Prognostic and predictive impact of NOTCH1 mutations in patients with chronic lymphocytic leukemia: a tertiary single-center experience

NOTCH1 mutations (NOTCH1^m) 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 NOTCH1^m remains controversial, particularly in the era of targeted therapies, and routine testing has not been universally adopted. A retrospective, real-world study of 271 consecutive CLL patients treated at our institution was conducted between 1999 and 2023. The association of NOTCH1^m with clinical outcomes and response to different treatment modalities, including chemoimmunotherapy (CIT), Bruton's tyrosine kinase inhibitors (BTKi), and venetoclax-based regimens, was evaluated. Primary endpoints included time to first treatment (TTFT), time to second treatment (TT2T), time to next treatment (TTNT), and overall survival (OS). NOTCH1^m were detected in 38/271 (14%) patients, predominantly the c.7541_7542delCT deletion (84%). After a median follow-up of 118 months, NOTCH1^m patients demonstrated significantly shorter OS compared to <i>NOTCH1</i> wild-type (NOTCH1^wt) 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 as the independent prognostic variable. Importantly, 44% of Richter transformation cases harbored NOTCH1^m. Among NOTCH1^m 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 NOTCH1^m and wild-type patients. In conclusion, NOTCH1^m are associated with adverse prognosis in CLL, primarily due to increased risk of Richter transformation. Our findings support incorporating <i>NOTCH1</i> mutational analysis into routine clinical practice for improved risk stratification and treatment selection.