Modeling and Simulation Support Eltrombopag Dosing in Pediatric Patients With Immune Thrombocytopenia.

Our objective was to support initial eltrombopag doses and dose titration based on modeling and simulation of plasma exposure and platelet count response in pediatric patients aged 1-17 years with previously treated chronic immune thrombocytopenia enrolled in two clinical studies. Data from 168 pediatric patients were used to develop a life-span population pharmacokinetic and pharmacodynamic model including three pharmacokinetic and four pharmacodynamic compartments enabling simulation of platelet counts for various starting doses and dose titration schedules. This work supported initial eltrombopag doses of 50 mg once daily (q.d.) for non-Asian patients aged ≥ 6 years and 25 mg q.d. for Asian patients, regardless of age, and for all patients aged 1-5 years, regardless of ethnic origin. Doses were escalated at 2-week intervals or reduced as needed according to each patient's platelet counts to both minimize the time to achieve target platelet counts and mitigate thrombocytosis. Clinicaltrials.gov Identifier: NCT00908037, NCT01520909.

Predictive Factors of Idiopathic Thrombocytopenic Purpura and Long-term Survival in Chinese Adults Undergoing Laparoscopic Splenectomy.

The study aimed to investigate the long-term outcomes of laparoscopic splenectomy (LS) in Chinese patients with chronic idiopathic thrombocytopenic purpura (ITP). This was a retrospective analysis of 114 patients with ITP who underwent LS from 2001 to 2013. Patients were classified according to response at last contact: complete response (CR), partial response (PR), and no response (NR). Patients with CR had the highest platelet levels and patients with NR had the lowest. A correlation was observed between postoperative peak platelet count and platelet count on 2-month postoperative (r=0.829, P<0.01). In total, 27 patients showed NR to LS. Ten patients recurred within 3 years. The 140-month response rate to LS was 68%. Multivariate analysis showed that age and postoperative platelet count were independently associated with CR/PR. In conclusion, LS achieved good outcomes in Chinese patients with ITP. Age and postoperative peak platelet were independently associated with response.

The Effects of Helicobacter pylori Eradication Therapy for Chronic IdiopathicThrombocytopenic Purpura.

BACKGROUND/AIMS: The aim of this study was to evaluate the ability of Helicobacter pylori eradication treatment to increase platelet counts in Korean patients with chronic idiopathic thrombocytopenic purpura (ITP). METHODS: A total of 102 patients were evaluated against two criteria. First, those diagnosed with H. pylori infections in whom eradication was successful were assigned to the H. pylori-positive and -eradicated group (n=39), whereas those diagnosed with H. pylori infections in whom eradication failed were assigned to the H. pylori-positive and -non-eradicated group (n=3), and those without H. pylori infections were assigned to the H. pylori - negative group (n=60). Second, patients with complete remission in whom the platelet recovery effect was maintained over the average follow-up period of 6 months after eradication therapy were defined as the responder group (n=58), whereas those with partial or no response were defined as the nonresponder group (n=44). RESULTS: The platelet counts of the H. pylori-positive and -eradicated group were significantly increased 6 months after eradication therapy compared to those of the H. pylori-positive and -non-eradicated group and the H. pylori-negative group (43.2±29.1 to 155.3±68.7×10³/µL vs 42.5±28.1 to 79.8±59.7×10³/µL vs 43.1±28.9 to 81.2±62.2×10³/µL; p=0.041). The eradication therapy success rate in the responder group was 100.0% (39/39), in contrast to the nonresponder group (0%, 0/3) (p<0.001). CONCLUSIONS: H. pylori eradication therapy was related to increased platelet count, and successful eradication affected the increased platelet count in Korean patients with chronic ITP.

TNF-α promoter single nucleotide polymorphisms and haplotypes associate with susceptibility of immune thrombocytopenia in Chinese adults.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-α) participates as a candidate susceptibility factor for immune thrombocytopenia (ITP). This study attempted to investigate the association between five single nucleotide polymorphisms (SNPs) spanning the TNF-α promoter and the susceptibility of primary ITP in Chinese Han adults. METHODS: In 215 adult primary ITP patients and 206 healthy controls, SNPs were detected by PCR-RFLP and PCR-SSP. The χ(2) test or fisher's exact test was used to compare frequencies of genotypes and alleles between patients and controls. Haplotypes were analyzed with the SHEsis online program. TNF-α, IFN-γ and Galectin-9 mRNA of 35 newly diagnosed adult ITP patients and 35 healthy controls were detected by qRT-PCR. RESULTS: The haplotype GGC (-238G/-308G/-857C) of TNF-α promoter was significantly associated with a decreased susceptibility of primary ITP, especially in males. The relative levels of mRNA expression of TNF-α, IFN-γ and Gal-9 in adult active primary ITP patients was significantly up-regulated compared with patients in remission and controls. CONCLUSIONS: This study represented the first report that the haplotype GGC of TNF-α was differentially associated with the susceptibility of primary ITP in Chinese Han adults. The up-regulation of TNF-α, IFN-γ and Galectin-9 was significantly correlated with active primary ITP in adult patients.

Dysplasia features of myelodysplastic syndrome in ethnically Chinese people.

OBJECTIVE: It was our aim to study the diagnostic significances of various dysplasia characteristics in myelodysplastic syndrome (MDS). METHODS: We analyzed 160 cases of primary MDS and a control group including 28 cases of paroxysmal nocturnal hemoglobinuria (PNH), 104 cases of idiopathic thrombocytopenic purpura (ITP), 53 cases of non-severe aplastic anemia (NSAA), 40 cases of megaloblastic anemia and 50 cases of infectious and autoimmune diseases. Peripheral blood smears and bone marrow morphology were reviewed. RESULTS: There was no significant difference in the occurrence rates of a variety of dysplasias in three lineages among MDS, megaloblastic anemia and PNH; however, changes in qualities and quantities in three lineages between NSAA and MDS were significantly different. ITP and MDS showed statistical differences in multiple changes in myeloid and erythroid cells. Significant differences also existed in multiple changes in erythroid series and megakaryocytes between infectious and autoimmune diseases and MDS. Morphological abnormalities highly related with MDS included multinucleated erythroblasts, ringed sideroblasts, poikilocytosis and gigantocytes, pseudo-Pelger neutrophils, ring-shaped nucleus, and micromegakaryocytes. CONCLUSIONS: It is difficult to discriminate megaloblastic anemia and PNH from MDS by means of cell morphology. Different dysplasias of MDS have specific diagnostic values.

Polymorphisms of the IL-23R gene are associated with primary immune thrombocytopenia but not with the clinical outcome of pulsed high-dose dexamethasone therapy.

Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder that is characterized by decreased platelet count. The interleukin-23 receptor (IL-23R) has been identified as a susceptibility gene for the development of multiple autoimmune diseases. To investigate the possible association of IL-23R gene single-nucleotide polymorphisms (SNPs) with ITP and the association with the clinical outcome of pulsed high-dose dexamethasone (HD-DXM) therapy, four SNPs in the IL-23R gene, rs10889677, rs1884444, rs7517847, and rs11209032, were tested in a cohort of 75 ITP subjects and 81 controls by direct sequencing. IL-23R rs1884444 GT/TT variant genotypes were observed to be associated with significantly increased risk of ITP as compared with controls (GT/TT vs. GG: odds ratio (OR) 2.776, 95 % confidence intervals (CI) 1.086-7.090, p = 0.028). However, other three SNPs revealed no statistically significant differences between patients and controls (rs10889677 CA/AA vs. CC: OR 2.200, 95 % CI 0.727-6.661, p = 0.155; rs11209032 GA/AA vs. GG: OR 0.747, 95 % CI 0.379-1.472, p = 0.399; rs7517847 TG/GG vs. TT: OR 1.031, 95 % CI 0.544-1.956, p = 0.925). Furthermore, IL-23R SNPs revealed no association with clinical outcome of HD-DXM therapy. This study suggests that polymorphism in the IL-23R gene, rs1884444, indicates a significant association with susceptibility to ITP in a recessive genetic model but does not have association with the clinical outcome of HD-DXM therapy.

A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia.

BACKGROUND: Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non-East Asian ITP descent. OBJECTIVES: To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. PATIENTS: We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30,000 µL(-1) in a multicenter study comprising a randomized, double-blind, placebo-controlled phase for 6-week evaluation (15 eltrombopag, and eight placebo) and an open-label phase for 6-month evaluation (23 eltrombopag). RESULTS AND CONCLUSIONS: The response rate (platelet count of ≥ 50,000 µL(-1) ) at week 6 of the 6-week double-blind phase was 60% in eltrombopag-treated patients and 0% in placebo-treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6-month open-label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5-50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423).

Chronic adult primary immune thrombocytopenia (ITP) in the Asia-Pacific region.

Patients with primary immune thrombocytopenia (ITP) from the Asia-Pacific region often exhibit characteristics distinct from those of patients from the West. Moreover, as the region itself is heterogeneous, the ITP landscape among individual Asia-Pacific countries can be diverse. The recently released international consensus report on ITP places new emphasis on ITP, but does not address the unique ITP landscape in the Asia-Pacific region, which is home to 60% of the world's population. In an attempt to characterize how the ITP landscape differs between the West and the Asia-Pacific region, an expert panel with representatives from Northeast Asia, Southeast Asia, and Australia was convened. Important differences were identified between the guidance provided in the international consensus report and experience in the Asia-Pacific region, namely diagnostic practices, incidence and approach to ITP secondary to H. pylori infection, systemic lupus erythematosus-related ITP, the use of bone marrow examination, initial treatment strategies, and the role of splenectomy, rituximab, and thrombopoietin receptor agonists.

Laparoscopic splenectomy and the treatment outcomes for idiopathic thrombocytopaenic purpura at North Shore Hospital.

AIM: Firstly, the demographics of laparoscopic splenectomy cases at North Shore Hospital (Takapuna, Auckland, New Zealand), the outcomes of operative technique, and perioperative complications by a single surgeon were reviewed. Secondly, analysis was performed on patients with idiopathic thrombocytopaenic purpura (ITP) with regard to platelet response and detection of preoperative predictors. METHODS: Laparoscopic splenectomy patients from 1998 to 2007 were reviewed with respect to demographics, operation and their complications. ITP outcomes, analysed separately, were categorised as complete remission for postsplenectomy platelet counts greater than 150 x 10(9)/L, partial remission as 30 - 149 x 10(9)/L and refractory as platelet counts less than 30 x 10(9)/L. The relationships between preoperative steroid, immunoglobulin transfusion and operative outcomes were analysed. RESULTS: 29 (67%) out of 43 laparoscopic splenectomies were for ITP. For ITP cases, 19 (65%) achieved complete remission and six (21%) partial remission at 3-month follow-up. Follow-up detected that two cases in each group had relapses after 3 months. Explorative data analysis suggested that a lack of preoperative transfusion may predict an approximately 80% chance of complete remission postsplenectomy. There was one conversion to an open splenectomy and no mortality with minimal complications. CONCLUSION: Cumulatively, in 86% of cases, laparoscopic splenectomy created a significant increase in platelet counts at 3-month postoperatively without any long-term morbidity. Although not strongly demonstrated, preoperative immunoglobulin transfusion may be correlated with remission.

A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura.

This phase II, multicenter, open-label, sequential-cohort, dose-escalation study was designed to evaluate the safety and efficacy of romiplostim, a novel peptibody that increases platelet production, in Japanese patients with chronic immune thrombocytopenic purpura (ITP). Sequential cohorts of four patients each received romiplostim (1, 3, or 6 microg/kg) subcutaneously on days 1 and 8 of the dose-escalation phase. Patients who achieved platelet responses (doubling of baseline platelet counts to > or =50 x 10(9)/L) continued romiplostim weekly during the treatment-continuation phase. Romiplostim produced dose-dependent increases in mean and peak platelet counts. Five patients received romiplostim during the treatment-continuation phase, with platelet counts > or =50 x 10(9)/L maintained in approximately half of the weekly assessments. Romiplostim was well tolerated. No severe, serious, or life-threatening adverse events were reported. No binding antibodies to romiplostim or thrombopoietin were detected. Romiplostim is safe and well tolerated in Japanese patients with chronic ITP and is effective in producing platelet count increases, consistent with the results from studies in non-Japanese patients. On the basis of these findings, a starting dose of 3 microg/kg was recommended for phase III evaluation of romiplostim in Japanese patients with chronic ITP.

Ethnicity and environment may affect the phenotype of immune thrombocytopenic purpura in children.

Little is known about the influence of environmental and ethnic factors on the epidemiology of immune thrombocytopenic purpura (ITP). Therefore we compared the initial presentation and condition after 6 mo in 90 Vietnamese and 89 German and Swiss children with newly diagnosed ITP. Data from the two cohorts were collected within the same time period. No differences in age and sex were observed between the Asian and European cohorts, but significant differences between initial platelet count, the occurrence of dry versus wet bleeding symptoms, and infection preceding the onset of ITP were found. Children who had chronic ITP also differed with respect to platelet count and postinfectious state, but not initial bleeding type. In addition, chronic ITP occurred more often than expected with a male to female ratio of 1.2 in Vietnam and 2 in Germany and Switzerland. The data support the potential influence of environmental or ethnic factors on the different aspects of ITP, and point to the need for further epidemiologic investigations.

Clinical significance of HLA-DRB1*0410 in Japanese patients with idiopathic thrombocytopenic purpura.

We performed HLA-A, -B, and -C antigen and -DR DNA typing in 111 Japanese patients with idiopathic thrombocytopenic purpura (ITP). DRB1*0410 was significantly increased in ITP patients compared with healthy controls (relative risk = 9.52, P < .05), but the other DRB1*04 alleles showed no significant differences. On HLA-DR serotyping, patients with Vogt-Koyanagi-Harada disease (VKH) had a high frequency of DR4, so we compared the frequencies of DRB1*04 suballeles between ITP and VKH. The high frequency of DRB1*04 was dependent on DRB1*0405 in VKH, but on DRB1*0410 in ITP. Plasma autoantibodies were studied in 111 patients using a microtiter well assay. Thirty-six patients had anti-GPIIb/IIIa autoantibodies, and antibody positivity was associated with HLA-DR4 (29 of 36, 80.6% v 28 of 75, 37.3%) but not with DRB1*0410. When HLA-DR4 and DRB1*0410 were compared between patients with a good or poor response to prednisolone, HLA-DR4 was decreased and DRB1*0410 was significantly decreased (chi2 = 11.455, P < .01) in patients with a good response. In conclusion, this study showed that genetically determined factors influence the course of ITP. However, our findings should be considered preliminary because of possible racial differences in HLA status between Japanese and other ITP patients.