Efficacy and safety of JAK inhibitor INC424 in patients with primary and post-polycythemia vera or post-essential thrombocythemia myelofibrosis in the Chinese population

Abstract

A phase II study (A2202) was performed to evaluate the efficacy and safety of JAK inhibitor ruxolitinib in 63 Chinese MF patients. Ruxolitinib was given twice a day (bid) at a starting dose of 15 mg (n=25) or 20 mg (n=38) based on a baseline platelet count. About 94.7% of the patients achieved a reduction in spleen size, 27.0% of which exhibited significant reduction (≥35%) at week 24. Significant improvement in debilitating constitutional symptoms, as assessed by MFSAF v2.0, was observed in patients treated with ruxolitinib. Ruxolitinib treatment was generally well tolerated by Chinese patients. Although the treatment was associated with an increase in certain adverse events (AEs) that were established as identified risks (anemia and thrombocytopenia), these AEs were considered manageable in this clinical setting. Ruxolitinib provided substantial reductions in splenomegaly and improvements in symptoms, and was well-tolerated by Chinese patients with MF.

Keywords

JAK / ruxolitinib / Chinese patients / myelofibrosis

References

[1] Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol 2008; 83(6): 491–497

[2] Mesa RA, Niblack J, Wadleigh M, Verstovsek S, Camoriano J, Barnes S, Tan AD, Atherton PJ, Sloan JA, Tefferi A. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer 2007; 109(1): 68–76

[3] Mesa RA. Assessing new therapies and their overall impact in myelofibrosis. Hematology Am Soc Hematol Educ Program 2010; 2010:115–121 PMID: 21239780 DOI: 10.1182/asheducation-2010.1.115

[4] Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 inmyeloproliferative disorders. N Engl J Med 2005; 352(17): 1779–1790

[5] Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365(9464): 1054–1061PMID:15781101

[6] Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene 2013; 32(21): 2601–2613

[7] Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366(9): 787–798

[8] Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Koumenis IL, Sun W, Sandor V, Kantarjian HM. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366(9): 799–807

[9] Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V, McQuitty M, Hunter DS, Levy RS, Passamonti F, Barbui T, Barosi G, Harrison CN, Knoops L, Gisslinger H; COMFORT-II investigators. 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(25): 4047–4053PMID:24174625

[10] Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA, Sarlis NJ, Peng W, Sandor V, Gopalakrishna P, Hmissi A, Stalbovskaya V, Gupta V, Harrison C, Verstovsek S; COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica 2015; 100(9): 1139–1145PMID:26069290

[11] Deisseroth A, Kaminskas E, Grillo J, Chen W, Saber H, Lu HL, Rothmann MD, Brar S, Wang J, Garnett C, Bullock J, Burke LB, Rahman A, Sridhara R, Farrell A, Pazdur R. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res 2012; 18(12): 3212–3217

[12] Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, Vannucchi AM, Mesa RA, Demory JL, Barosi G, Rumi E, Tefferi A. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009; 113(13): 2895–2901

[13] Passamonti F, Maffioli M, Caramazza D, Cazzola M. Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget 2011; 2(6): 485–490

[14] Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood 2014; 124(24): 3529–3537

[15] Mesa RA, Gotlib J, Gupta V, Catalano JV, Deininger MW, Shields AL, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH, Hare T, Erickson-Viitanen S, Sun W, Sandor V, Levy RS, Kantarjian HM, Verstovsek S. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2013; 31(10): 1285–1292

[16] Mesa RA, Verstovsek S, Gupta V, Mascarenhas J, Atallah E, Sun W, Sandor VA, Gotlib J. Improvement in weight and total cholesterol and their association with survival in ruxolitinib-treated patients with myelofibrosis from COMFORT-I. Blood (ASH Annual Meeting Abstracts) 2012; 120(21): 1733 (abstract)

[17] Cervantes F. How I treat myelofibrosis. Blood 2014; 124(17): 2635–2642

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg