Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes

Srdan Verstovsek,1 Jason Gotlib,2 Vikas Gupta,3 Ehab Atallah,4 John Mascarenhas,5 Alfonso Quintas-Cardama,1 William Sun,6 Nicholas J Sarlis,6 Victor Sandor,6 Richard S Levy,6 Hagop M Kantarjian,1 Ruben A Mesa71University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Stanford Cancer Institute, Stanford, CA, USA; 3Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; 4Medical College of Wisconsin, Milwaukee, WI, USA; 5Mount Sinai School of Medicine, New York, NY, USA; 6Incyte Corporation, Wilmington, DE, USA; 7Mayo Clinic, Scottsdale, AZ, USAPurpose: 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.Patients and methods: COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 109/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100–200 × 109/L and >200 × 109/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.Conclusion: 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.Keywords: COMFORT-I, dose titration, JAK2 inhibitor, myelofibrosis, ruxolitinib, treatment-related cytopenias