Phase I study of ruxolitinib in previously treated patients with low or intermediate-1 risk myelodysplastic syndrome with evidence of NF-kB activation

Leuk Res. 2018 Oct;73:78-85. doi: 10.1016/j.leukres.2018.09.004. Epub 2018 Sep 14.


Therapeutic options for patients with lower-risk myelodysplastic syndrome (MDS) who have failed prior therapies are limited particularly after hypomethylating agent. Several studies have indicated that deregulation of innate immunity signaling is critical in the pathogenesis of MDS. This process involves Toll-like receptor stimulation, cytokine overexpression, and nuclear factor-kB (NF-kB) activation. Since ruxolitinib, a JAK1/JAK2 inhibitor, suppresses NF-kB expression, we conducted a phase 1 dose-escalation study to determine the safety and efficacy of ruxolitinib in previously treated lower-risk MDS patients with evidence of NF-kB activation. Nineteen patients, 8 with chronic myelomonocytic leukemia and 11 with MDS, were enrolled. No dose limiting toxicity was observed and the maximum tolerated dose was 20 mg twice daily. Responses were restricted to MDS patients with an overall response rate of 22% [hematological improvement in platelets (HI-P) = 2, hematological improvement in erythrocytes (HI-E) = 1, partial cytogenetic response (PCyR) = 1]. Of these patients, 2 relapsed (HI-P and PCyR) and 2 continue to be in HI-P and HI-E, respectively, with ongoing therapy. Meaningful improvement in bone marrow dysplasia was only seen in a patient who achieved HI-E. Phosphorylated p65 (pp65) decreased in 6 of 15 patients (40%) including the 2 patients with continued response to treatment and increased in a patient who relapsed after a short-lived HI-P. This suggests potential correlation between reduction in pp65 expression and response duration. In conclusion, ruxolitinib was well-tolerated in previously treated lower-risk MDS patients with evidence of NF-kB activation and resulted in low but significant frequency of responses. (NCT01895842).

Keywords: IL-8; Myelodysplastic syndromes; NF-kB; TNF-α; Toll-like receptors.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / pathology
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes* / drug therapy
  • Myelodysplastic Syndromes* / metabolism
  • Myelodysplastic Syndromes* / pathology
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism*
  • Nitriles
  • Pyrazoles / administration & dosage*
  • Pyrimidines
  • Risk Factors
  • Transcription Factor RelA / biosynthesis*


  • Neoplasm Proteins
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • RELA protein, human
  • Transcription Factor RelA
  • ruxolitinib
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2

Associated data