Is ruxolitinib a potentially useful drug in hematological malignancies with RAS pathway hyperactivation?

It was with great interest that we read this journal’s article by Sachs et al. in which, in a preclinical mouse model, the critical role of Stat5 in the development and maintenance of myeloproliferative neoplasms (NPM) initiated by Nf1-deficiency, has been nicely demonstrated.1 Since neurofibromin encoded by NF1 is a negative regulator of the RAS signaling pathway, deletion of NF1 leads to hyperactive RAS signaling.2 Since STAT5 is a downstream effector of JAK2,3 the authors also investigated the effects of the JAK1/2 inhibitor ruxolitinib in this model. Interestingly, the authors show that attenuation of Stat5 signaling in Nf1-deficient mice, using either a genetic Stat5a/b hypomorphic knock-out or pharmacological Jak2 inhibition by ruxolitinib abrogated MPN, rescued hyperactive signaling pathways, and reversed the expansion of immature myeloid cells.1 Furthermore, they showed that peripheral blood mononuclear cells (PB MNC) from a patient with activated KRAS juvenile myelomonocytic leukemia (JMML) displayed reduced colony formation in response to JAK2 inhibition by ruxolitinib.1

We originally reported that extensive in vitro formation of colony-forming unit-granulocyte-macrophage (CFU-GM) without exogenous growth factors can be found in a subset of patients with chronic myelomonocytic leukemia (CMML).4 We demonstrated that this spontaneous myeloid colony formation in CMML is a granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent in vitro phenomenon,5 and that CMML patients with high spontaneous CFU-GM growth (>100/10 PBMNC) have a worse prognosis compared to patients with low CFU-GM growth, suggesting clinical significance of our observation.6 We have recently demonstrated that high in vitro myeloid colony formation in the absence of exogenous growth factors is highly associated with molecular aberrations in RASopathy genes in CMML patients.7 We have also reported the in vitro effects of the specific JAK2 inhibitor TG101209 on autonomous CFU-GM formation from PB MNC of CMML patients.8 TG101209 was found to either block or strongly inhibit spontaneous CFU-GM growth in all 10 patients tested. This inhibitory effect was dose-dependent and significantly more pronounced as compared to the inhibitory effect on stimulated CFU-GM growth from normal individuals. Among the 10 patients included in this study, PB MNC from 6 patients were tested by next-generation sequencing and, in 5 of them, RAS signaling hyperactivation was documented due to mutations in NRAS (n=3) or PTPN11 (n=2), respectively. In a CMML patient with an NRAS mutation, leukocytosis and splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we demonstrated a spleen response and the disappearance of constitutional symptoms associated with a decrease of autonomous CFU-GM formation ex vivo.

These data, along with ours, hence suggest that the inhibition of the JAK2-STAT5 pathway by ruxolitinib may have therapeutic potential, not only in JMML, but also in other RAS-driven hematological malignancies including CMML. This hypothesis seems to be supported by data from a recent multi-institution phase I trial of ruxolitinib in patients with CMML,9 which showed that splenomegaly, which is commonly associated with RAS pathway hyperactivation,10 was reduced in 5 of 9 patients by the study drug.