title: Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes.
abstract: OBJECTIVE
  Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.
  
  
  METHODS
  COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 10(9)/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100-200 × 10(9)/L and >200 × 10(9)/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).
  
  
  RESULTS
  The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8-12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.
  
  
  CONCLUSIONS
  This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Stanford Cancer Institute, Stanford, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.affiliation: Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Ehab
authors.initials: E
authors.lastname: Atallah
authors.affiliation: Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintas-Cardama
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: William
authors.initials: W
authors.lastname: Sun
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Sarlis
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Sandor
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Levy
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
keywords: COMFORT-I; JAK2 inhibitor; dose titration; myelofibrosis; ruxolitinib; treatment-related cytopenias