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Can the NOTCH Network Be Used to Refine Risk Stratification in CLL?

By: Myles Starr
Posted: Friday, August 27, 2021

In patients with chronic lymphocytic leukemia (CLL), activation of NOTCH receptors appears to have a negative impact on the time to first treatment. According to Paolo Sportoletti, PhD, of the Institute of Hematology-Centro di Ricerca Emato-Oncologica at the University of Perugia, Italy, and colleagues, focusing on different components of the NOTCH network may prove to be of use in refining risk stratification for patients with this hematologic malignancy.

“Understanding of the NOTCH network in CLL may not only help to refine prognosis, but also expand therapeutic strategies based on the use of single anti-NOTCH molecules or their combination with new drugs,” the study investigators commented in Frontiers in Oncology.

Western blot analysis of the cleaved (Val1744) intracellular domain of NOTCH1 (ICN1) was performed on the blood of 163 patients with CLL. There was ICN1 expression in 120 of those tested. In the ICN1-positive group, 52.5% had NOTCH1-mutated and 47.5% had NOTCH1 wild-type disease. According to the authors, the definition of mutated or wild type was “based on the NOTCH1 allelic frequency (AF) assigned by droplet digital polymerase chain reaction: patients with mutated disease had an AF > 0.03%, whereas patients with wild-type disease had an AF ≤ 0.03%.”

Although the time to first treatment was shorter for the group that had NOTCH1 mutations compared with the NOTCH1 wild-type group (80 vs. 131 months, P = .04), assessment of the prognostic significance of ICN1 activation revealed that all ICN1-positive patients had reductions in the time to first treatment compared with ICN1-negative patients (67 vs. 154 months; P < .05). These findings suggest that NOTCH1 activation, both mutated and wild type, may prove to be a negative prognosticator in CLL. Overall survival rates between those with ICN1-positive or -negative disease were similar. Co-expression of ICN2 and JAG1 with ICN1 was analyzed, but larger studies with more patients are needed to confirm whether their co-expression is detrimental to patients with CLL.

Disclosure: The study authors reported no conflicts of interest.



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