ESH CLL 2022 | The role of NOTCH1 mutation in CLL

NOTCH1 mutation is one of the most common mutations found in CLL, with about 10 to 15% of patients having a NOTCH1 mutation. Interestingly, there are other mutations outside of NOTCH1 in other regulatory proteins that seem to have a similar effect on NOTCH1 signaling, thereby increasing it that we find also in CLL but at much lower rates. In general, I think the NOTCH1 signaling pathway is a major pathway that CLL utilizes in order to proliferate and survive and it does seem to associate with more aggressive and more proliferative disease.

Many studies have shown early time to first treatments. When we were using chemo immunotherapy, NOTCH1 mutations identify patients who will do inferior based on certain approaches, and the nice thing is, is that we have now been able to show that NOTCH1 mutations, while predicting a course prior to therapy that might be a little bit more aggressive, all current evidence shows that when you use novel therapeutics like BTK inhibitors, BCL2 inhibitors, et cetera, this poor risk prognosis seems to be overcome and those patients with NOTCH1 mutations seem to be doing just as well as everyone else and it’s somewhat lost its prognostic significance in terms of identifying high-risk CLL once treatment starts.

With that said, it does associate with aggressive disease. Patients do need treatment sooner. It does associate with other high-risk features, and one of the other things that we worry about in patients with NOTCH1 mutations is that they are at higher risk for transformation seemingly and, thus, we need to monitor them closely. I think we do need to think about NOTCH1 mutated CLL a little bit differently than other patients that don’t have this mutation as it does identify higher risk disease.