XPO1 mutations are a novel predictor of shorter time to first treatment in early stage CLL patients

In approximately 70% of newly diagnosed cases, CLL presents at an early clinical stage and is managed with a watch & wait strategy. Until now, few clinical and molecular inform on the risk of treatment requirement. On these grounds, we aimed at identifying new molecular markers that may predict early treatment requirement and may help clinicians to better plan the watch & wait strategy in asymptomatic early stage CLL patients. 295 Binet A CLL patients who referred to our institution were subjected to next-generation-sequencing (NGS) in a panel of recurrently mutated genes in CLL. Two validation multicenter cohorts of 402 treatment naïve Binet A CLL patients (Binet A validation cohort) and 395 untreated Rai 0 CLL patients (Rai 0 validation cohort) were also included and analyzed for XP01 mutations. The primary endpoint was time to first treatment (TTFT). In the training cohort, NGS mutational analysis showed that XP01 was mutated in 7 (2.4%) patients. In univariate analysis, trisomy 12 (p=0.001), unmutated IGHV genes (p<0.0001) and mutations of XP01 (p<0.0001), NOTCHI (p<0.001) and SF3B1 (p=0.022) were associated with a shorter TTFT. By multivariate analysis, XPOI mutations (p=0.002) and unmutated IGHV genes (p<0.0001) maintained an independent association with a shorter TTFT. XPO1 mutational analysis was subsequently investigated in 2 independent multicenter cohorts of early stage CLL patients. In the Binet A validation cohort (N=402 patients), XPO1 was mutated in 15 (3.7%) patients and was associated with a shorter TTFT (p=0.004). Similarly, also in the Rai 0 validation cohort, (N=395 patients), XP01 was mutated in 8 (2.0%) patients and was associated with a shorter TTFT (p<0.001). By combining the training and the validation cohorts (N=1092 patients), a total of 30 somatically acquired XP01 mutations were identified (2.7% of patients). More precisely, 27 (90.0%) mutations affected XP01 codon E571 and 3 (10.0%) codon D624. From a clinical perspective, patients carrying either XPO1 E571 or D624 mutations showed superimposable outcome in terms of TTFT (p=0.345). Based on these results, XP01 mutational analysis might be incorporated in other prognostic scores and help clinicians to refine the management of the watch and wait strategy for early stage CLL.