Thrombopoietin receptor analogs (TPO-RAs) are indicated for splenectomized immune thrombocytopenia refractory to corticosteroids or immunoglobulins, intravenous, or as second-line therapy when splenectomy is contraindicated. Herein, we report a case of left transverse and superior sagittal sinus thrombophlebitis in a 49-year-old woman with chronic immune thrombocytopenia who received 10 days of eltrombopag treatment. Etiologic assessment ruled out acquired thrombophilia and antiphospholipid syndrome. Pharmacovigilance investigation confirmed causality between eltrombopag and the cerebral events, necessitating the definitive discontinuation of the drug. The patient was treated with anticoagulants and anticonvulsants. This evolution was marked by clinical recovery and significant radiological improvement of the thrombotic event. Cerebral venous thrombophlebitis within TPO-RA treatment remains rare, and without codified recommendations, a strict assessment of patients at risk of thrombotic events remains necessary prior to TPO-RA initiation.

We monitored platelet activation by means of P-selectin and platelet monocyte aggregates (PMA) and platelet function by whole blood multiple electrode aggregometry and platelet adhesion under high shear in chronic immune thrombocytopenia patients to define changes in platelet activation during treatment with eltrombopag. Overall, platelet activation and function normalized with increasing platelet counts. However, P-selectin, which was already elevated before treatment, and PMA increased further transiently during the first weeks. The increases in P-selectin and in PMA indicate ongoing platelet activation during the early period of treatment.

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BACKGROUND:

Eltrombopag (EPAG), an oral thrombopoietin receptor agonist (TPO-RA), has been proven to improve the hematologic response without increasing toxic effects as a first-line therapy combined with standard immunosuppressive treatment (IST) in adults with severe aplastic anemia (SAA). Nevertheless, the clinical evidence on the efficacy of EPAG in children with acquired aplastic anemia is limited and controversial.

METHODS:

We performed a single-center, retrospective study to analyze the clinical outcomes of fifteen patients aged ≤18 years with newly diagnosed acquired SAA who received first-line IST and EPAG (EPAG group) compared with those of forty-five patients who received IST alone (IST group) by propensity score matching (PSM).

RESULTS:

There was no difference in the overall response (OR) rate between the EPAG group and IST group (53.3% vs. 46.7% at 3 months, P = 0.655; 66.7% vs. 57.8% at 6 months, P = 0.543), but the complete response (CR) rate was statistically significant (20.0% vs. 4.4% at 3 months, P = 0.094; 46.7% vs. 13.3% at 6 months, P = 0.012). The median time to achieve a hematological response in the EPAG and IST groups was 105 days and 184 days, respectively. No difference was observed in the event-free survival (EFS) or overall survival (OS) rates.

CONCLUSION:

Adding EPAG to standard IST as the first-line treatment for children with acquired SAA improved the rapidity of hematological response and the CR rate but did not improve the OR or EFS rates.

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Despite documented success of immunosuppressive therapy (IST) in the treatment of AA, a minority of patients remain refractory, most responses are incomplete, and use of hematopoietic cell transplantation (HCT) is limited in older patients or those with significant comorbidities. While the introduction of the cMpl agonist eltrombopag (EPG) as salvage therapy or in conjunction with IST has revolutionized treatment for refractory AA. It may be effective in improving primary response rates to IST, engaging growth factor receptors with agonistic therapeutics (such as EPG) and also has the potential to promote evolution/expansion of mutant clones, thereby increasing the rate of progression to secondary myelodysplastic syndromes (MDS), a serious complication of AA occurring in 10-20% of patients. Clonogenic somatic mutations typical of MDS in patients with AA and PNH may increase the risk of progression to MDS. DNA from marrow samples of primary refractory AA patients was subjected to analysis before and after initiation of EPG to evaluate clonal expansion or evolution using a targeted multiamplicon deep NGS panel of all ORFs of the top 60 most commonly mutated genes in MDS. In addition to the EPG treatment group, a case control cohort matched for age and duration from AA diagnosis to last clinical follow up (who did not receive EPG), was studied. Among 210 AA patients treated at Cleveland Clinic, we identified 26 who were treated with EPG for IST-refractory AA; median duration of treatment was 56 wks. The overall response rate after 12 weeks of therapy was 58% (15/26), while 31% of patients (8/26) showed stable disease with intermittent transfusions (one of whom underwent HCT). In 3 non-responders, one developed PNH, one had refractory AA/PNH, and one progressed to AML (see below). Expansion of PNH granulocytes after EPG treatment was observed in 23% of patients (6/26). In addition, 15% (4/26) had atypical subclonal chromosomal abnormalities. Prior to EPG, at least a single somatic event was found in 31% of patients (8/26), with 2 patients harboring 2 mutations. Events included CEBPA, EZH2, BCOR/BCORL1, ASXL1, U2AF1/2, TET2, and DNMT3A mutations. Following EPG therapy, acquisition of new somatic mutations was observed in 23% of cases, including RUNX1, U2AF1, BCOR, RIT1, and CEBPA. In cases with pre-existing clones, 6 clones expanded (e.g., BCOR or ASXL1 from VAF of 8 to 21% and 9 to 29%, respectively) despite clinical hematologic response, while in 2 cases clones disappeared (e.g., U2AF2 and BCORL1). In 54% of cases (14/26), we found detectable levels of a PNH clone at the time of diagnosis. Six of those cases had PNH clonal expansion post-EPG treatment, of which two developed clinically significant PNH clonal burden requiring eculizumab therapy. In the case-control cohort, 26 AA patients who received IST but were not treated with EPG, were followed for comparable time periods, and no evidence of progression to MDS was recorded. One patient was noted to have trisomy 15 on cytogenetics at diagnosis. “MDS type” molecular mutations were present in 10 patients similar to EPG cohort. Among these patients, 3 had persistent clones of U2AF1, DNMT3A, and STAT3 over one year without acquisition of any new molecular mutations. . PNH granulocytes expanded in 50% of AA cases, decreased in 30% and stayed stable in 20%. Thus, we did not observe any difference in expansion of PNH clones between those treated and untreated with EPG (p=0.73). Unlike for PNH clones, accounting for both new evolution and expansion of preexisting molecular mutations, the frequency of these clonal events was significantly higher in the EPG treated group (p=0.009). In conclusion, we observed occasional expansion of clones with potentially leukemogenic mutations during treatment with EPG in pts with AA. While higher rates of MDS evolution were not observed in this cohort of EPG treated patients, we found that serial evaluation of somatic mutations can inform clonal evolution and can potentially be used as abiomarker for evaluation of risk for post-AA MDS. Continued use of EPG in such patients should be judicious.

DBA is a rare bone marrow failure syndrome clinically defined by onset of hypoproliferative anemia in early childhood accompanied by a grossly normocellular bone marrow. With age, a significant fraction of patients progress to pancytopenia and a hypocellular bone marrow, with some increased risk of progression to leukemia. Autosomal dominant or sporadic heterozygous mutations in genes encoding for ribosomal subunit proteins have been etiologically linked to DBA. How loss of function mutations in ribosomal proteins results in selective loss of erythroid progenitors with variable severity is incompletely understood. Chronic transfusion therapy and corticosteroid treatment can alleviate anemia, but both cause severe long term toxicities. Hematopoietic stem cell transplantation, when available, is the only definitive treatment modality for the hematological manifestations, and the only known treatment for DBA patients once pancytopenia develops. Here we report on a 28 year old female patient diagnosed with DBA at age of one month based on clinical criteria. Recent mutational analysis identified a novel mutation in intron 4(c.356+3>C) of the RPS19 gene affecting a known splice donor site that has previously reported in DBA patients. She did not respond to corticosteroids and was maintained on transfusions. She failed various experimental therapies including danazol, hematopoietic growth factors including IL-3 and GM-CSF, and anti-thymocyte globulin/cyclosporine without sustained clinical response. After treatment with daclizumab in 2006 her transfusion requirements decreased for about 4 years. In 2012 she presented with progressive pancytopenia and hypocellular bone marrow without overt dysplasia, and normal cytogenetic analysis. She required red cell transfusions. The patient was enrolled in a clinical research protocol investigating the efficiency and safety of the thrombopoietin receptor agonist eltrombopag (EPAG) in patients with moderate aplastic anemia or those with bone marrow failure with unilineage cytopenia (ClinicalTrials.gov: NCT01328587). The study is designed as a non-randomized, phase II, dose modification study with the primary endpoint hematological response at 16 weeks. EPAG was administered at 50mg daily and escalated every 2 weeks by 25 mg to the maximal dose of 300mg daily. At response assessment the patient's hemoglobin (Hgb) improved from 7.0g/dl to 8.9g/dl and platelets from 112K/ul to 171k/ul. She required no further transfusions, and was deemed a responder. EPAG was subsequently continued at the same dose level for an additional 6 months when the peripheral cells counts peaked at Hgb 11.9g/dl, platelets 251K/ul, ANC 3.19 K/ul, and EPAG was discontinued for protocol-defined robust response. After discontinuation of EPAG the patient's hemoglobin steadily declined over a period of 8 months. EPAG was reinitiated at 300mg per protocol. Peripheral blood cell counts rapidly improved and the EPAG dose was slowly tapered. The patient is currently on EPAG 50mg daily with normal blood cell counts. We have not observed any EPAG related toxicities in our patient, and repeated cytogenetic studies on bone marrow documented a normal karyotype. To the best of our knowledge this is the first report documenting EPAG efficacy in a DBA patient. Trautman et al. (2012) previously reported a DBA patient that failed treatment with low dose EPAG after six months. Our observation warrants further systematic investigation of EPAG treatment for DBA patients within a clinical research study setting.

An open-label, dose-adjustment extension study to evaluate the safety and efficacy of eltrombopag for treatment of subjects with ITP who have previously been enrolled in the eltrombopag trial TRA108109 (NCT00540423).

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia, with platelet counts <100 × 109/L. Eltrombopag is an oral small-molecule nonpeptide thrombopoietin-receptor agonist that has shown to increase platelet production. It is approved for the management of patients with chronic ITP (aged ≥1 year) who are refractory to other treatments (eg, corticosteroids, immunoglobulins). The recommended eltrombopag dose in patients with chronic ITP is 25mg once daily, OD (East Asians, 12.5mg OD or 25mg every other day) in pediatrics aged 1-5 years, and 50mg OD (East Asians, 25mg OD) in adults and pediatrics aged 6-17 years at initiation, followed by dose adjustment to a maximum of 75mg OD based on platelet counts. REVIEU study was conducted in accordance with risk management plan in five European Union (EU) countries to document eltrombopag utilization patterns in real-world practice. Here, we report the eltrombopag data on the subset of adult patients (aged ≥18 years) with ITP as primary diagnosis. Aims: To evaluate the real-world data to determine drug utilization patterns among adult patients with ITP receiving eltrombopag within five EU countries. Methods: REVIEU study was a multinational, multicenter, retrospective, medical chart review in patients with a documented past treatment with eltrombopag between the period immediately after first approval/launch in May 2010 and September 2014 (ie, dispensed at least once by the pharmacy and patient received at least one dose) for whatever reason. Patients who participated or were participating in a randomized eltrombopag clinical trial were excluded.(Table Presented) Results: Overall, 287 adult patients with ITP (chronic [>12 months], 75.3%; persistent [3-12 months], 10.8%; acute [<3 months], 13.6%; unknown [n=1]) were included, majority in Spain (n=128) followed by Italy (n=67), Greece (n=36), France (n=29), and Germany (n=27). Eltrombopag was the first treatment with no prior ITP therapies in 12 (4.2%) [acute, 10.3%; persistent, 6.5%; chronic, 2.8%] patients. A total of 99 (34.6%) patients received one prior therapy (corticosteroids, 79 [27.6%]), 128 (44.8%) patients received two prior therapies (corticosteroids+immunoglobulin, 114 [39.9%]), and 47 (16.4%) patients received three prior therapies (corticosteroids, immunoglobulins, and splenectomy). In total, the majority of patients received at least one prescription of corticosteroids (252, 88.1%) followed by immunoglobulins (180, 62.9%), and splenectomy (64, 22.4%) prior to eltrombopag initiation. Patients received an average daily dose of eltrombopag 45.6mg (chronic ITP, 44.6mg; persistent ITP, 43.1mg; acute ITP, 53.0mg) during the study. Overall, dose changes were reported in 749 adult ITP prescriptions (down-titration, 53.7%; up-titration, 43.7%; no change in dose, 2.7%). 49.1% of dose changes were reported during the first 6 months of treatment (35% in first 3 months). The main reasons for dose change included: disease improvement (30.4%), no treatment response (26.8%) and others (27.1%). Disease improvement accounted for down-titration in 51.2% (206/402) and up-titration in 4.6% (15/327), and no treatment response for up-titration in 54.4% (178/327) and down-titration in 5.0% (20/402) of adult patients with ITP. Proportion of patients with platelet counts by ITP disease phase, and by eltrombopag dose are reported in Table 1. Summary/Conclusions: The majority of adult patients with ITP (75.3%) were diagnosed with chronic ITP, and were treated with eltrombopag as second-line or greater therapy after corticosteroids and immunoglobulins, in line with the approved indication. Eltrombopag was also prescribed in 24.4% of adult patients with acute and persistent ITP. The starting dose followed the summary of product characteristics (SmPC) recommendations in the majority of cases and dose modifications were generally according to platelet counts. Data from REVIEU study have shown that eltrombopag use in the real world setting is largely consistent with the EU label and is considered part of ITP medical therapies.