The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

Experimental Hematology & Oncology

Haifa-Kathrin Al-Ali⁸  Jean-Jacques Kiladjian⁵  Heinz Gisslinger¹  Koen Theunissen⁶  Christian Recher²  Viktoriya Stalbovskaya⁷  Mari McQuitty⁷  Prashanth Gopalakrishna⁷  Nadja Jäkel⁸  Hilde Demuynck³  Dietger Niederwieser⁸  Claire N. Harrison⁹  Mary Frances McMullin⁴ 

[1]Medical University of Vienna, Vienna, Austria

[2]Institut Universitaire du Cancer de Toulouse, Université de Toulouse III, Toulouse, France

[3]H. Hartziekenhuis, Roeselare, Belgium

[4]Center for Cancer Research and Cell Biology, Queen’s University, Belfast, UK

[5]Hôpital Saint-Louis et Université Paris Diderot, Paris, France

[6]Limburgs Oncologisch Centrum, Hasselt, Belgium

[7]Novartis Pharma AG, Basel, Switzerland

[8]University of Leipzig, Leipzig, Germany

[9]Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

关键词: ESA;    Erythropoiesis-stimulating agents;    Anemia management;    Ruxolitinib;    Myelofibrosis;   

Others  :  1227942
DOI  :  10.1186/s40164-015-0021-2

 received in 2015-05-26, accepted in 2015-09-03,  发布年份 2015

【 摘 要 】

Background

Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35–54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

Results

Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

Conclusions

Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

【 授权许可】

   
2015 McMullin et al.

【 参考文献 】

• [1]Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E et al.. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009; 113:2895-2901.
• [2]Cervantes F, Martinez-Trillos A. Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013; 14:873-884.
• [3]Levine RL, Gilliland DG. Myeloproliferative disorders. Blood. 2008; 112:2190-2198.
• [4]Mesa RA. Assessing new therapies and their overall impact in myelofibrosis. Hematology Am Soc Hematol Educ Prog. 2010; 2010:115-121.
• [5]Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer. 2010; 1:979-993.
• [6]Tefferi A. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013; 88:141-150.
• [7]Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014; 7:89-101.
• [8]Guglielmelli P, Vannucchi AM. Struggling with myelofibrosis-associated anemia. Leuk Res. 2013; 37:1429-1431.
• [9]Tefferi A, Lasho TL, Jimma T, Finke CM, Gangat N, Vaidya R et al.. One thousand patients with primary myelofibrosis: the Mayo Clinic experience. Mayo Clin Proc. 2012; 87(1):25-33.
• [10]Harrison C, Mesa R, Ross D, Mead A, Keohane C, Gotlib J et al.. Practical management of patients with myelofibrosis receiving ruxolitinib. Expert Rev Hematol. 2013; 6(5):511-523.
• [11]Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio J et al.. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012; 366:799-807.
• [12]Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V et al.. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366:787-798.
• [13]Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF et al.. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015; 100:479-488.
• [14]Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V et al.. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013; 122:4047-4053.
• [15]Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL et al.. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010; 116(20):4045-4059.
• [16]Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol. 2009; 83:154-155.
• [17]Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Granell M, Vallansot R et al.. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol. 2006; 134:184-186.
• [18]Tsiara SN, Chaidos A, Bourantas LK, Kapsali HD, Bourantas KL. Recombinant human erythropoietin for the treatment of anaemia in patients with chronic idiopathic myelofibrosis. Acta Haematol. 2007; 117:156-161.
• [19]Tefferi A. How I treat myelofibrosis. Blood. 2011; 117:3494-3504.
• [20]Elliott S, Pham E, Macdougall IC. Erythropoietins: a common mechanism of action. Exp Hematol. 2008; 36:1573-1584.
• [21]Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol. 2013; 6:79-85. BioMed Central Full Text
• [22]Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011; 10:127-140.
• [23]Gotlib J. JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside. Hematology Am Soc Hematol Educ Prog. 2013; 2013:529-537.