TY - JOUR
T1 - Impact of genotype on leukaemic transformation in polycythaemia vera and essential thrombocythaemia
AU - Alvarez-Larrán, Alberto
AU - Senín, Alicia
AU - Fernández-Rodríguez, Concepción
AU - Pereira, Arturo
AU - Arellano-Rodrigo, Eduardo
AU - Gómez, Montse
AU - Ferrer-Marin, Francisca
AU - Martínez-López, Joaquín
AU - Camacho, Laura
AU - Colomer, Dolors
AU - Angona, Anna
AU - Navarro, Blanca
AU - Cervantes, Francisco
AU - Besses, Carlos
AU - Bellosillo, Beatriz
AU - Hernández-Boluda, Juan Carlos
PY - 2017/9/1
Y1 - 2017/9/1
N2 - © 2017 John Wiley & Sons Ltd 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, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2–0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9–4·6, P = 0·09). Myelofibrotic transformation increased leukaemic risk, except in CALR-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 JAK2 V617F negative clone in 17 (58%) cases, eleven of them being previously JAK2 V617F-positive. JAK2 V617F-mutated leukaemia was significantly associated with complex karyotype and acquisition of TP53 mutations, whereas EZH2 and RUNX1 mutations were more frequent in JAK2 V617F-negative leukaemia. Survival was longer in JAK2 V617F-unmutated leukaemia (343 days vs. 95 days, P = 0·003). In conclusion, CALR genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a JAK2 V617F-negative clone is TP53 independent and shows better survival.
AB - © 2017 John Wiley & Sons Ltd 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, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2–0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9–4·6, P = 0·09). Myelofibrotic transformation increased leukaemic risk, except in CALR-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 JAK2 V617F negative clone in 17 (58%) cases, eleven of them being previously JAK2 V617F-positive. JAK2 V617F-mutated leukaemia was significantly associated with complex karyotype and acquisition of TP53 mutations, whereas EZH2 and RUNX1 mutations were more frequent in JAK2 V617F-negative leukaemia. Survival was longer in JAK2 V617F-unmutated leukaemia (343 days vs. 95 days, P = 0·003). In conclusion, CALR genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a JAK2 V617F-negative clone is TP53 independent and shows better survival.
KW - essential thrombocythaemia
KW - genotype
KW - myeloid leukaemia
KW - polycythaemia vera
KW - prognostic factors
U2 - 10.1111/bjh.14762
DO - 10.1111/bjh.14762
M3 - Article
VL - 178
SP - 764
EP - 771
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 5
ER -