The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients

Guglielmelli, Paola, Lasho, Terra L., Rotunno, Giada, Score, Joannah, Mannarelli, Carmela, Pancrazzi, Alessandro, Biamonte, Flavia, Pardanani, Animesh, Zoi, Katerina, Reiter, Andreas, Duncombe, Andrew, Fanelli, Tiziana, Pietra, Daniela, Rumi, Elisa, Finke, Christy, Gangat, Naseema, Ketterling, Rhett P., Knudson, Ryan A., Hanson, Curt A., Bosi, Alberto, Pereira, Arturo, Manfredini, Rossella, Cervantes, Francisco, Barosi, Giovanni, Cazzola, Marie, Cross, Nicholas C. P., Vannucchi, Alessandro M. and Tefferi, Ayalew (2014) The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia, 28 (9), 1804-1810. (doi:10.1038/leu.2014.76). (PMID:24549259)

Abstract

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of five 'prognostically-detrimental' mutated genes (ASXL1, EZH2, SRSF2, IDH1/2). Herein, we evaluate the additional prognostic value of the 'number' of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had 2 or more mutated genes. The presence of 2 or more mutations predicted the worst survival: median 2.6 years (HR 3.8, 95%CI 2.6-5.7) vs 7.0 years (HR 1.9, 95%CI 1.4-2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of IPSS (HR 2.4, 95% CI 1.6-3.6) and DIPSS-plus (HR 1.9, 95% CI 1.2-3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5-10.7), also Mayo validated. CALR mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the 'number' of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.

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Contributors

Author: Nicholas C. P. Cross

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