Herling CD, Coombes KR, Benner A, et al. - In order to recognize treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia who are likely to achieve durable remissions with fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy, researchers constructed a gene expression signature and sought validation for it in this retrospective cohort study including 2 cohorts of treatment-naive patients (aged ≥ 18 years) with chronic lymphocytic leukaemia. They built a robust, reproducible 17-gene signature that allowed the discrimination between IGHV-unmutated patients who were likely to achieve a long-term remission after front-line FCR chemoimmunotherapy and those likely to derive benefit from alternative front-line regimens. This gene signature was validated in the validation cohort; a cause-specific hazard ratio of 1·90 was generated for patients with an unfavourable prognosis compared with those with an intermediate prognosis. For those with an unfavourable prognosis vs those with an intermediate prognosis, the median time to progression was estimated to be 39 months (IQR 22–69) and 59 months (28–84), respectively. Overall, the proposed 17-gene signature enabled the detection of a subset of treatment-naive patients who were likely to derive substantial benefit from FCR chemoimmunotherapy.