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

Author(s): Klaus Geissler, Eva Jäger, Agnes Barna, Michael Gurbisz, Temeida Graf, Elmir Graf, Maike Stegemann, Thomas Nösslinger, Michael Pfeilstöcker, Sigrid Machherndl-Spandl, Reinhard Stauder, Armin Zebisch, Heinz Sill, Leopold Öhler, Rajko Kusec, Gregor Hoermann, Peter Valent

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.

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