The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial

Summary Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia ( CLL ) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re‐examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL 4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5–9%, 60 (12%) had 10–14% and 11 (2%) had ≥15% prolymphocytes. We show that a higher proportion of prolymphocytes (≥10%) was independently associated with NOTCH 1 mutations ( P  = 0·006), absence of 13q deletion ( P  = 0·001), high CD 38 expression ( P  = 0·02) and unmutated IGHV genes ( P  = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ≥10% vs <10% prolymphocytes (13% vs 2%) respectively ( P  < 0·0001). ≥10% prolymphocytes was also associated with a shorter progression‐free survival (Hazard ratio [ HR ] 1·50 [95% confidence interval [ CI ]: 1·16–1·93], P  = 0·002) and overall survival ( HR 1·99 [95% CI : 1·53–2·59], P  < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease.