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Novel Mutation and CLL Resistance to BTK and SYK Inhibition: Case Study

By: Lauren Harrison, MS
Posted: Friday, November 20, 2020

Although targeting various components of the B-cell receptor (BCR) pathway has been useful in the treatment of chronic lymphocytic leukemia (CLL), a recent case study highlights a novel somatic variant of PLCG2, which rendered the patient nonresponsive to ibrutinib and entospletinib. PLCG2 is a downstream target of BCR and is activated by splenic tyrosine kinase (SYK) phosphorylating the BCR. Vikram Raghunathan, MD, of the Oregon Health & Science University, Portland, published this report with colleagues in the European Journal of Haematology.

The 58-year-old male patient had peripheral flow cytometry results consistent with a diagnosis of CLL. Fluorescent in situ hybridization analysis revealed a deletion of chromosome 13q in 59% of his cells. The patient was subsequently treated with obinutuzumab for six cycles and had disease remission for 2 years. The patient was then enrolled in a clinical trial with continuous administration of the SYK inhibitor entospletinib plus six cycles of obinutuzumab. A novel variant of the PLCG2 gene with a variant allele frequency of 43% was identified at this time, along with a mutation in SF3B1, with a variant allele frequency of 34%.

Six months after entospletinib was discontinued, the patient experienced recurrence, and both the PLCG2 and SF3B1 mutations were still present. The patient was treated with ibrutinib, rituximab, cyclophosphamide, vincristine, and prednisone for six cycles. Afterward, the previously noted PLCG2 and SF3B1 mutations were still present, along with a new p53 mutation. Germline testing on buccal mucosa revealed the novel PLCG2 mutation was somatic in origin.

Researchers proposed this patient’s lack of response to both entospletinib and ibrutinib was a result of this PLCG2 mutation, possibly representing a resistance mechanism to SYK inhibition. Constitutive activity of PLCG2 may bypass the need for SYK signaling.

“The physiologic consequences of the novel variant described in this report are unknown, though it may augment calcium‐dependent BCR pathway signaling, enabling resistance to Bruton tyrosine kinase inhibition,” hypothesized the authors.

Disclosure: For full authors’ disclosures, visit onlinelibrary.wiley.com.



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