Mutation‐enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera

Abstract

Survival prediction in essential thrombocythaemia (ET) and polycythaemia vera (PV) is currently based on clinically-derived variables; we examined the possibility of integrating genetic information for predicting survival. To this end, 906 molecularly-annotated patients (416 Mayo Clinic; 490 University of Florence, Italy), including 502 ET and 404 PV, were recruited. Multivariable analysis identified spliceosome mutations to adversely affect overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival; TP53 mutations predicted leukaemic transformation in ET; "adverse" mutations occurred in 51 (10%) ET and 8 (2%) PV patients. We confirmed the independent survival effect of adverse mutations [hazard ratio (HR) 2Á4, 95% CI 1Á6-3Á5], age >60 years (6Á6, 4Á6-9Á7), male sex (1Á8, 1Á3-2Á4) and leukocytosis ≥11 9 10 9 /l (1Á6, 1Á1-2Á2), in ET, and adverse mutations (7Á8, 3Á1-17Á0), age >67 years (5Á4, 3Á6-8Á1), leukocytosis ≥15 9 10 9 /l (2Á8, 1Á8-4Á2) and thrombosis history (2Á0, 1Á4-2Á9), in PV. HR-based risk point allocation allowed development of three-tiered mutation-enhanced international prognostic systems (MIPSS) which were validated in both cohorts and performance was shown to be superior to conventional scoring systems. Spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression. TP53 mutations predict leukaemic transformation in ET.

Impact of Integrated Genetic Information on Diagnosis and Prognostication for Myeloproliferative Neoplasms in the Next-Generation Sequencing Era

“…We also found that RUNX1 mutations were predictive of leukemic transformation. This nding is consistent with previous studies that demonstrated that RUNX1 mutations had adverse impacts on leukemia-free survival in PV and ET patients [16,17] and that RUNX1-mutated PMF patients had inferior overall survival and leukemia-free survival [35]. Another important gene was ASXL1; mutations in this gene are typically associated with brotic progression.…”

“…Results of recent studies indicate that gene mutations are signi cant prognostic factors in MPN and mutation-enhanced prognostic systems for MPNs have been introduced [14][15][16]. These systems can be used to determine risk for survival as well as disease progression, including leukemic transformation and brotic progression [17,18].…”

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

“…Furthermore, they also suggested the independent survival effect of adverse mutations, age >67 years, leukocyte count ≥15 × 10 9 /L, and previous thromboses in PV. A subsequent hazard ratio (HR)-based risk point allocation allowed the development of a three-tiered mutation-enhanced international prognostic system (MIPSS) whose performance was shown to be superior to other conventional scoring systems [39].…”

Novel Concepts of Treatment for Patients with Myelofibrosis and Related Neoplasms

“…Beyond cytopenias, as patients with MF live longer with the disease, clinicians have learned to manage other issues associated with long-term use of ruxolitinib, such as weight gain, hyperlipidemia and infectious risks. Improvements in our understanding of the molecular events underlying disease pathogenesis and progression, particularly the role of “non-driver” mutations, have not only enabled more refined prognostication [ 114 , 115 , 116 , 117 ], but may also inform therapeutic choices. For example, spleen response to ruxolitinib in MF is inversely correlated with the number of non-driver mutations; patients with ≥3 mutations have a shorter time to treatment discontinuation and OS than those with fewer mutations [ 118 ].…”