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NOTCH1 Mutation in CLL and Response to Ibrutinib

By: Lauren Harrison, MS
Posted: Wednesday, October 14, 2020

According to a recent study, patients with NOTCH1-mutated chronic lymphocytic leukemia (CLL) treated with ibrutinib appear to have tumor cells with defective apoptosis and lower nodal shrinkage. This led to a shorter progression-free and overall survival. The findings were reported by Valter Gattei, MD, of the Centro Di Riferimento Oncologico di Aviano in Aviano, Italy, and colleagues in Haematologica.

“The therapeutic options for NOTCH1-mutated patients could be represented by either new small molecules combination approaches or from antibodies targeting NOTCH1,” concluded the authors.

This study retrospectively analyzed data from 180 patients with CLL treated with 420 mg of ibrutinib between 2014 and 2019 at three different centers in Italy. The researchers then looked for explanations regarding patient outcomes, including mutations in NOTCH1 and the ratio between Bax and Bcl-2. The population included 65 patients with mutated NOTCH1. Ibrutinib therapy was stopped in 73 patients for either disease progression or adverse events.

Mutations in the NOTCH1 gene were associated with a Bax/Bcl-2 ratio of less than 1.5 and an expression of CD49d. In addition, mutations in NOTCH1 were associated with reduced redistribution lymphocytosis. After 3 months on ibrutinib, the mean peripheral lymphocyte percentage change was 14% in patients with NOTCH1 mutations and 54% in patients with wild-type NOTCH1. Patients with this mutation also had an inferior nodal response to ibrutinib at 6 months compared with patients with wild-type NOTCH1.

These findings combined to produce a significant shortening of progression-free survival (34%) and overall survival rates (76%) among patients with NOTCH1 mutations. A subset of patients with the mutation and a lower Bax/Bcl-2 ratio had the worst progression-free and overall survival. Multivariate analysis of progression-free and overall survival was used to confirm that NOTCH1 mutations may be considered an independent prognosticator in patients with CLL.

Disclosure: The authors reported no conflicts of interest.



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