Photo Credit: Artur Plawgo

Adding additional clinical and genetic information improved the performance of prognostic scores in secondary myelofibrosis, researchers in France report.

An article in the American Journal of Hematology reported an in-depth characterization of clinical and molecular differences between primary and secondary myelofibrosis (MF). Researchers also found that two newer prognostic scores, the Mutation-Enhanced International Prognostic Scoring System 70 (MIPSS70) and MIPSS70+ v2.0, stratified risk in patients with secondary MF more accurately than the myelofibrosis secondary to polycythemia vera and essential thrombocythemia prognostic model (MYSEC-PM). These two scores also are the first to account for additional mutations besides SRSF2 status in patients with secondary MF.

Several prognostic scores have been developed for patient risk stratification and appropriate treatment allocation in primary MF. These include the IPSS, Dynamic IPSS (DIPSS), and DIPSS-plus. Studies have highlighted the prognostic significance of molecular alterations in primary MF, particularly mutations in High Molecular Risk (HMR) genes such as ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1. Consequently, these genetic and molecular alterations were incorporated into the latest prognostic scores, including MIPSS70, MIPSS70-plus, and MIPSS70+ v2.0.

“As opposed to primary MF, few studies explored mutations prognosis significance in secondary MF,” explained Matteo Guerra and colleagues. “The MYSEC-PM was specifically developed for secondary MF and displays a more accurate prognostic performance than IPSS and DIPSS. However, no molecular prognostic models accounting for additional mutations in SMF have yet been described.”

Characterizing Patient Populations

The researchers examined the clinical and molecular landscapes of 455 patients with MF. Slightly more than half of patients (53%, n=227, plus 14 with pre-myelofibrosis) had primary myelofibrosis, whereas 28% had myelofibrosis secondary to post-essential thrombocythemia (post-ET) (n= 128), and 19% (n=86) had myelofibrosis secondary to post- polycythemia vera (post-PV).

Patients received treatment and follow-up care from 2011 to 2021. Patients with primary MF were a median of 58 years old, whereas those with secondary disease were a median of 62 years old. Women made up 33.2% of those with primary MF and 57.9% of the secondary MF cohort (P<.001).

The primary and secondary MF groups had similar complete blood counts except for platelet counts, which were higher in the secondary cohort. The researchers wrote this difference was driven by platelet levels in the subgroup of patients with post-ET MF. There was also no statistically significant difference between primary and secondary disease in terms of response to first-line treatment or at the time of last news from patients. The cohorts had similar overall survival (85.2% in primary vs 79.4% in secondary MF, P=0.065).

Most patients with ET are women, and women tend to be more represented in post-ET MF. However, Guerra and colleagues noted that women comprised 58% of patients with post-PV MF in their study, significantly more than the 33%-35% seen in the overall PV population.

“Thus, gender seems to play a role on myelofibrotic evolution,” the researchers explained. “As younger patients with PV and ET tend to be women, it seems logical that their risk of fibrotic progression is increased.”

The genetic mutations driving primary MF were JAK2V617F in 57.5% of patients (n=139), CALR in 26.1% of patients (n=63), and MPL in 7.5% of patients (n=18). Twenty patients with primary MF (8.3%) tested triple-negative for these mutations, with no driver found.

In the secondary MF cohort, nearly all patients with post-PV disease (n=85, 98.8%) had JAK2V617F as a driver mutation, whereas in post-ET MF, 59 patients (46.1%) had JAK2V617F as a driver mutation, 7% had MPL (n=9), and 49 (38.3%) had CALR. Ten patients with secondary MF (7.8%) tested triple negative.

Evaluating MF Prognostic Scores

The researchers examined the performance of prognostic scores, with a particular focus on using scores designed for primary disease in patients with secondary MF.

The researchers used Harrell’s C-index to analyze concordance of the IPSS and DIPSS. In those with secondary MF, the IPSS had a concordance index of 0.725 compared with 0.694 for the DIPSS. The MYSEC-PM, which is specifically meant for secondary disease, compared favorably with the other two scores, with a C-index of 0.731.

The MIPSS70 demonstrated a high performance index in secondary MF (C-index=0.731), as did the MIPSS70+ v 2.0 (C-index=0.794). Both scores outperformed the MYSEC despite being designed for primary MF.

“These results confirm that adding cytogenetic and molecular data improves prognostic scores, in line with a recent study highlighting DIPSS+ (showed) better performance compared with MYSEC-PM in secondary MF,” Guerra and colleagues wrote.

“We show a differential molecular landscape of each disease subtype, suggesting diverse physiopathologies, despite similar overall survival and transformation-free survival,” the researchers concluded. “Finally, our study validates MIPSS70 and MIPSS70+ v2.0 as the first molecular scores accounting for additional mutations and cytogenetic abnormalities in secondary MF, therefore improving accurate prognosis stratification.”