Background. It has been proposed that immune thrombocytopenia (ITP) may have pro-thrombotic characteristics and low platelet counts may prevent a higher incidence of thrombotic events (TEEs).1-3 In the UK General Practice Research Database, incidence rates for TEEs were 1.35/100 patient years (PYs) (95% CI [0.99, 1.79]) for patients with ITP vs 1.16/100 PYs (95% CI [0.99, 1.35]) in patients without ITP.1 Similar results were found in a US claims database study.4 Despite increasing acceptance of this premise, the reason why patients with ITP are prone to thrombotic events is not well understood. Aim. To describe the frequency of potential laboratory predictors of thrombophilia in patients with chronic ITP. Method. Adult patients with chronic ITP5 were enrolled in a phase 4, open-label, 2-year study to evaluate potential changes from baseline in bone marrow reticulin, associated to longterm treatment with eltrombopag. Patients with a prior history of a TEE and ≥2 risk factors for thrombosis were not eligible for the study. A “thrombophilia panel”collected at baseline comprised multiple known or suspected laboratory predictors of thrombosis. Patients could not have been treated with a TPO-R agonist in the 6 months prior to enrollment. All patients provided signed informed consent prior to study initiation. Results. In this ongoing study, baseline thrombophilia panels were available for 80 patients as of the date of this evaluation (Feb 2011). Mean age was 41 years; 70% (n=56) were female; mean BMI was 24.9 (range, 15.5-40.5). The median time since ITP diagnosis was 4 years (range, 0.2-45.7 years). 5/80 patients had prior exposure to eltrombopag. Most patients did not report a family or personal history of TEEs (n=75). Five patients reported clinical risk factors potentially associated with thromboembolic events (atrial fibrillation [n=1], arterial HTN [n=3]), and cardiac insufficiency [n=1]). The majority of tests in the thrombophilia panel were normal; however, many patients (Table 1) had abnormal levels of well known or suspected predictors of thrombosis or markers or activation of the coagulation cascade: ß2-Glycoprotein 1 (22/80), d-dimer (29/80), Factor VIII (46/80), Lupus anticoagulant (15/80), and Protein S activity (decreased, 14/80). Two patients in the study reported a

TEE:

1 DVT (study day 31) and 1 infective thrombophlebitis requiring anticoagulation (study day 27). Both patients had baseline increases in d-dimer, Factor VIII, and Lupus anticoagulant (detected and confirmed). Summary/Conclusions. To our knowledge this is the only published report of a thrombophilia profile in a cohort of patients with chronic ITP. The multiple baseline abnormalities in possible predictors of thrombophilia may support the theory that ITP is a pro-thrombotic disease. The potential correlation of such abnormalities with TEEs will be the topic of further reports as the study progresses. (Table Presented).

BACKGROUND:

Few therapeutic options are currently available for patients (pts) with severe aplastic anemia (SAA) refractory to antithymocyte globulin (ATG) plus ciclosporine (CsA) and not eligible for allogeneic stem cell transplantation. It has recently been reported that eltrombopag (ELT), a TPO receptor agonist, is efficient to improve tri-lineage blood counts in this setting. However, real-life use of this drug is still largely unknown. In pts with SAA refractory to ATG, physicians can accede to ELT in France through a compassionate use program. We took advantage of this program to assess the efficacy and safety of ELT in SAA pts.

PATIENTS AND METHODS:

The French National Reference Center for Aplastic Anemia conducted identified (already seen at SAA diagnosis), and karyotype was a failure in 1 pt.

CONCLUSION:

We report here the first real-life multicenter study about the use of ELT in SAA. In a particular severe pts population with no other treatment possibility, we confirm a 40% rate of hematological improvement with transfusion independence. Some of the pts who were not eligible to ATG plus CsA (comorbidities) also received ELT first line with similar response rates. Elderly pts unfit for ATG may thus benefit from this treatment which at the best should be given through prospective clinical trials. (Figure Presented).

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Background: Eltrombopag (EPAG) is an oral non-peptide thrombopoietinreceptor agonist licensed for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia (cITP). In children with cITP, there is no agreed-upon standard treatment, and the risks of long-term consequences from current treatments are unacceptable to many families and physicians. Aims: This phase III study was conducted to confirm the efficacy, safety, and tolerability of EPAG in children with cITP. The primary objective was to assess the efficacy of EPAG relative to placebo (PBO) in achieving a consistent platelet response defined as counts ≥50 Gi/L (without rescue) for ≥6 out of 8 weeks between weeks 5 and 12 when administered to pediatric subjects with insufficient response to prior ITP treatment. Methods: Subjects were aged between 1 and <18 years with a confirmed diagnosis of cITP (duration >12 months) and platelet count <30 Gi/L at day 1. Informed consent (and assent as appropriate) was provided. Subjects were stratified as: 12-17 years (Cohort 1), 6-11 years (Cohort 2), and 1-5 years (Cohort 3). Part 1 was a 13-week, double-blind (DB), 2:1 randomization to EPAG or PBO. Subjects could continue stable baseline ITP medications. DB treatment was unblinded at week 13 then subjects began 24 weeks of openlabel (OL) treatment with EPAG. Subjects aged 6-17 years weighing ≥27 kg started treatment at 50 mg, and those weighing <27 kg at 37.5 mg. Subjects aged 1-5 years started treatment at 1.2 mg/kg. Dosing at all ages was reduced for East Asian subjects. Dose was adjusted based on platelet counts to a maximum of 75 mg daily. (Figure presented) Results: 92 subjects were enrolled: 33 to Cohort 1, 39 Cohort 2, and 20 Cohort 3. 63 and 29 subjects were randomized to EPAG and PBO, respectively. 3.4% of subjects on PBO entered the study on ITP treatment compared to 20.6% on EPAG; 6.3% on EPAG had previously undergone splenectomy compared to none on PBO. Dosing regimens: During the DB phase, 63.5% of subjects on EPAG required ≥2 dose adjustments. The median daily dose during the OL phase was 67.7 mg for Cohort 1, 56.9 mg for Cohort 2, and 42.8 mg for Cohort 3. Efficacy: 39.7% of subjects on EPAG met the primary endpoint of consistent response compared to 3.4% on PBO (P<0.001). Response rates were similar across age cohorts at 39% for Cohort 1, 42% Cohort 2, and 36% Cohort 3. 74.6% of subjects on EPAG achieved platelet counts ≥50 Gi/L at least once during the first 12 weeks compared to 20.7% on PBO (P<0.001) (Figure 1). Clinically significant bleeding (World Health Organization grade 2-4) was present at baseline in 28.6% on EPAG and 13.8% on PBO compared to 4.8% at the end of DB phase on EPAG and 6.9% on PBO. In the OL phase, 80.5% of subjects achieved platelet counts ≥50 Gi/L at least once during 24 weeks. Safety: The most common adverse events (AEs) that occurred more frequently on EPAG than PBO included nasopharyngitis, rhinitis, cough, and upper respiratory tract infection. Grade 3/4 AEs occurred in 12.7% of EPAG and 10.3% of PBO subjects. Serious AEs were reported in 8% of subjects on EPAG compared to 14% on PBO. In Part 1, 2 subjects (3%) on EPAG discontinued treatment due to AEs of increased liver transaminases, compared to 1 subject (3%) on PBO who discontinued due to bleeding. Safety in the OL phase was consistent with that in the DB phase. No deaths were reported. Summary and Conclusions: PETIT2 met its primary endpoint, demonstrating that a consistent response to EPAG can be achieved in children with cITP. There were no new safety concerns and few discontinuations due to AEs.

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Background and Aims: Thrombocytopenia limits the ability to initiate and maintain peginterferon alfa-2b [PEG-2b]+ribavirin therapy in patients with cirrhosis due to hepatitis C (HCV). PEG- 2b is not recommended for patients with platelets <100 Gi/L. Eltrombopag is an oral thrombopoietin receptor agonist that improved sustained virologic response (SVR) in ENABLE 1 (PEG- 2a/ribavirin). ENABLE 2 was a second study to evaluate the ability of eltrombopag to increase platelet counts, providing patients with pre-existing thrombocytopenia the opportunity to initiate PEG-2b and achieve SVR. Methods: In Part 1, patients with HCV and platelets <75 Gi/L received eltrombopag 25 mg, increased to 50, 75, or 100mg daily until platelets reached ≥100 Gi/L to enter Part 2. In Part 2, patients eligible for PEG-2b (1.5 mg/kg/week) and ribavirin (weight-based dosing) were randomized 2:1 to eltrombopag or placebo. Treatment was administered for 24 weeks or 48 weeks according to genotype. The primary endpoint was SVR. Results: 805 patients were enrolled, 80% with bridging fibrosis or cirrhosis (FibroSURE×). Median platelets were 59Gi/L at enrollment and 93Gi/L by week 2 of eltrombopag treatment. 759 patients (94%) initiated HCV therapy (eltrombopag, 506; placebo, 253). In Part 2, median platelet counts in the eltrombopag and placebo arms were 136 Gi/L vs 140 Gi/L at randomization but 105 Gi/L vs 51 Gi/L at week 4, and >50 Gi/L throughout for 81% vs 23% of patients. Compared with placebo, eltrombopag was associated with improved SVR (19% vs 13%, p = 0.0202), fewer antiviral dose reductions (54% vs 73%, p = 0.0001), improved early virological response (EVR; 62% vs 41%, p < 0.0001), and end-of-treatment response (38% vs 23%, p < 0.0001). Adverse event (AE) rates were (eltrombopag, placebo): any AE (94%, 93%); serious AE (20%, 15%); events suggestive of decompensation (15%, 8%); thromboembolic events (4%, <1%), and death (4%, 2%). Conclusions: Eltrombopag increased and maintained platelet counts throughout PEG-2b/ribavirin treatment in patients who would otherwise be ineligible for antiviral therapy. Eltrombopag treatment was associated with clinically meaningful improvement in SVR, as previously reported with PEG-2a/ribavirin treatment in ENABLE 1. Unlike previously reported in ENABLE 1, there was an increased incidence of thromboembolic complications with eltrombopag treatment, which requires further analysis.