Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients

Abstract

The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis‐free survival (MFS) in WHO‐defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy (n = 718); Mayo Clinic, USA (n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy (n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3–4.9), male sex (2.1, 1.2–3.9), palpable splenomegaly (2.1, 1.2–3.9), CALR 1/1‐like or MPL mutation (3.4, 1.9–6.1) and JAK2V617F variant allele frequency > 35% (4.2, 1.6–10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: “high molecular risk” category included patients with JAK2V617F VAF >35%, CALR type 1/1‐like or MPL mutations; all other driver mutation profiles were assigned to “low molecular risk” category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years (p < 0.001; HR 6.1; 95% CI 3.2–11.7); Mayo Cohort, 16% vs. 7% at 10 years and 44% vs. 25% at 20 years (p < 0.001; HR 2.5; 95% CI 1.6–4.1); and Rome cohort 7.8% vs. 4.6% at 10 years and 31.2% vs. 7.1% at 20 years (p = 0.007, HR 2.7; 95% CI 1.3–5.8). The present study provides practically useful risk signals for fibrotic transformation in ET and facilitates identification of patients who require close monitoring and appropriate counseling.

The international consensus classification of myeloid neoplasms and acute Leukemias: myeloproliferative neoplasms

“…In particular, the association of TP53 mutations and leukemic transformation in ET is underscored 29 . A more recent study included 1607 WHO‐defined ET patients from three independent centers of excellence and showed a higher risk of fibrotic progression in patients harboring JAK2 V617F allele burden >35% and CALR type 1/like or MPL mutations 30 ; in the particular study, among the 479 cases from the Mayo Clinic, fibrotic progression was documented in 16% versus 7% at 10 years and 44% versus 25% at 20 years, in the presence versus absence of these high risk molecular markers 30 . Driver mutational status has not been shown to predict survival in ET 49 but JAK2 mutations in ET have been associated with increased risk of thrombosis, leading to the development of IPSET‐thrombosis (see below), a globally applicable risk model for thrombosis in ET 31,32 …”

“…As is the case with fibrotic transformation rates, blast transformation rates are also expected to be higher (2%) in younger patients due to long disease duration 47 . Integration of molecular information in risk assessment of progression to post‐ET MF (Table 3) was recently exploited 30 . Although in post‐ET MF the most frequently used treatment remains HU, an increase in the use of the JAK1/2 inhibitor ruxolitinib has to be noted 48 .…”

Towards a Personalized Definition of Prognosis in Philadelphia-Negative Myeloproliferative Neoplasms

“…Haider et al showed a high risk of fibrotic progression in MPL-positive ET [48]. Recently, type 1/type 1-like CALR and MPL were confirmed to be associated with reduced SMF-FS [49]. In the same paper, within JAK2V617F positive cases, those with AB > 35% have a higher risk of evolution [49].…”

“…Recently, type 1/type 1-like CALR and MPL were confirmed to be associated with reduced SMF-FS [49]. In the same paper, within JAK2V617F positive cases, those with AB > 35% have a higher risk of evolution [49]. As for M-GVs, deep sequencing analysis showed that somatic mutations in at least one gene among SH2B3, SF3B1, TP53, IDH2, EZH2, and mostly U2AF1 were associated with shorter SMF-FS [39].…”

“…Apart from the above evidence, in clinical practice, it could be useful to perform a bone marrow examination in ET and PV patients that develop anyone of the minor criteria for SMF diagnosis to recognize it earlier [3]. Besides, driver mutation signature in ET and JAK2V617F AB in PV could be used to establish a genotype-driven follow-up [4,49,55]. Information on the predictive role of M-GVs such as splicing mutations is growing, but to date, there is no clear indication for routinely performing NGS in PV/ET and tailoring patients' monitoring on its results.…”