Venetoclax in the Treatment of CLL: Open Doors for the Longest Possible Maintenance of Remission Without Active Therapy
William G. Wierda from MD Anderson Cancer Center in Houston, USA, and Francesco P. Tambaro from Azienda Ospedaliera di Rilievo Nazionale Santobono-Pausilipon in Naples, Italy, evaluate in their report for the journal Blood from April 2020 the practical aspects and benefits of using venetoclax in the first-line treatment of chronic lymphocytic leukemia (CLL), as well as in cases of relapsing/refractory forms of the disease.
Options for Targeted CLL Treatment
Options for targeted CLL treatment include, besides the oral BCL-2 inhibitor venetoclax, BTK (Bruton's tyrosine kinase) inhibitors and PI3K (phosphatidylinositol-3-kinase) inhibitors. Their benefits in terms of prolonged progression-free survival (PFS) compared to chemoimmunotherapy have been demonstrated in randomized clinical trials in both the first-line treatment and relapsing/refractory CLL cases. However, studies directly comparing these targeted therapies do not yet exist. These agents differ in their target structure of action, therapeutic approach, and toxicity profiles and side effects. Currently, the prospect of a fixed duration of treatment with maintaining remission without therapy, allowing the discontinuation of continuous exposure to potentially toxic treatment, is an attractive prospect.
Venetoclax in Practice
Venetoclax offers targeted treatment that very effectively eliminates CLL, including cases with high-risk 17p deletion or TP53 mutation and cases refractory to chemoimmunotherapy. It is used in the first-line treatment as well as in patients with refractory/relapsing CLL. Safe initiation of treatment and gradual escalation of venetoclax require assessment of tumor lysis syndrome (TLS) risk and monitoring based on risk stratification. Extended treatment with a fixed duration of venetoclax is well-tolerated, sometimes causing mild myelosuppression but rarely requiring dose adjustment due to toxicity (mainly neutropenia).
Combination with anti-CD20
Response to venetoclax treatment is enhanced by adding an anti-CD20 monoclonal antibody. Evidence is available supporting the benefits of combining venetoclax with obinutuzumab in first-line CLL treatment and combining venetoclax with rituximab in relapsing CLL. Most patients treated with a venetoclax regimen achieve a state of undetectable minimal residual disease (uMRD) with a fixed duration of treatment. This opens up the possibility of maintaining remission without treatment for a period which can be very long for patients with favorable disease characteristics.
Conclusion
Current research is focusing on combining targeted agents in CLL treatment to achieve the highest possible uMRD with a short fixed duration of treatment. The cited article also provides three case studies illustrating the use of venetoclax in the treatment of CLL in clinical practice.
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Source: Wierda W. G., Tambaro F. P. How I manage CLL with venetoclax-based treatments. Blood 2020 Apr 23; 135 (17): 1421−1427, doi: 10.1182/blood.2019002841.
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