Chronic Lymphocytic Leukemia Coverage from Every Angle

NOTCH1 Regulatory Pathway Mutations: Predictive of Outcomes in CLL?

By: Joseph Fanelli
Posted: Thursday, April 22, 2021

According to correspondence published in the American Journal of Hematology, three mutations in genes associated with the transmembrane receptor NOTCH1MED12, FBXW7, and SPEN—may be linked to cases of aggressive chronic lymphocytic leukemia (CLL) that are also seen with NOTCH1-mutated CLL. John N. Allan, MD, of Weill Medical College at Cornell University, New York, and colleagues determined that these three mutations may be predictors of shorter time-to-first-treatment spans and may be associated with similar baseline factors seen in NOTCH1-mutated CLL, such as trisomy 12, CD38 positivity, and IGHV-unmutated status.

“We believe that the presence of any of these three mutations in CLL should prompt consideration of clinicians to manage patients in a similar way as they might a NOTCH1-mutated patient with CLL,” the authors concluded.

In this retrospective study, the authors evaluated 362 treatment-naive patients with CLL who were diagnosed from 1991 to 2020. All patients had undergone a targeted lymphoid-specific next-generation sequencing panel.

The authors found that of the 362 patients evaluated, 52 (14.4%) had at least one mutation in the NOTCH1 receptor gene or regulatory pathway. Specifically, 20 patients (5.5%) had mutations in NOTCH1 regulatory pathway genes, including 6 with MED12 mutations, 11 with FBXW7 mutations, and 5 with SPEN mutations. NOTCH1 mutations were seen in 34 patients (9.4%), with 2 having co-occurring NOTCH1 regulatory pathway mutations and NOTCH1 mutations.

After a median follow-up of 4.25 years, the authors found that both patients with NOTCH1 regulatory pathway mutations and NOTCH1 mutations had a significantly shorter time-to-first-treatment duration than those with wild-type mutations. No difference was observed in the time-to-first-treatment duration between patients with NOTCH1 regulatory pathway mutations and NOTCH1 mutations. Following multivariate analysis, the only independent predictors for shorter time-to-first-treatment durations were IGHV-unmutated status, deletion 11q, and TP53 distribution.

Disclosure: The authors reported no conflicts of interest.

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