Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials

被引:244
作者
Bussel, James [1 ]
Arnold, Donald M. [2 ,3 ]
Grossbard, Elliot [4 ]
Mayer, Jiri [5 ]
Trelinski, Jacek [6 ]
Homenda, Wojciech [7 ]
Hellmann, Andrzej [8 ]
Windyga, Jerzy [9 ]
Sivcheva, Liliya [10 ]
Khalafallah, Alhossain A. [11 ]
Zaja, Francesco [12 ]
Cooper, Nichola [13 ]
Markovtsov, Vadim [4 ]
Zayed, Hany [4 ]
Duliege, Anne-Marie [4 ]
机构
[1] Weill Cornell Med, New York, NY USA
[2] McMaster Univ, Michael G DeGroote Sch Med, Hamilton, ON, Canada
[3] Canadian Blood Serv, Hamilton, ON, Canada
[4] Rigel Pharmaceut, San Francisco, CA USA
[5] Fak Nemocnice Brno, Brno, Czech Republic
[6] Wojewodzki Szpital Specjalisty Im M Kopernika Lod, Lodz, Poland
[7] Wojewodzki Szpital Specjalisty Im J Korczaka & Ak, Slupsk, Poland
[8] Med Univ Gdansk, Univ Clin Ctr, Gdansk, Poland
[9] Inst Hematol & Transfuzjol, Warsaw, Poland
[10] MHAT Hristo Botev, Internal Dept 1, AD, Vratsa, Vratsa, Bulgaria
[11] Univ Tasmania, Menzies Inst Med Res, Launceston, Tas, Australia
[12] Univ Udine, Clin Ematol, DAME, Udine, Italy
[13] Hammersmith Hosp, London, England
关键词
TYROSINE KINASE INHIBITOR; RHEUMATOID-ARTHRITIS; DOUBLE-BLIND; INADEQUATE RESPONSE; PHASE-III; PURPURA; SYK; EFFICACY; SPLENECTOMY; ELTROMBOPAG;
D O I
10.1002/ajh.25125
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Spleen tyrosine kinase (Syk) signaling is central to phagocytosis-based, antibody-mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on-treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double-blind, placebo-controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n=101) or placebo (n=49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets >= 50000/mu L at >= 4 of 6 biweekly visits, weeks 14-24, without rescue therapy). Baseline median platelet count was 16000/mu L; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P=.0003). Overall responses (defined retrospectively as >= 1 platelet count >= 50000/mu L within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P=.0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti-motility agents). Fostamatinib produced clinically-meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.
引用
收藏
页码:921 / 930
页数:10
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