Potential Prognostic Markers in CLL: NOTCH1 Pathway Mutations
Posted: Friday, August 23, 2019
Since NOTCH1 is among the most frequently mutated genes in chronic lymphocytic leukemia (CLL) and is a marker of aggressive disease and poor prognosis, would other mutations in the NOTCH1 signaling pathway serve as similar markers? The answer appears to be yes. Researchers evaluated the time to first treatment in patients with mutations compared with those who were wild type for NOTCH1, MED12, FBXW7, and SPEN and reported their results at the 2019 American Society for Clinical Oncology (ASCO) Annual Meeting (Abstract 7524).
John N. Allan, MD, of Weill Cornell Medicine, New York Presbyterian Hospital, in New York, and colleagues undertook a single-center retrospective database review of 506 patients diagnosed with CLL between 1980 and 2018. All underwent whole-exome profiling between 2015 and 2018 with a lymphoid-specific, 75-gene, next-generation sequencing panel.
About 24% of patients (121/506) had at least one mutation in the NOTCH1 signaling pathway. Compared with those with no such mutation, they had a shorter time to first treatment (median 3.93 vs. 5.02 years; P = .002). The patients with mutations also had higher rates of CD38 positivity (40.9% vs. 22.9%; P ≤ .001), trisomy 12 (36.0% vs. 15.8%; P ≤ .001), and IGVH-unmutated status (71.3% vs. 44.1%; P ≤ .001). In addition, those with such mutations were diagnosed at an older age (62.0 vs. 60.0 years; P = .04). IGVH-unmutated status and CD38 positivity remained independently predictive for time to first treatment.
“NOTCH1-mutated patients have poor response to chemoimmunotherapy,” noted Dr. Allan and co-investigators. “Future research [could] determine whether mutations in MED12, FBXW7, or SPEN may also predict for poor response to front-line chemoimmunotherapy or novel agents.”
Disclosure: The study authors’ disclosure information may be found at coi.asco.org.
