RAS/MAPK Pathway Mutations Show Association With Adverse Survival Outcomes in Myelofibrosis

Patients with myelofibrosis and RAS/MAPK pathway mutations (RASMT) demonstrated an association with inferior survival outcomes and adverse phenotypic features in a study presented during the 25th European Hematology Association Annual Congress. The investigators also concluded that the presence of RASMT might be able to predict a reduced response to JAK2 inhibitors.

Of 464 patients with World Health Organization-defined myelofibrosis in this trial, there were 64 RASMT in 59 patients (12.7%). The investigators of the study assessed the prevalence of RASMT, including NRAS, KRAS, and CBL, in this setting and investigated implications in terms of phenotype, prognosis, and therapy. CBLMT were found in 26 (5.6%) patients, NRASMT were found in 25 (5.4%), and KRASMT were in 13 (2.8%).

Significantly worse survival was associated with patients with RASMT who were treated with a JAK2 inhibitor. The median for these patients was 30 months and patients without RASMT had a median of 91 months (HR, 4.6; 95% CI, 2.0-10.6; P =.0001). This data suggests that treatment with JAK2 inhibitors does not overcome the negative prognostic indication of RASMT, according to the study presenter Giacomo Coltro, MD.

Lower symptoms response rate was associated with RASMT at baseline, with 4 out of 9 (44%) patients with RASMT showing symptoms response at 6 months compared with 43 out of 52 (83%) patients with RAS wild-type (P =.0118). None of the 8 patients with RASMT at baseline achieved spleen response at 6 months versus 29 out of 49 (59%) patients without RASMT (P =.0019).

In a multivariate regression logistic model, which included clinical and molecular variable, patients with RASMT were associated with having a lower probability of achieving a symptoms response at 6 months with JAK2 inhibitors.

“Similarly, in the same multivariate model that included several clinical molecular variables, RASMT were confirmed to be an independent predictor of inferior spleen response at 6 months,” Coltro said.

The response of patients with RASMT to JAK2 inhibitors was a primary aim of this study; there were 61 (13%) patients included in this analysis who had fully evaluable response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet criteria. Patients had a median treatment time of 28 months (range, 2-120). There was not a significant difference in anemia response rate according to RAS pathway mutational status at baseline.

According to current clinical and molecular prognostic models, patients with RASMT were more likely to be classified as having higher risk disease in the International Prognostic Scoring System (IPSS), dynamic IPSS, and the mutation-enhanced IPSS for transplant-age patients (MIPSS70) risk stratification.

A multivariate survival analysis showed that patients with RASMT had a significantly inferior overall survival outcomes at a median of 51.4 months (95% CI, 31.4-72.9) compared with 140.2 months (95% CI, 110.8-148.6) for patients who were RAS wild-type (HR, 2.3; 95% CI, 1.6-3.2; P <.0001). This disadvantage in survival remained significant in a multivariate model including MIPSS70 risk factors and karyotype information (HR, 1.7; 95% CI, 1.1-2.7; P <.0177).

When looking at the rate of leukemic transformation, RASMT were associated with a higher rate at 28% versus 10% for patients without RASMT (P <.0001). They also had a higher cumulative incidence of transformation to blast phase, at 27% in a 5-year confidence interval compared with 10% (P =.0044).

Based on these findings, the investigators looked at prognostic models with MIPSS70 and RAS-enhanced MIPSS70, but they found that RASMT did not add prognostically meaningful information to the current molecularly annotated models.

“This is likely due to the fact that RASMT are usually associated with…clinical and molecular variables that define high risk disease,” Coltro explained.

The investigators found that patients with RASMT were more likely to be diagnosed with overt primary myelofibrosis than prefibrotic primary myelofibrosis compared to RAS wild-type patients. These patients had an association with high risk clinical and laboratory features such as older age; higher white blood cell count, peripheral blood blasts, prevalence of red blood cell transfusion dependence, and CD34-positive cells; lower hemoglobin and platelet count; and constitutional symptoms.

In patients with RASMT, there was a correlation with high risk molecular signatures. These patients were more likely to be triple negative than wild-type patients. They also had a higher affinity for higher risk genes such as ASXL1MT, EZH2MT, and SRSF2MT.

“RASMT associated with adverse phenotypic features were concluded to be an independent predictor of inferior overall survival and were associated with a higher cumulative incidence of leukemic transformation,” Coltro said. “Probably the most important findings of our study are the important implications of RASMT in response to JAK inhibitors since they may predict reduced response in terms of both symptoms and spleen response likely by mediating drug resistance.”

_Reference

_{Coltro G, Rotunno G, Mannelli L, et al. RAS/MAPK pathway mutations are associated with adverse survival outcomes and may predict resistance to JAK inhibitors in myelofibrosis. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S211.}