Clinical Pearls & Morning Reports
Kinase inhibitors blocking B-cell receptor signaling and the BCL2 (B-cell lymphoma 2) antagonist venetoclax have been introduced and are fundamentally changing the chronic lymphocytic leukemia (CLL) treatment landscape. Read the NEJM Review Article here.
Q: What are some of the features of CLL?
A: CLL is the most common leukemia in adults in Western countries, with a male predominance and an average age at diagnosis of 72 years. CLL is 10 to 20 times as common in Western countries as in Asia, suggesting that genetic factors, environmental factors, or both influence susceptibility to the disease. The presentation and clinical course are highly variable, ranging from asymptomatic, indolent disease that may never require therapy (in approximately 30% of patients) to active disease.
Q: In broad outlines, how has therapy for CLL evolved over time?
A: Before the introduction of the new agents, CLL therapy was based mostly on chemotherapy comprising alkylating agents, nucleoside analogues, and glucocorticoids. The addition of anti-CD20 antibodies to chemotherapy resulted in prolonged survival with both low-intensity regimens and higher-intensity regimens, and chemoimmunotherapy therefore became standard therapy before the advent of the new agents. A series of randomized trials showed better survival with the new agents (kinase inhibitors and venetoclax), leading to a decline in the use of chemoimmunotherapy.
A: The mutation status of IGHV genes influences the natural history of CLL. IGHV mutation analysis distinguishes patients whose CLL cells express mutated IGHV with 2% or greater deviation from the IGHV germline sequence (who generally have indolent disease) from patients with unmutated CLL with less than 2% deviation (who present with more active and treatment-resistant disease). These differences in clinical behavior have been linked to differences in B-cell receptor responsiveness. Unmutated CLL clones respond to various autoantigens, triggering robust B-cell receptor signaling, whereas mutated CLL cells display more selective binding to restricted antigens and less active B-cell receptor signaling. Consequently, mutated CLL clones remain stable or expand at a slower rate than clones from patients with unmutated CLL. The negative prognostic effect of unmutated IGHV is overcome when patients are treated with the new targeted agents. Long-term follow-up of patients receiving ibrutinib as frontline therapy showed that the survival of patients with unmutated CLL was excellent and similar to the survival of those with mutated IGHV.
A: Because of autoimmune side effects (hepatitis, colitis, and pneumonitis), infectious side effects (pneumocystis pneumonia and cytomegalovirus infection), and lower efficacy than the Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib and acalabrutinib), idelalisib (an isoform-selective phosphatidylinositol 3-kinase inhibitor) is not the first-choice kinase inhibitor for CLL therapy, but it is a valuable alternative for patients in whom BTK inhibitors are associated with unacceptable side effects. Venetoclax is an orally administered, potent selective inhibitor of BCL2. Venetoclax is an attractive alternative if BTK inhibitors have unacceptable side effects or if limited-duration therapy is preferred. In addition, venetoclax is active in CLL that has developed resistance to kinase inhibitors (ibrutinib or idelalisib), with an overall response in 65% of patients and a median progression-free survival of 24.7 months.