Role of NOTCH1 Mutations in CLL

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Deep genomic sequencing has identified recurrent mutations in the NOTCH1 proto-oncogene in approximately 5% to 10% of patients with chronic lymphocytic leukemia (CLL), explains Thomas J. Kipps, MD. Mutations in the NOTCH1 gene have been associated with rapid disease progression and inferior survival in patients with CLL.

In the CLL 8 trial of the German CLL group, the addition of rituximab to fludarabine plus cyclophosphamide did not demonstrate an improvement in progression-free survival in patients with a NOTCH1 mutation. These findings suggest that NOTCH1 could predict a lack of benefit with rituximab. However, research will need to confirm whether this observation holds true with other CD20 inhibitors.

Although not yet confirmed, NOTCH1 appears to downregulate CD20, reducing the probability of response to anti-CD20 monoclonal antibodies, Kipps suggests. Clinical studies are currently assessing the role of NOTCH1 mutations on resistance to therapy. Additionally, therapeutic approaches using agents that block NOTCH1 activation or kinase inhibitors that target B-cell receptor signaling are currently in progress.