Non–Driver Gene Mutations May Hold Predictive Value in ET and PV

A recent study suggests that non–driver mutations may hold prognostic value in essential thrombocythemia (ET) and polycythemia vera (PV), both of which are Philadelphia chromosome–negative neoplasms (Ph-MPNs) that have known driver mutations.

ET is characterized by thrombocytosis and bone marrow megakaryocytic hyperplasia, and PV is characterized by erythrocytosis with bone marrow panmyelosis. Both conditions have known driver mutations that are seen in most affected patients. For ET, these mutations include JAK2V617F, MPLW515L/K, and frameshift mutations at CALR exon 9. In PV, JAK2V617F and JAK2 exon 12 mutations are common.

Non–driver mutations are often found in another subgroup of Ph-MPNS, primary myelofibrosis (PMF), and some of these mutations are connected to poor prognosis. The current study, published in European Journal of Haematology, analyzed non–driver mutations in Japanese patients with PV and ET to determine whether they have prognostic value.

There were 264 patients with PV and 579 with ET included in the study. Compared with findings in PMF, non–driver mutation frequency was much lower in ET and PV. Overall, 31% of PV patients and 24.5% of ET patients had non–driver mutations vs 52.6% in prefibrotic PMF and 65.6% in overt PMF.

Patients with ET or PV also had fewer high–molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH2, and U2AF1) compared with PMF patients. Notably, a multivariable logistic regression analysis found that ASXL1 mutation, one of the most frequently identified among MPNs in general, was a risk factor for leukemic transformation, with an HR of 4.68 (P = .006).

Although the frequency of driver mutations overall and of HMR mutations was lower in PV and ET relative to PMF, the frequencies of TET2 and DNMT3A mutations, which have less impact, were similar across Ph-MPN subtypes.

“These results suggest that the increase of the mutation load is mainly caused by the acquisition of HMR mutations and that the functional roles of the mutations are different in view of pathogenesis and progression of Ph-MPNs,” the authors wrote. Previous research also supports this notion. They hypothesize that the lower-impact TET2 and DNMT3A mutations may contribute to the development of Ph-MPNs and that HMR mutations may play into disease progression.

The study also assessed a proposed risk-stratification tool, the mutation-enhanced international prognostic system (MIPSS), in both ET and PV. The MIPSS-ET factors in SRSF2, SF3B1, U2AF1, and TP53, and the MIPSS-PV factors in SRSF2 to adjust prognoses. The study compared MIPSS risk groups with actual overall survival (OS) in patients who had PV or ET.

Patients were stratified into low-, intermediate-, and high-risk groups based on the MIPSS-PV and MIPSS-ET models, and OS was calculated from day of diagnosis. A total of 261 patients with PV and 560 patients with ET had evaluable data for the prognostic model analysis. OS was significantly shorter in patients classified as high risk in the ET and PV cohorts.

Overall, the MIPSS models were predictive of prognosis in the Japanese patients in the study.

While HMR mutations were relatively infrequently seen in patients with PV and ET, the findings support the need for a long-term prospective observational study to assess the impact of HMR mutations on prognosis and leukemic transformation risks in PV and ET, the authors concluded. Following up on patients with these mutations, particularly ASXL1 mutations, is recommended for PV and ET patients.

Reference

Morishita S, Hashimoto Y, Furuya C, et al. Non-driver gene mutation analysis in a large cohort of polycythemia vera and essential thrombocythemia. Eur J Haematol. Published online October 8, 2022. doi:10.1111/ejh.13882