BRIEF RESEARCH REPORT article
Front. Oncol.
Sec. Hematologic Malignancies
This article is part of the Research TopicPredicting Prognosis in Chronic Lymphocytic Leukemia in the Contemporary Targeted Therapy Era: Where Do We Stand?View all 3 articles
Prognostic and Predictive Impact of NOTCH1 Mutations in Patients with Chronic Lymphocytic Leukemia: A Tertiary Single-Center Experience
Provisionally accepted
Mattia D'Antiga1
Andrea Serafin1Francesco Angotzi1Alessandro Cellini1Arianna Bevilacqua1Giovanni Leone1Nicolò Danesin1Chiara Adele Cavarretta1
Francesco Piazza1
Erich Piovan1Laura Bonaldi2
LIVIO TRENTIN1
ANDREA VISENTIN1*- 1University of Padua, Padua, Italy
- 2Istituto Oncologico Veneto IRCCS, Padua, Italy
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
NOTCH1 mutations (NOTCH1m) occur in 6-12% of newly diagnosed chronic lymphocytic leukemia (CLL) patients, increasing to 15-20% in relapsed cases. Despite their clinical relevance, the independent prognostic impact of NOTCH1m remains controversial, particularly in the era of targeted therapies, and routine testing has not been universally adopted. We conducted a retrospective, real-world study of 271 consecutive CLL patients treated at our institution between 1999-2023. We evaluated the association of NOTCH1m with clinical outcomes and response to different treatment modalities, including chemoimmunotherapy (CIT), Bruton's tyrosine kinase inhibitors (BTKi), and venetoclax-based regimens. Primary endpoints included time to first treatment (TTFT), time to second treatment (TT2T), time to next treatment (TTNT), and overall survival (OS). NOTCH1m were detected in 38/271 (14%) patients, predominantly the c.7541_7542delCT deletion (84%). After a median follow-up of 118 months, NOTCH1m patients demonstrated significantly shorter OS compared to NOTCH1 wild-type (NOTCH1wt) patients (244 vs 293 months, HR 1.92, p=0.032), but this was not confirmed in a COX multivariate analysis where immunoglobulin heavy-chain variable region (IGHV) resulted the independent prognostic variable. Importantly, 44% of Richter transformation cases harbored NOTCH1m. Among NOTCH1m patients, targeted therapies showed superior TT2T compared to CIT (NR vs 48 months, p=0.024). No significant difference was observed in TTFT or TTNT between NOTCH1m and wild-type patients. In conclusion NOTCH1m are associated with adverse prognosis in CLL, primarily due to increased risk of Richter transformation. Our findings support incorporating NOTCH1 mutational analysis into routine clinical practice for improved risk stratification and treatment selection.
Keywords: CLL, NOTCH1, overall survival, Prognosis factors, target therapy
Received: 16 Oct 2025; Accepted: 11 Dec 2025.
Copyright: © 2025 D'Antiga, Serafin, Angotzi, Cellini, Bevilacqua, Leone, Danesin, Cavarretta, Piazza, Piovan, Bonaldi, TRENTIN and VISENTIN. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: ANDREA VISENTIN
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.