GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis

Abstract

International collaborations over the years have produced a series of prognostic models for primary myelofibrosis (PMF), including the recently unveiled mutation-enhanced international prognostic scoring systems for transplant-age patients (MIPSS70 and MIPSS70-plus). In the current study, we considered the feasibility of a genetically inspired prognostic scoring system (GIPSS) that is exclusively based on genetic markers. Among 641 cytogenetically annotated patients with PMF and informative for previously recognized adverse mutations, multivariable analysis identified “VHR” karyotype, “unfavorable” karyotype, absence of type 1/like CALR mutation and presence of ASXL1, SRSF2, or U2AF1Q157 mutation, as inter-independent predictors of inferior survival; the respective HRs (95% CI) were 3.1 (2.1–4.3), 2.1 (1.6–2.7), 2.1 (1.6–2.9), 1.8 (1.5–2.3), 2.4 (1.9–3.2), and 2.4 (1.7–3.3). Based on HR-weighted risk points, a four-tiered GIPSS model was devised: low (zero points; n = 58), intermediate-1 (1 point; n = 260), intermediate-2 (2 points; n = 192), and high (≥3 points; n = 131); the respective median (5-year) survivals were 26.4 (94%), 8.0 (73%), 4.2 (40%), and 2 (14%) years; the model was internally validated by bootstrapping and its predictive accuracy was shown to be comparable to that of MIPSS70-plus. GIPPS offers a low-complexity prognostic tool for PMF that is solely dependent on genetic risk factors and, thus, forward-looking in its essence.

Genetically inspired prognostic scoring system (GIPSS) outperforms dynamic international prognostic scoring system (DIPSS) in myelofibrosis patients

“…The MIPSS70 was compared with IPSS, MIPSS70-plus to DIPSS-plus and GIPSS to MIPSS70-plus. 6,7 A high rate of concordance was seen in these analyses, though comparison of MIPSS70 to IPSS compares a 3-tiered model to a 4-tiered model making concordance assessments more difficult. Moreover, concordance should be expected in these cases as they share many prognostic variables.…”

“…Numerous prognostic scoring systems have been developed and validated in an effort to better identify patients with high-risk disease who would most benefit from AHSCT. 1,[4][5][6][7][8][9] Historically, prognostic systems in myelofibrosis (MF) have relied solely upon clinical variables with arbitrary cutpoints often utilized to separate "high" from "low." The Lille score, developed in 1996, stratified patients into three risk groups based solely on hemoglobin and white blood cell count.…”

“…The progressive utilization of molecular information culminated with the publication of the genetically inspired prognostic scoring system for primary myelofibrosis (GIPSS) which relies solely on genomic inputs to stratify patients into low, intermediate-1 (int-1), intermediate-2 (int-2), and high risk categories. 7 While the development of an ostensibly disease-specific prognostic model is certainly a substantive achievement, the lack of shared prognostic inputs with traditional models (eg, IPSS, DIPSS, etc.) raises the potential for significant disagreement between models.…”

Myeloproliferative neoplasms: Diagnostic workup of the cythemic patient

“…Other frequently co‐occurring mutations affect genes involved in splicing, including SF3B1 , U2AF1 , ZRSR2, and SRSF2 . Mutations in ASXL1 , EZH2, and SRSF2 are associated with poor survival in PMF; furthermore, ASXL1 mutations confer poorer survival independent of the Dynamic IPSS (DIPSS)‐plus model, which incorporates cytogenetic but not mutational risk . Similarly, mutations in TET2 lead to reduced overall survival and leukemia‐free survival in a cohort of 197 patients …”

“…Mutations in ASXL1, EZH2, and SRSF2 are associated with poor survival in PMF; furthermore, ASXL1 mutations confer poorer survival independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic but not mutational risk. 20,21 Similarly, mutations in TET2 lead to reduced overall survival and leukemia-free survival in a cohort of 197 patients. 22 karyocyte morphology, which range from small "dwarf" cells in CML to clustered "bulbous" megakaryocytes in PMF and large "staghorn" megakaryocytes in ET.…”