By determining the relationship between a set of somatic mutations and established prognostic clinical features with time-to-first treatment (TTFT), study researchers identified potential early drivers of disease among treatment-naive chronic lymphocytic leukemia (TN CLL) patients. The study findings were recently published in the British Journal of Haematology.1

The study included 384 TN CLL patients, from which 196 peripheral blood samples and 188 bone marrow samples were obtained and interrogated using a targeted gene analysis with a 29-gene panel. The targeted gene analysis revealed that 148 patients (38.5%) had none of the 29 gene mutations, and the most frequently mutated genes were ATM (15.6%), NOTCH1 (15.6%), SF3B1 (14.3%), and TP53 (11.2%).

To determine the significance of a particular gene, patients with 1 mutated gene were compared with those with no detectable mutations. ATM (P <.001), BIRC3 (P <.001), CXCR4 (P <.001), NOTCH1 (P <.001), SF3B1 (P =.02), and SPEN (P =.04) were associated with significantly shorter median TTFT compared with patients without mutations.

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A univariate analysis showed that several mutated genes and clinical features were correlated with shorter TTFT, including mutated ATM (P <.001), mutated NOTCH1 (P <.001), mutated SF3B1 (P =.002), unmutated immunoglobulin heavy chain variable region (IGHV) (P <.001), chromosome 11q deletion (P <.001), trisomy 12 (P <.001), and advanced Rai (P =.05) and Binet (P <.001) stages.

The only 2 variables, however, to maintain statistical significance in a multivariate analysis were mutated ATM (hazard ratio [HR], 2.13; 95% CI, 1.40–3.25; P <.001) and unmutated IGHV (HR, 2.40; 95% CI, 1.40–3.24; P <.001).

“In a comprehensive analysis of all known clinical prognostic factors and 29 gene mutations in patients with TN CLL, mutated ATM and unmutated IGHV were the strongest predictors of TTFT,” the study authors wrote. “These results suggest that these two abnormalities are the most robust drivers of early CLL disease and progression.”


Hu B, Patel KP, Chen HC, et al. Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients [published June 26, 2019]. Br J Haematol. doi: 10.1111/bjh.16042