Impact of genotype on leukaemic transformation in polycythaemia vera and essential thrombocythaemia

<jats:title>Summary</jats:title><jats:p>The influence of driver mutations on leukaemic transformation was analysed in 1747 patients with polycythaemia vera or essential thrombocythaemia. With a median follow‐up of 7·2 years, 349 patients died and 62 progressed to acute leukaemia or myelodysplastic syndrome. Taking death as a competing risk, <jats:italic>CALR</jats:italic> genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2–0·9, <jats:italic>P</jats:italic> = 0·039], whereas <jats:italic>JAK2</jats:italic> V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9–4·6, <jats:italic>P</jats:italic> = 0·09). Myelofibrotic transformation increased leukaemic risk, except in <jats:italic>CALR</jats:italic>‐mutated patients. Next generation sequencing of 51 genes at the time of transformation showed additional mutations (median number: 3; range: 1–5) in 25 out of 29 (86%) assessable cases. Mutations (median: 1; range: 1–3) were detected in 67% of paired samples from the chronic phase. Leukaemia appeared in a <jats:italic>JAK2</jats:italic> V617F negative clone in 17 (58%) cases, eleven of them being previously <jats:italic>JAK2</jats:italic> V617F‐positive. <jats:italic>JAK2</jats:italic> V617F‐mutated leukaemia was significantly associated with complex karyotype and acquisition of <jats:italic>TP53</jats:italic> mutations, whereas <jats:italic>EZH2</jats:italic> and <jats:italic>RUNX1</jats:italic> mutations were more frequent in <jats:italic>JAK2</jats:italic> V617F‐negative leukaemia. Survival was longer in <jats:italic>JAK2</jats:italic> V617F‐unmutated leukaemia (343 days vs. 95 days, <jats:italic>P</jats:italic> = 0·003). In conclusion, <jats:italic>CALR</jats:italic> genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a <jats:italic>JAK2</jats:italic> V617F‐negative clone is <jats:italic>TP53</jats:italic> independent and shows better survival.</jats:p>