• Publikační typ
• abstrakt z konference MeSH

This review summarizes the history of the development of thrombopoietic agents and discusses their potential use in chemotherapy-induced thrombocytopenia. RECENT FINDINGS: A new generation of thrombopoietic agents have had preliminary success in the treatment of thrombocytopenia. The initial thrombopoietic agents were recombinant and pegylated human megakaryocyte growth factor. These agents showed promise in the treatment of chemotherapy-induced thrombocytopenia but had the unfortunate side effect of promoting the development of antibodies against endogenous thrombopoietin and subsequent refractory thrombocytopenia. Now, a second generation of synthetic thrombopoietic agents including AMG 531 and eltrombopag have shown promise in the treatment of thrombocytopenia in patients with immune thrombocytopenia purpura and hepatitis C without the development of an immunological response. As these new agents see broader use, many questions regarding their safety and their most effective administration need to be answered. SUMMARY: The second generation of thrombopoietic agents has been shown to correct thrombocytopenia in selected diseases with a minimum of side effects. Looking forward, there is great potential for their use in other forms of thrombocytopenia, including chemotherapy-induced thrombocytopenia, but there are also many questions remaining regarding their best and safest use.

• MeSH
• benzoáty terapeutické užití   MeSH
• chronická nemoc MeSH
• hepatitida C farmakoterapie   virologie   MeSH
• hydraziny terapeutické užití   MeSH
• idiopatická trombocytopenická purpura farmakoterapie   chemicky indukované   virologie   MeSH
• klinické zkoušky jako téma MeSH
• krvácení MeSH
• lidé MeSH
• pyrazoly terapeutické užití   MeSH
• receptory Fc terapeutické užití   MeSH
• transportní proteiny terapeutické užití   MeSH
• trombocytopenie farmakoterapie   chemicky indukované   MeSH
• trombocyty účinky léků   MeSH
• trombopoéza účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

• MeSH
• cytaferéza MeSH
• leukaferéza MeSH
• výměna plazmy MeSH
• Publikační typ
• kongresy MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• terapie
• hematologie a transfuzní lékařství
• alergologie a imunologie

• MeSH
• elektrická stimulace MeSH
• elektromyografie MeSH
• lidé MeSH
• monosynaptický reflex MeSH
• poranění míchy účinky záření   MeSH
• svalová kontrakce MeSH
• Check Tag
• lidé MeSH

Two randomized, double-blind, placebo-controlled studies demonstrated responses (≥50 000/μL) to fostamatinib in adults with long-standing immune thrombocytopenia (ITP). The long-term safety and efficacy of fostamatinib were evaluated in a follow-on, open-label extension (OLE) study. Patients received double-blind fostamatinib in the randomized trials, and responders continued the same dose, 100 to 150 mg BID, in the OLE study. Nonresponders received 100 mg BID for 4 weeks and could escalate to 150 mg BID at week 4. Endpoints included stable response, platelet count ≥50 000/μL at 4/6 biweekly (randomized trials) or 2/3 monthly visits (OLE), and overall response, ≥1 platelet count ≥50 000/μL during weeks 1 to 12. A total of 146 patients received fostamatinib including 123 in the OLE study. Median treatment duration was 6.7 months. Baseline median ITP duration was 8 years and median platelet count was 16 000/μL; prior treatments included thrombopoietic (TPO) agents (47%), splenectomy (35%), and rituximab (32%). Twenty-seven (18%) patients achieved a stable response with median duration of >28 months and a median platelet count of 89 000/μL. Sixty-four (44%) patients achieved an overall response (including stable responders) with a median platelet count of 63 000/μL and a median response duration of >28 months. Twenty-four of 71 (34%) patients who had failed TPO agents achieved overall responses to fostamatinib. The most common adverse events (AEs) were diarrhea, hypertension, nausea, epistaxis, and abnormal liver function tests. Most AEs were mild/moderate and resolved or were managed with dose reduction, dose interruption, and/or secondary medication. Almost half of the patients achieved an overall response, and most of these maintained their responses for >2 years. No new or increased frequency of AEs was seen at up to 31 months of treatment.

• MeSH
• časové faktory MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• idiopatická trombocytopenická purpura krev   farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• oxaziny * aplikace a dávkování   škodlivé účinky   MeSH
• počet trombocytů MeSH
• pyridiny * aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• clonidin aplikace a dávkování   MeSH
• lidé MeSH
• paraplegie farmakoterapie   MeSH
• spinální injekce MeSH
• svalová spasticita farmakoterapie   MeSH
• Check Tag
• lidé MeSH

• MeSH
• clonidin aplikace a dávkování   MeSH
• lokomoce MeSH
• paraplegie farmakoterapie   MeSH
• poranění míchy farmakoterapie   MeSH
• spinální injekce MeSH

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 ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14-24, without rescue therapy). Baseline median platelet count was 16 000/μL; 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 ≥50 000/μL 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.

• MeSH
• chronická nemoc MeSH
• dospělí MeSH
• idiopatická trombocytopenická purpura farmakoterapie   MeSH
• kinasa Syk aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• oxaziny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• počet trombocytů MeSH
• pyridiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• splenektomie MeSH
• trombocyty účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. METHODS: PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. FINDINGS: Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3-140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. INTERPRETATION: Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events. FUNDING: GlaxoSmithKline.

• MeSH
• benzoáty aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• chronická nemoc MeSH
• dítě MeSH
• dvojitá slepá metoda MeSH
• hydraziny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• idiopatická trombocytopenická purpura farmakoterapie   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• počet trombocytů MeSH
• předškolní dítě MeSH
• pyrazoly aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• receptory thrombopoetinu agonisté   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH