therapies are also associated with a unique spectrum of adverse events, with current guidelines recommending monitoring prior to and during treatment for known toxicities. The introduction of new agents and continually emerging evidence on their use in CLL underscore the importance of regular educational updates on new data and outcomes for the multidisciplinary team.

As a result of participating in this educational activity, clinicians should be able to:
• Interpret and apply clinical trial and real-world evidence to inform optimal sequencing of therapy for R/R CLL 
• Identify and mitigate barriers impeding integration of novel therapies in accordance with guideline recommendations and in alignment with the latest scientific evidence
• Formulate individualized, long-term treatment plans for patients with R/R CLL
• Implement multidisciplinary collaboration frameworks to engage patients, personalize treatment selection, and manage TRAEs in patients with R/R CLL

• Treatment selection for R/R CLL
  o Selection of therapy in patients who are naive to targeted therapy
  o Selection of therapy for disease progression or toxicity after a covalent BTK inhibitor
  o Selection of therapy for disease progression or toxicity after venetoclax
  o Supporting clinical trial efficacy and safety data
  o Dose modification or interruption of covalent BTK inhibitors
  o Retreatment with venetoclax
  o Mechanisms of disease resistance to targeted agents
• Double refractory CLL
  o Patient outcomes
  o Available agents and clinical trial data
  o Available and emerging noncovalent BTK inhibitors
  o CAR T-cell therapy
• Personalizing treatment
• Case presentation: 67-year-old man who experiences disease progression while receiving a covalent BTK inhibitor followed by double refractory CLL

Provided by the Academy for Continued Healthcare Learning (ACHL).

Supported by an educational grant from Lilly.

On December 3, 2025, pirtobrutinib received an expanded FDA approval for use in patients with R/R CLL who have previously been treated with a covalent BTK inhibitor.