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Understanding the Role of BTK and PLCG2 Mutations in Chronic Lymphocytic Leukemia Resistance and Relapse

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Mason Walker
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Understanding the Role of BTK and PLCG2 Mutations in Chronic Lymphocytic Leukemia Resistance and Relapse

Understanding the Role of BTK and PLCG2 Mutations in Chronic Lymphocytic Leukemia Resistance and Relapse

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Chronic lymphocytic leukemia (CLL) is a common type of blood cancer characterized by the uncontrolled growth of B cells, a type of white blood cell. While several treatment options exist, including the drug ibrutinib, some patients experience resistance and relapse. Recent research has highlighted the role of genetic mutations in this resistance, particularly in the genes BTK and PLCG2, which are frequently mutated in CLL resistant to ibrutinib. This understanding prompts further investigation into the prevalence of these genetic alterations and their role in contributing to ibrutinib resistance.

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Role of BTK and PLCG2 Mutations in Ibrutinib Resistance

Studies have uncovered patterns of mutations in CLL patients treated with ibrutinib, focusing on the BTK and PLCG2 genes. These mutations are frequent and often associated with ibrutinib resistance. However, the relationship between these mutations and disease progression remains a topic of ongoing research. For instance, the majority of patients with relapsed CLL treated with zanubrutinib or ibrutinib did not acquire a BTK or PLCG2 mutation at the time of disease progression. This finding indicates that these mutations may not be the primary drivers of resistance and relapse in this population.

Implications for Treatment

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The discovery of these mutations and their potential role in CLL resistance has significant implications for treatment strategies. Understanding the impact of treatment history on the likelihood of acquiring these mutations could inform the sequencing of targeted therapies for each patient. For instance, patients treated with covalent BTK inhibitors are likely to remain sensitive to other BTK-targeting therapies, even in the presence of non-C481 mutations.

Responses to Other Therapies

Despite the potential for resistance, responses to certain therapies remain high in patients with these mutations. Data from the BRUIN trial indicates that responses on pirtobrutinib, a non-covalent BTK inhibitor, remained high in patients with baseline BTK mutations. The efficacy of pirtobrutinib in patients with both wild-type and C481 mutated CLL suggests potential strategies to overcome ibrutinib resistance.

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Progression-Free Survival with Zanubrutinib

In addition to pirtobrutinib, other therapies have demonstrated efficacy in the treatment of relapsed/refractory chronic lymphocytic leukemia. The ALPINE study found sustained superior progression-free survival of Zanubrutinib versus Ibrutinib for the treatment of relapsed/refractory CLL and small lymphocytic lymphoma. Interestingly, the study also found that acquired BTK and PLCG2 mutations may not drive progression after Zanubrutinib/Ibrutinib treatment in relapsed CLL, further underscoring the complexity of the relationship between these mutations and disease progression.

Conclusion

While BTK and PLCG2 mutations are frequently associated with ibrutinib resistance in chronic lymphocytic leukemia, their role as primary drivers of disease progression and resistance is still under investigation. Understanding these genetic alterations and their impact on treatment response is crucial for optimizing CLL management. Continued research in this area holds the potential to improve treatment strategies and patient outcomes.

Chronic Lymphocytic Leukemia
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