Mutations of the Exportin 1 (XPO1) Gene Predict Shorter Time to First Treatment in 1092 Early Stage Chronic Lymphocytic Leukemia Patients. Α Training/Validation Study

Background. Approximately 70% of newly diagnosed chronic lymphocytic leukemia (CLL) patients present in early Binet or Rai stage, may never require treatment, and may have a life expectancy similar to that of the general population. Two independent and recent studies have identified the clinical and immunogenetic variables associated with shorter time to first treatment (TTFT) in Binet A and Rai 0 CLL (Condoluci et al., Blood 2020; Cohen et al., Haematologica 2020). However, the clinical impact of gene mutations in predicting TTFT is not completely understood. Purpose. Using a training/validation approach, we aimed at identifying new molecular biomarkers that may predict early treatment requirement and may help clinicians to better plan the watch and wait strategy in asymptomatic early stage CLL patients. Methods. The training cohort included 295 CLL in Binet A stage who did not require treatment for at least 3 months after diagnosis. The two validation multicenter cohorts included 402 treatment-naïve Binet A CLL patients (Binet A validation cohort) and 395 untreated Rai 0 CLL patients (Rai 0 validation cohort), respectively. In the training cohort, tumor genomic DNA was isolated from peripheral blood mononuclear cells at the time of diagnosis and was analyzed in the coding exons plus splice sites of the most frequently mutated genes in CLL with a next-generation-sequencing (NGS) approach using a variant allele frequency (VAF) threshold of 5%. In the validation series, the XPO1 gene (exons 15 and 16) was analyzed by NGS or by Sanger sequencing. The primary endpoint was TTFT defined as the time interval between the date of CLL diagnosis and the date of first CLL treatment. Results. In the training cohort, NGS mutational analysis showed that XPO1 was mutated in 7 (2.4%) patients. In univariate analysis, trisomy 12 (HR 2.42; 95% CI 1.43-4.15; p=0.001), unmutated IGHV genes (HR 4.51; 95% CI 2.83-7.05; p