Impact of RAS-Pathway Activation on Phenotype and Outcome in Patients with Chronic Myelomonocytic Leukemia and a TET2/SRSF2 Comutation

Abstract

In unselected patients with chronic myelomonocytic leukemia (CMML) the prognostic impact of RAS mutations remains unclear. Restricting analysis to molecularly defined subgroups such as to patients with a TET2/SRSF2 comutation may be more appropriate to study the effects of RAS pathway mutations on the phenotype and clinical outcome. 87/291 CMML patients in our unselected real world “Austrian Biodatabase for CMML” (ABCMML) were found to have a TET2/SRSF2 comutation. In 37 of them mutations in at least one RAS-pathway component (NRAS, KRAS, CBL, NF1 and PTPN11) were detected. Patients with additional RASopathy gene mutations had higher WBC counts, and lower Hb and platelet values. Moreover, RAS-pathway activation was more frequently associated with splenomegaly, signs of transformation and high growth factor independent colony growth. The median survival of TET2/SRSF2-mutant CMML patients with additional molecular RAS-pathway aberrations was 15 months as compared to 38 months in patients without such mutations (p=0.0026). Interestingly, the presence of RASopathy gene mutations was not associated with a poor outcome in CMML patients without a TET2/SRSF2 comutation. We confirm here in a common molecularly defined subgroup of CMML patients that RAS-pathway activation is associated with changes in the clinicohematologic phenotype and an inferior outcome.