Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (4) : 437-443     DOI: 10.1007/s11684-016-0472-9
RESEARCH ARTICLE |
Efficacy and safety of JAK inhibitor INC424 in patients with primary and post-polycythemia vera or post-essential thrombocythemia myelofibrosis in the Chinese population
Xin Du1,Daobin Zhou2()
1. Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
2. Department of Hematology, Peking Union Medical College Hospital, Beijing 100730, China
Download: PDF(169 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
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     
Corresponding Authors: Daobin Zhou   
Just Accepted Date: 12 October 2016   Online First Date: 17 November 2016    Issue Date: 01 December 2016
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-016-0472-9     OR     http://academic.hep.com.cn/fmd/EN/Y2016/V10/I4/437
Age (year)
Mean (SD) 54.3 (12.44)
Median (range) 55.0 (25–79)
Gender, n (%)
Female 31 (49.2)
Male 32 (50.8)
Type of MF, n (%)
PMF 49 (77.8)
PPV–MF 5 (7.9)
PET–MF 9 (14.3)
Time from diagnosis (year)
Mean (SD) 4.02 (4.960)
Median (range) 1.33 (0.1–20.3)
Palpable spleen size (cm) below costal margin
Mean (SD) 15.78 (7.041)
Median (range) 15.00 (6.0–45.0)
Spleen volume (cm3)
Mean (SD) 2421.9 (1024.25)
Median (range) 2236.0 (685–6076)
Baseline platelet count (K/ml)
Mean (SD) 281.81 (174.871)
Median (range) 227.00 (96.0–986.0)
Baseline hemoglobin count (K/ml)
Mean (SD) 10.32 (2.768)
Median (Range) 9.90 (4.7–17.9)
<10 g/dl, n (%) 34 (54.0)
≥10 g/dl, n (%) 29 (46.0)
Baseline circulating blasts (%)
Mean (SD) 0.97 (1.015)
Median (range) 1.00 (0.0–5.0)
ECOG PS, n (%)
0 34 (54.0)
1 26 (41.3)
2 3 (4.8)
≥3 0
Tab.1  Demographic and baseline characteristics (total n = 63)
Spleen volume Baseline (cm3) Week 24 (cm3) % Change from baseline at week 24
n 63 53 53
Mean (SD) 2421.9 (1024.25) 1731.8 (845.7) −26.94 (17.850)
Median 2236.0 1478.0 −25.11
Range 685?6076 345?3874 −72.4?5.3
Tab.2  Percentage change in spleen volume from baseline at week 24
Fig.1  Waterfall plot of percent change from baseline in spleen volume at week 24.
Fig.2  Kaplan–Meier estimates for time to first reduction (of at least 35%) in spleen volume among the responders.
PT All grades
n (%)
Grade 3/4
n (%)
Any PT 59 (93.7) 33 (52.4)
Anemia 32 (50.8) 21 (33.3)
Platelet count decreased 22 (34.9) 5 (7.9)
Thrombocytopenia 14 (22.2) 1 (1.6)
Alanine aminotransferase increased 12 (19.0 0
Aspartate aminotransferase increased 10 (15.9) 0
Diarrhea 10 (15.9) 0
Neutrophil count decreased 8 (12.7) 1 (1.6)
Pyrexia 8 (12.7) 1 (1.6)
Upper respiratory tract infection 8 (12.7) 2 (3.2)
γ-glutamyltransferase increase 7 (11.1) 2( 3.2)
Lung infection 5 (7.9) 4 (6.3)
Weight increased 5 (7.9) 2 (3.2)
Abdominal distension 5 (7.9) 1 (1.6)
White blood cell count decreased 5 (7.9) 0
Activated partial thromboplastin time prolonged 4 (6.3) 0
Blood bilirubin increased 4 (6.3) 0
Blood iron increased 4 (6.3) 0
Blood urea increased 4 (6.3) 0
Tab.3  Frequent adverse events (at least 5% in all grades) in the study regardless of relation to the study drug
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
doi: 10.1002/ajh.21183 pmid: 18429051
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
doi: 10.1002/cncr.22365 pmid: 17123268
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
doi: 10.1056/NEJMoa051113 pmid: 15858187
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): 1054–1061 PMID:15781101
doi: 10.1016/S0140-6736(05)74230-6
6 Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene 2013; 32(21): 2601–2613
doi: 10.1038/onc.2012.347 pmid: 22869151
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
doi: 10.1056/NEJMoa1110556 pmid: 22375970
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
doi: 10.1056/NEJMoa1110557 pmid: 22375971
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): 4047–4053 PMID:24174625
doi: 10.1182/blood-2013-02-485888
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): 1139–1145 PMID:26069290
doi: 10.3324/haematol.2014.119545
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
doi: 10.1158/1078-0432.CCR-12-0653 pmid: 22544377
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
doi: 10.1182/blood-2008-07-170449 pmid: 18988864
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
doi: 10.18632/oncotarget.281 pmid: 21646683
14 Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood 2014; 124(24): 3529–3537
doi: 10.1182/blood-2014-05-577635 pmid: 25472969
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
doi: 10.1200/JCO.2012.44.4489 pmid: 23423753
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
doi: 10.1182/blood-2014-07-575373 pmid: 25232060
[1] LIU Hongxing, TONG Chunrong, CAI Peng, GU Jiangying, LIN Yuehui, TENG Wen, WANG He, ZHANG Ying, ZHU Ping. Observation of a higher JAK2 V617F homozygous mutated clone in polycythemia vera compared to essential thrombocythemia[J]. Front. Med., 2008, 2(3): 309-313.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed