Second-line Treatment For Immune Thrombocytopenia Research Articles

What is the best second-line treatment for immune thrombocytopenia?

The choice between thrombopoietin receptor agonists (TPO-RAs) and anti-CD20 as the preferred second-line therapies for immune thrombocytopenia remains in the eye of the beholders. Each has major advantages and certain weaknesses. Stolz etal. describe a single-centre experience that whets our appetite for a large randomized controlled trial comparing a TPO agonist and an anti-CD20 agent. Commentary on: Stolz etal. Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia - A single center retrospective analysis. Br J Haematol 2024; 205:1121-1125.

Rituximab versus Splenectomy in Chronic Primary ITP: Experience of a Single Hematology Clinic.

Immune thrombocytopenia (ITP) is an acquired immune-mediated disease that lacks an underlying etiology. Steroids are the main first-line treatment of ITP, while the second-line treatment consists primarily of splenectomy and rituximab. This study aimed to assess and compare the response to rituximab and splenectomy. This retrospective comparative study reviewed ITP patients treated at a single private hematology clinic from 2007 to 2019. Seventy-four ITP patients were recruited, 27 were on rituximab, and 47 had undergone splenectomy. The initial platelet counts and bleeding symptoms were recorded, and initial and long-term responses to treatment were evaluated based on the American Society of Hematology guidelines. The mean age of the patients was 42.1 years with a male-to-female ratio of 1:1.8. The initial mean platelet count was comparable between the rituximab and splenectomy groups (p = 0.749). The initial complete response (CR) differed significantly between the rituximab and splenectomy groups (44.4% versus 83%, p = 0.002). The five-year response rate was significantly higher in the splenectomy than in the rituximab group (74% versus 52%, log-rank 0.038). Splenectomy was the only significant predictive factor for long-term response (OR = 0.193, p = 0.006). The overall response revealed that splenectomy appeared superior to rituximab as a second-line treatment of ITP. Splenectomy was the only positive prognostic indicator of sustained response.

Clinical and Genetic Characteristics of 30 Patients Misdiagnosed As Having ITP with Non-Muscle Myosin Heavy Chain 9-Related Disease (MYH9-RD): A Retrospective Analysis in China

Introduction : Non-muscle myosin heavy chain 9-related diseases (MYH9-RD) are rare autosomal dominant platelet (PLT) disorders presenting as nonsyndromic forms characterized by macrothrombocytopenia with giant PLTs and leukocyte inclusion bodies or as syndromic forms combining these hematological features with deafness, nephropathy, or cataracts. Owing to its low incidence and similar clinical manifestations, it is easily misdiagnosed as immune thrombocytopenia (ITP), leading to inappropriate treatment. To improve the diagnosis of this rare thrombocytopenic disease and minimize the misdiagnosis rate, we retrospectively analyzed the clinical, treatment, and genetic characteristics of patients with MYH9-RD who were initially misdiagnosed with ITP and compared the differences between pediatric and adult patients. Methods: Patients from various sites in China were enrolled. The inclusion criteria were macrothrombocytopenia on peripheral blood smear, MYH9 gene mutation detected by next-generation sequencing or whole exon sequencing and verified by Sanger sequencing, and absence of other acquired thrombocytopenia diseases. We collected basic information, clinical manifestations, and laboratory test results via medical records and telephone interviews. Results: Of the 30 patients, 17 were male, 13 were female, 14 were children, and 16 were adults. There was no significant difference in the mean PLT count (×10 9/L) at the time of diagnosis between children and adults (50.5 vs. 33.4, P=0.188). However, the median duration of misdiagnosis was significantly shorter in children (0.1 y vs. 9 y, P=0.000) (Table 1). Overall, 5 patients showed no signs of bleeding, while 25 presented with bleeding manifestations: 11 with skin bleeding spots and ecchymosis, 15 with epistaxis, 6 with gingival bleeding, and 3 with increased menstrual volume. Moreover, 21 patients showed no non-hematological manifestations, while 9 presented with non-hematological manifestations, which occurred exclusively in adult patients. Among the latter, 6 patients had nephropathy (2 underwent renal transplantation, and 2 underwent regular dialysis), 5 had hearing impairment (4 underwent high-frequency hearing impairment, and 1 received a cochlear implant due to deafness), and 1 had a congenital cataract. All patients received first- or second-line treatment for ITP. The most common treatment in children was immunoglobulins (12/14), followed by steroids (5/14) and traditional Chinese medicine (2/14). No children received >3 types of treatment, 4 children received >1, and 6 adult patients received >3. The highest number of treatment type for a single patient was up to 7. The median duration of ITP treatment was 1.5 y for adults and 0.1 y for children ( P=0.002). All patients presented heterozygous missense mutations in MYH9; 17/30 were spontaneous mutations, 7/30 were familial mutations (involving 6 paternal and 1 maternal origin), and 6/30 cases had an unknown inherited type. Fourteen cases were located in the N-terminal globular head region, and 16 cases were located in the C-terminal tail domain (Figure 1). Two novel mutations (not recorded in the Global Variome database), p. G1517V and p. K1674Q, were identified. In 2 adult patients with p.R702C mutations, proteinuria occurred in adolescence, followed by chronic renal failure (CRF), end-stage renal failure, and hearing loss. The 3 children with p.R702C mutation were aged <4 years and exhibited no non-hematological symptoms. Three of the 5 adults with p.E1841K mutations had CRF and underwent kidney transplantation. Conclusion s : Compared with pediatric patients, adult patients are more likely to be misdiagnosed with ITP, receive more types of inappropriate treatment for a longer period of time, and have more common non-hematological manifestations. To improve diagnostic accuracy and reduce the misdiagnosis rate for patients with thrombocytopenia, especially those with a poor response to ITP treatments, attention should be paid to mean PLT volume, family history, and genetic screening. Consistent with previous reports, patients with the p.R702C mutation showed early-stage kidney injury and hearing loss. The incidence of spontaneous mutations (56.7%) was significantly higher than previously reported (25-35%). The genetic characteristics of MYH9-RD and genotype-phenotype relationships in China require further clarification.

Effect of Hetrombopag Combined with Rhtpo in Patients with Severe Immune Thrombocytopenia

Background: Severe Immune Thrombocytopenia (ITP) is a life-threatening acquired hemorrhagic disease with dramatically decreased platelet number and clinical bleeding symptoms. Some patients with severe ITP did not respond to first-line treatment including steroids and Intravenous Immunoglobulin (IVIG). It was critical for them to use effective treatments to promote platelet and reduce the risk of fatal bleeding. Clinical practice guidelines have recommended the use of thrombopoietin receptor agonist (TPO-RA) as a second-line treatment for ITP. Recombinant human thrombopoietin (rhTPO) and hetrombopag are two distinct TPO-RAs with different mechanisms. As reported, there remains no study assessing the efficacy and safety of hetrombopag combined with rhTPO in the treatment of ITP. Therefore, the present study aimed to investigate the efficacy of hetrombopag plus rhTPO in Chinese patients with severe ITP, focusing on the short rather than the long-term efficacy, such as quickly increasing platelet count and significantly reducing bleeding, which would be more meaningful for severe patients whose platelet count <10 × 10 9/L. Methods: This was a prospective, open-label, single-center study with a planned enrollment of 30 patients. The inclusion criteria were patients ≥ 18 years, diagnosed with primary immune thrombocytopenia, platelet count <10 × 10 9/L, or bleeding score ≥ 5. Patients receiving other ITP drugs as maintenance therapy were eligible if previous glucocorticoid therapy doses were stable, and rituximab was used for at least 2 months and other immunosuppressants were stable for at least 4 weeks. Patients who had received IVIG, avatrombopag, eltrombopag, or romiplostim within 2 weeks prior to enrollment were excluded. Histories of platelet transfusion one week before treatment were excluded. Hetrombopag was given at 5 mg/day for 28 days, while rhTPO was administered at 300 U/kg subcutaneously daily for 14 days. When PLT > 100 × 10 9/L, rhTPO should be discontinued. When PLT > 150 × 10 9/L, the dosage of hetrombopag was reduced to 2.5mg/day, and it would be discontinued if PLT > 250 × 10 9/L. The primary endpoints were proportion of subjects with platelet count ≥30×10 9/L and at least doubled the baseline platelet count within 28 days. Secondary endpoints included bleeding score, incidence of thrombotic events, and adverse events (AEs). Results: As to July 27, 2023, a total of 20 patients were included in this study, with a median age of 36 years and a male proportion of 50%. Among them, 70% (14 cases) were newly diagnosed ITP patients. 50% of patients have received ≥ 1 line of previous treatment, of which 2 patients have received IVIG treatment and both have achieved CR (PLT ≥ 100 × 10 9/L). The baseline median platelet count was 5 × 10 9/L, and 95% (19 cases) of patients had active bleeding with a bleeding score of ≥ 1 point. The median duration for hetrombopag at dose of 5mg is 8.0 days, and rhTPO is 6.5 days. After combined treatment, the median time for platelet counts reached 30, 50, and 100 × 10 9/L was 4.5 days, 6 days, and 7 days, respectively. Among them, the median platelet count reached 103 × 10 9/L after 7 days treatment and 214.5 × 10 9/L after 15 days. Within 15 days of combined treatment, 15% (3 cases) of patients achieved partial platelet reaction (PLT > 50 × 10 9/L, without bleeding), and 85% (17 cases) achieved complete platelet reaction (PLT > 100 × 10 9/L, without bleeding). In terms of safety, two patients experienced liver function abnormalities, both of which were grade 1-2. One was related to treatment drugs, and the other was associated with underlying autoimmune liver disease. No thrombotic events occurred in all patients. Conclusion: This study innovatively explores the efficacy and safety of combination therapy with hetrombopag and rhTPO in the treatment of severe ITP. It is preliminarily confirmed that this combination therapy can effectively and quickly improve the early platelet response of ITP patients, avoid bleeding damage, and is expected to become a new treatment choice for severe ITP patients. We also look forward to the overall efficacy evaluation results of all patients after completing treatment in the future.

Avatrombopag in Immune Thrombocytopenia (ITP). Real-Life Experience of Its Use in Hospitals within the Community of Madrid, Spain (AVAMAD STUDY)

Introduction Thrombopoietin receptor agonists (TPO-RAs) are recommended as second-line treatment for immune thrombocytopenia (ITP) according to the Spanish ITP group (GEPTI) guidelines. Avatrombopag (AVA) is an oral TPO-RA, recently launched in Spain, for which we have little data available beyond the pivotal trial. The main objectives of our study were to evaluate the efficacy and safety of AVA in patients with ITP. Methods In this observational, retrospective, multicenter study in 10 hospitals in the Community of Madrid, we have analyzed adult patients with ITP treated with AVA from July 2022-May 2023. Demographic characteristics, response, rescue therapy, adverse effects and treatment discontinuation were analyzed. The definition of ITP and response were those described by Provan et al. The study protocol was designed and applied in accordance with the principles of the Declaration of Helsinki. Statistical analysis was performed using IBM SPSS Statistics v28.0. Fisher and Mann-Whitney tests were used for bivariate analysis and Kaplan-Meier curves for response time. Results A total of 66 patients were included. The median age was 52 years old (IQR 34-71). Table 1 describes the general characteristics. There was a median of 2 (IQR1-3) previous lines of treatment before starting AVA. The reasons for its initiation were: refractoriness to previous treatment and/or corticodependence in 39% (25/66), loss of response in 34% (22/66), switch due to patient preference in 14% (9/66) and switch due to adverse effects with previous treatment in 5% (3/66). In 8% (5/66) there was more than one reason for change. The previous line of treatment is described in Table 1. The median platelet count at baseline was 36x10 9/L(IQR 13-61). With a median follow-up of 16 weeks (IQR 8-28), 86% of the pateints (57/66) were responders. 73% had complete response. 24% percent (16/66) required salvage therapy. In the bivariate analysis, 100% of those aged ≥65 years presented response vs. 75% in <65 years (p=0.003). A complete response was achieved in 88.6% of women versus 54.8% of men (p=0.002). Patients with complete response received fewer lines of treatment (1 [IQR 1-3] vs 3.5 [IQR 2-6]); p< 0.001). Complete response was achieved in 60.5% of patients who received previous treatment with eltrombopag (p=0.01), in 47.8% of those with romiplostim (p<0.001), in 40% with rituximab (p=0.02), in 33.3% with splenectomy (p=.0.01) and in 22.2% with fostamatinib (p=0.00).The median time from initiation of AVA to response was 2,1 weeks [IQR 2-4] (Figure 1). Twelve patients (18%) discontinued AVA due to: lack of response (n=6), adverse effects (n=3), one patient prior to scheduled surgery, and In these patients AVA was restarted with dose adjustment. Adverse effects are described in Table 1. Conclusions The results of the use of AVA in real-life demonstrated a high response rate, more favorable in the initial lines of treatment. In addition, it reduces the need for salvage therapy and has a low adverse effect profile. A larger number of patients and a longer follow-up are needed to verify these results and to answer some questions such as whether it is possible to discontinue AVA treatment after response and the percentage of patients with sustained response following AVA discontinuation.

Low-Dose Rhein Sensitizes Platelet Production to Thrombopoietin Receptor Agonists (TPO-RA) in Immune Thrombocytopenia

Introduction: Primary immune thrombocytopenia (ITP) is an immune-mediated disorder characterized by isolated thrombocytopenia and risk of hemorrhage. Impaired megakaryocyte maturation and insufficient platelet formation, induced by platelet-specific autoantibodies or ITP plasma, play vital roles in its pathogenesis. Although thrombopoietin receptor agonists (TPO-RA) is recommended the first choice among second-line treatment of ITP, clinical data have indicated that nearly half of ITP patients failed or relapsed during eltrombopag maintenance, and increasing drug dose cannot reverse therapeutic response. Diacerein, hydrolyzed into its active metabolite rhein after oral administration, is a non-steroidal anti-inflammatory drug used in osteoarthritis. Our team first observed that 3 ITP patients with low platelet levels (30-50 ×109/L) during eltrombopag treatment, achieved significant platelet response (≥100×109/L) after taking diacerein concomitantly due to the complaint of arthralgia. These data suggested that diacerein may have sensitization effect on TPO-RA, and this novel combination is expected to boost thrombopoiesis in ITP. Thus, in vitro and in vivo experiments were performed to explore the role of TPO-RA plus rhein in megakaryocyte growth and platelet formation in ITP. Methods: Twenty-eight eltrombopag-inefficient or relapsed ITP patients and 15 healthy volunteers were included in this study. We sorted CD34+ cells from healthy umbilical cord blood mononuclear cells, then cultured them in SFEM medium containing thrombopoietin, interleukin-3, stem cell factor and 10% serum from either ITP patients or healthy donors. Different doses of eltrombopag combined with rhein (0-100 μM) were added on the fourth day, and cell suspension was collected on the 14th day. Flow cytometry, RNA sequencing, proteomic sequencing and cytokine assay were performed to evaluate the overlaying effect and underlying mechanisms of rhein on eltrombopag. In addition, active ITP murine models were established to evaluate the therapeutic effects of romiplostim plus rhein in vivo. Results: Compared with eltrombopag, eltrombopag combined with low-dose rhein significantly increased the proportion of CD41+, CD41+CD42+, CD41+CD61+ megakaryocytes in vitro. We further found that eltrombopag plus low-dose rhein significantly promoted polyploid maturation and apoptosis of CD41+ megakaryocytes, as well as platelet production in vitro (Fig 1). The ITP mice exhibited profound thrombocytopenia, and their platelet counts decreased significantly by the second week after irradiation. Our data showed that romiplostim plus low-dose rhein significantly alleviated thrombocytopenia than romiplostim monotherapy on day 21 and day 28 (Fig 2). Mice receiving different doses of rhein monotherapy were comparable in platelet counts with control group. Flow cytometry analysis suggested that the combination therapy significantly increased megakaryocyte percentage and polyploidization than romiplostim in ITP mice. Subsequently, RNA sequencing and proteomic analysis revealed that the combination of eltrombopag and low-dose rhein promoted megakaryocyte growth and platelet formation, decreased proinflammatory cytokines, and upregulated phosphorylated PI3K in vitro. Cytokine analysis indicated that eltrombopag plus low-dose rhein significantly increased supernatant level of TGF-β, and reduced IFN-α, IFN-γ, IL-12p70, IL-17A and IL-18 than eltrombopag. Furthermore, it was confirmed that the addition of rhein to TPO-RA significantly promoted megakaryocyte PI3K phosphorylation in vitro and in vivo. PI3K inhibition offset the enhanced effect of eltrombopag plus low-dose rhein over eltrombopag in megakaryocyte maturation and platelet formation. Conclusions: In sum, our data reveal a sensitizing role of rhein to TPO-RA in megakaryocyte polyploidization and platelet formation in ITP, and this novel combination therapy warrants further investigation as an optimized strategy for ITP patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment patterns and outcomes of second-line rituximab and thrombopoietin receptor agonists in adult immune thrombocytopenia: A Canadian retrospective cohort study

BackgroundThe optimal choice of second-line treatment for immune thrombocytopenia (ITP) is unclear. Guidelines recommend either rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA). There is, however, scarce data comparing treatment patterns, outcomes and resource utilization across second-line treatments. Despite Canada's universal healthcare system, publicly funded access to second-line ITP therapies is highly variable across provinces/territories. ObjectivesTo describe treatment patterns and compare health service utilization and outcomes among recipients of second-line rituximab and TPO-RA for ITP. MethodsIn this multicentre retrospective cohort study, we included adults who received second-line ITP therapies rituximab, eltrombopag and romiplostim (2012-2020) in Alberta, Canada. Patients were identified through a provincially-funded special drug access (STEDT) program. We examined treatment patterns, predictors of second-line treatment, hospitalizations, blood product utilization, and outcomes. Kaplan-Meier survival curves were used to estimate the cumulative incidence of ITP-related hospitalizations (bleeding or infections), overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to examine the impact of second-line therapy on OS. Results223 patients received rituximab (67 %), eltrombopag (29 %), and romiplostim (4 %). TPO-RA recipients experienced significantly longer time from ITP diagnosis to second-line therapy compared with rituximab recipients (15.9 vs 6.7 months, P < 0.0001), accompanied by significantly higher platelet and IVIG utilization prior to second-line therapy. Age (adjusted odds ratio [aOR] 1.04, 95 % CI 1.02–1.07, P < 0.0001) and prior intracranial hemorrhage (aOR 12.7, 95 % CI 1.6–272.8, P = 0.03) were significant predictors of second-line TPO-RA. TPO-RA is associated with a trend towards longer median RFS (6.3 vs 3.8 years, P = 0.06) compared with rituximab, and similar rates of ITP-related hospitalizations, major bleeding, and thromboembolism. Age, time period, and Charlson comorbidity index, but not second-line ITP therapy, were significant predictors of OS. ConclusionsOur study identified older age and intracranial hemorrhage as predictors of second-line TPO-RA prescription in a real-world practice. There were no significant differences in hospitalizations and outcomes between second-line rituximab and TPO-RA, although delayed initiation of TPO-RA was associated with higher blood product utilization.

Does eltrombopag lead to thrombotic events? A pharmacovigilance study of the FDA adverse event reporting system.

Eltrombopag is an orally bioavailable drug developed as a second-line treatment for immune thrombocytopenia. However, there are limited reports on thrombotic events related to eltrombopag use. This study aimed to assess the relationship between eltrombopag and thrombotic events in a large population extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. A total of 525 FAERS reports on thrombotic events associated with eltrombopag alone and 59 on those associated with the simultaneous use of eltrombopag and glucocorticoids, from Q1 2004 to Q3 2021, were included. Reports of thrombotic events were analysed using the following algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). The time to onset and outcomes of thrombotic events between the two groups were also analysed. A total of 525 reports of thrombotic events with eltrombopag were identified. Compared with eltrombopag alone, the concomitant use of eltrombopag and glucocorticoids was associated with a higher incidence of thrombotic events based on higher ROR (9.92, 95% two-sided CI 7.58-12.97 vs. 3.46, 95% two-sided CI 3.17-3.77), PRR (9.06, χ2 =427.37 vs. 3.37, χ2 =881.55), IC (3.18, 95% one-sided CI=2.43 vs. 1.75, 95% one-sided CI=1.6), and EBGM (9.06, 95% one-sided CI=7.23, vs 3.36, 95% one-sided CI=3.13). Our findings support an association between thrombotic events and eltrombopag use. Moreover, concomitant use of eltrombopag and glucocorticoids appeared to result in an even higher incidence of thrombotic events.

Treatment patterns of thrombopoietin receptor agonists among adults with primary immune thrombocytopenia: A Korean nationwide population-based study

IntroductionThrombopoietin receptor agonists (TPO-RAs) are a reliable second-line immune thrombocytopenia (ITP) treatment. Despite an increase in use of TPO-RAs, the treatment pattern among adults with ITP is not well understood. Materials and methodsFrom January 2015 to December 2018, ITP patients were identified using the Korean Health Insurance Review and Assessment Service database. ResultsOf the total 3885 adult patients with ITP, 1745 (44.9%) required treatment, with a median follow-up duration of 31.4 months (range, 0.1–59.8 months). Of these, 46.5% and 36.6% continued treatment for more than 6 months and more than 12 months, respectively. Corticosteroids were the most common first-line therapy. Of the treated patients, 83 (4.8%) received TPO-RAs (eltrombopag, 86.7%; romiplostim, 13.3%). The median age of the group treated with TPO-RAs was 62 years, 62.6% were female, and the median time from first diagnosis to initial TPO-RA treatment was 12.5 months (range, 0.4–48.0 months). A total of 52 (62.7%) patients received TPO-RAs as a second-line treatment for ITP. Splenectomy was performed in 19 patients (22.9%) before initiation of TPO-RAs. When clinical efficacy was analyzed before and during TPO-RA use, there was a significant decrease in platelet transfusion and a tendency toward reduced bleeding events. ConclusionsThis population-based study is the first to describe the treatment pattern of TPO-RAs for ITP among patients in Korea.

An Observational Study of Fostamatinib As Second Line Therapy in Adult Patients with Immune Thrombocytopenia (ITP) in Real-World Clinical Practice

Background: In immune thrombocytopenia (ITP), autoantibody-bound platelets are targeted for phagocytosis by Fcγ-receptors on macrophages in a spleen tyrosine kinase (SYK)-dependent signaling pathway. Fostamatinib is a potent oral SYK inhibitor that demonstrated efficacy for the treatment of ITP in two phase 3 randomized, placebo-controlled, double-blind studies and long-term durable responses in the phase 3 open-label extension study. In these studies, 146 patients with ITP were treated with fostamatinib, and 54% had a platelet response (platelet count ≥50,000/µL), which was maintained over a median of 86% of treatment days. These studies led to approval of fostamatinib in the US, Europe, and Canada as a therapy for chronic ITP in adult patients who have had an insufficient response to a prior treatment. Further, a post-hoc analysis showed that, in those who received fostamatinib as second-line therapy (following steroids ± immunoglobulins), 78% achieved a platelet response, which was maintained over a median of 83% of treatment days. 1 Adverse events (AEs) were reported in 72% of second-line patients and 86% of all patients, and common AEs were similar between second-line patients and the total patient population. 1, 2 Bleeding events were reported in 24% of second-line patients vs. 41% of all patients. The results of the post hoc analysis underscored the necessity for further evaluation of fostamatinib as a second-line therapy for ITP.We are conducting a multi-center, prospective, observational, two cohort study of fostamatinib as second-line therapy for the management of ITP in adult patients who have an insufficient response to prior steroids ± immunoglobulins.Aim: This study will evaluate clinical outcomes and safety of fostamatinib as second-line therapy for ITP in adult patients in real-world clinical practice. Patients will also be assessed for quality of life and utilization of health care resources during the study.Methods: The study (FORTE; NCT04904276; O-FOSTA-901) is being conducted at 10 sites across the US and will enroll 45 patients with ITP into 2 cohorts (see Figure). The study is registered at https://clinicaltrials.gov/ct2/show/NCT04904276. The study aims to enroll adult patients with a confirmed diagnosis of ITP and an inadequate response to prior steroids ± immunoglobulins. Patients who have received any prior ITP treatment other than steroids or immunoglobulins will be excluded. Patients who will initiate fostamatinib as second-line therapy at study entry will be enrolled into Cohort 1; patients currently receiving fostamatinib as second-line therapy with the intent to continue treatment will be enrolled in Cohort 2 (historical platelet counts will be retrospectively collected). Patients will be treated by their clinician at the clinician's discretion (not pre-specified by a study protocol).Primary outcome measures will include platelet count over time, duration of platelet count elevation, use of ITP rescue medication, changes in dosing, use of concomitant ITP medications, incidence of serious and ITP-related AEs, and quality of life. Quality of life assessments will utilize the SF-36v2 and ITP-PAQ. All data will be collected at regularly scheduled clinic visits according to the clinician's normal practice for 12 months or until fostamatinib is discontinued.Summary: This ongoing observational study of adult patients with ITP will enable further characterization of the risk/benefit profile of fostamatinib as a second-line treatment for ITP and will provide insight on how clinicians manage ITP in a real-world setting without the constraints of a clinical trial protocol.

A Canadian Cost-Effectiveness Analysis for the Treatment of Immune Thrombocytopenia: Assessing the Relative Value of with Eltrombopag Versus Romiplostim

Background:Eltrombopag (EPAG) was evaluated as a second line treatment for adult chronic immune thrombocytopenia (ITP) in the 2005 Phase III RAISE randomized, placebo-controlled trial. More than 80% of patients reached satisfactory platelet counts within two weeks. However, the relative value of EPAG as a second line treatment for ITP remains to be formally assessed.Objective:This study aimed to estimate the cost-effectiveness of treating ITP with comparable thrombopoietin receptor agonists: EPAG versus Romiplostim (ROMI).Methods:A cost-effectiveness model was developed from a Canadian payer perspective. In the base case, Markov model was implemented to estimate the benefits and costs expected with each treatment over a lifetime time horizon. Three health states based on the clinical pathway and current guidelines for the treatment of ITP were included in the model: (1) on treatment, (2) treatment failure/discontinuation, and (3) mortality. As reducing bleeding is the therapeutic goal in ITP, bleeding rates were incorporated into the model. Pre-mortality, patients could experience three events: no bleeding, mild/moderate bleeding, or severe bleeding. Data on EPAG use were obtained from the EXTEND study, an open-label extension of four trials including RAISE. For ROMI, data were obtained from Phase III trials and a subsequent extension study. Lifetime overall survival was extrapolated by applying constant treatment-specific mortality rates derived from severe bleeding events and natural mortality rates. As no health-related quality of life data were collected during the RAISE clinical trial, EPAG health state utilities were obtained from other relevant studies (Szende, 2010; Leontiadis, 2010; ROM NICE submission TA221). The costs of drugs (primary and secondary therapy), rescue medications, routine care, bleeding episodes, adverse events, and mortality were incorporated into the model. Costs, in Canadian dollars, were derived from the relevant pricing databases. Costs and benefits were discounted at 1.5% per year according to CADTH guidelines.Results:EPAG-treated patients gained 22.53 life years (LY) and 18.81 quality-adjusted life years (QALY) while those treated with ROMI gained 22.45 LYs and 18.80 QALYs. The total cost for EPAG treatment was estimated at $513,301 versus $805,025 for ROMI treatment. EPAG was dominant (lower cost, greater benefit) in terms of both costs per LY and costs per QALY. Sensitivity analyses supported base case findings. Deterministic sensitivity analysis predicted the greatest sensitivity to variations in the rates of severe bleeding, discontinuation, and natural mortality. The probabilistic sensitivity analysis demonstrated the probability of cost-effectiveness was 55.7% at both $25,000 and $50,000 thresholds and EPAG was therefore a reasonably efficient use of resources. In a subsequent cost-consequence analysis, EPAG patients experienced fewer severe bleeding events (0.05 versus 0.08 for ROMI) and, overall, their annual costs were lower ($65,514 versus $96,914 for ROMI).Conclusion:Both EPAG and ROMI has demonstrated significant improved in bleeding versus the standard of care in the phase 3 clinical trial.s These results were applied in the economic analysis and EPAG proved to be more cost-effective as compared to ROMI. DisclosuresRoy:Novartis: Employment, Equity Ownership. Neyra:Novartis: Employment. El Ouagari:Novartis: Employment.

Accessory Splenectomy: the Keystone of Success in the Treatment for Refractory Immune Thrombocytopenia

Splenectomy is officially recognized as second-line treatment for immune thrombocytopenia. Accessory spleens are known to have a role in recurrence and laparoscopic exploration for detection is recommended by many. The aim of the study was to investigate on accessory splenectomy as resolutive treatment for refractory thrombocytopenia. A review of the literature was completed on PubMed looking for articles where at least one accessory splenectomy had been performed for refractory thrombocytopenia. Measures used for the statistical analysis were as follows: sex; age; surgical approach; latency to recurrence; radiological tests; identified, retrieved, and missed accessory spleens; location and size of accessory spleens; and follow-up. Outcome was evaluated in terms of platelet count, need for medical treatment, and response. Thirty-three articles from 1976 (95 patients) satisfied criteria for the analysis. In the young, accessory spleens were more frequently missed at imaging. Number and size of accessory spleens resulted to be inversely correlated. Smaller accessory spleens carried increased likelihood to be missed. Number of radiological tests used to detect accessory spleens yielded better outcomes, in particular, when ultrasonography, computed tomography and scintigraphy were used in combination. In the case of refractory immune thrombocytopenia, the presence of accessory spleens needs to be investigated. A special focus is required to young patients or those with multiple accessory spleens, where imaging fails to detect them more frequently. The use of combined radiological techniques has shown improved outcome and should be preferred. A meticulous laparoscopic exploration follows next and becomes crucial to achieve long-term response.

Avatrombopag for the treatment of immune thrombocytopenia

ABSTRACTIntroduction: Thrombopoietin-receptor agonists (TPO-RAs) are the only American Society of Hematology (ASH) guideline-advocated, second-line treatment for immune thrombocytopenia (ITP) that have been validated by randomized, controlled trials with a placebo comparator. Avatrombopag is a new candidate in this class that has been investigated as a treatment option for the treatment of ITP.Areas covered: In this Drug Profile, we provide a review of the clinical data of avatrombopag, which was approved in May 2018 by the United States Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with chronic liver disease undergoing an invasive procedure, and an opinion of its potential place in the current evidence-based ITP treatment landscape.Expert commentary: Avatrombopag induces doubling of platelet counts, increasing them to above 50 X 109/L, and prevents the need for platelet transfusions while minimizing the need for rescue medications. Treatment-emergent adverse events (TEAEs) are comparable to placebo. Oral delivery, a 5-day dosing schedule and good tolerability (<1% discontinuation rate) with no clinically significant hepatoxicity make it a promising entrant as a potential second-line treatment for ITP. Further, data from a phase 3 study in patients with ITP supports its utility in the treatment of patients with ITP.

Long-term efficacy of partial splenic embolization for the treatment of steroid-resistant chronic immune thrombocytopenia.

Thrombopoietin-receptor agonists have been recently introduced for a second-line treatment of immune thrombocytopenia (ITP). Splenectomy has tended to be avoided because of its complications, but the response rate of splenectomy is 60-80% and it has still been considered for steroid-refractory ITP. We performed partial splenic embolization (PSE) as an alternative to splenectomy. Between 1988 and 2013, 91 patients with steroid-resistant ITP underwent PSE at our hospital, and we retrospectively analyzed the efficacy and long-term outcomes of PSE. The complete response rate (CR, platelets > 100 × 109/L) was 51% (n = 46), and the overall response rate (CR plus response (R), > 30 × 109/L) was 84% (n = 76). One year after PSE, 70% of patients remained CR and R. The group with peak platelet count after PSE ≥ 300 × 109/L (n = 29) exhibited a significantly higher platelet count than the group with platelet count < 300 × 109/L (n = 40) at any time point after PSE. The failure-free survival (FFS) rates at 1, 5, and 10years were 78, 56, and 52%, respectively. Second PSE was performed in 20 patients who relapsed (n = 14) or had no response to the initial PSE (n = 6), and the overall response was achieved in 63% patients. There were no PSE-related deaths. These results indicate that PSE is a safe and effective alternative therapy to splenectomy for patients with steroid-resistant ITP as it generates long-term, durable responses.

Th2 Cytokine Polymorphisms, IL-4 -590 CC Genotype and IL-10RB K47E, Increase the Requirement of Second-Line Treatment for Chronic ITP

[Introduction] Immune thrombocytopenia (ITP) is an autoimmune disorder showing T helper type1 (Th1) cytokine polarization. Second-line treatment for ITP is generally used for patients with persistent thrombocytopenia and bleeding tendency after steroid treatment. We have recently shown Th1/Th2 cytokine polymorphisms affect the risk of chronic ITP. However, no previous study has demonstrated the association between Th1/Th2 cytokine polymorphisms and treatment response for chronic ITP. We explored the influence of Th1/Th2 cytokine polymorphisms to the clinical features and treatment response in patients with chronic ITP.[Patients and Methods] The present study included 126 Japanese patients (92 female and 34 male, median age: 47.7, range: 2.4-82.3 years) diagnosed with chronic ITP according to the criteria of ITP International Working Group. The patient characteristics were summarized in Table1. We examined Th1/Th2 cytokine polymorphisms: INF-g +874T/A, INF-gR -611G/A, IL-4 -590C/T, IL-4Ra Q576R, IL-10 -592C/A, IL-10RA I224V, and IL-10RB K47E using by PCR based method and direct sequencing. Clinical characteristics, including age, gender, platelet number, bleeding tendency, treatment response were also investigated. Second-line treatment was defined as additional therapy after steroid treatment. This study was approved by the Institutional Review Board of Gunma University Hospital.[Results] We divided chronic ITP patients (n=126) into 2 groups: the patients who received second-line treatment (SL group, n=36) and the patients who did not receive second-line treatment (non-SL group, n=90). In SL-group, the splenectomy was performed in 19 patients (51.4%) and thrombopoietin receptor agonists were given in only 7 patients (19.4%). The clinical characteristics and Th1/Th2 cytokine genotype frequencies of SL group and non-SL group were shown in Table1. The patients in SL group showed severer thrombocytopenia at diagnosis (SL group: median 12.0~109/L vs. non-SL group: median 31.0~109/L, p value=0.001). However, no significant difference was observed between SL group and non-SL group in gender, age, or bleeding tendency. As compared to non-SL group, SL group had significantly higher frequencies of IL-4 -590 CC genotype (low expression type) (SL group: 25.0% vs. non-SL group: 8.9%, p=0.02) and IL-10RB K47E non-EE genotype (low expression type) (SL group: 86.1% vs. non-SL group: 66.7%, p=0.03). Multivariate analysis of requirement for second-line treatment showed an independent significance of IL-4 -590C/T CC genotype (p=0.01) and severe thrombocytopenia (p<0.05). Furthermore, IL-10RB K47E non-EE genotype was associated with thrombocytopenia during the clinical course and requirement for second-line treatments in all patients with ITP.[Conclusion] Our data suggest that Th2 cytokine polymorphisms, IL-4 -590 CC genotype and IL-10RB K47E, increase the requirement of second-line treatment for chronic ITP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Laparoscopic splenectomy for second-line treatment of immune thrombocytopenia – analysis of 53 patients and current perspectives

Background Splenectomy is a well-established second-line treatment for immune thrombocytopenia but novel medical therapies have changed the management of this disease. The objective of this study is to analyze the current results of splenectomy as a second-line treatment.

Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP.

New agents are being used as second-line treatment for immune thrombocytopenia (ITP) and have brought into question the relevance of splenectomy for steroid-resistant ITP. We retrospectively analysed 73 patients who underwent splenectomy for ITP at our institution over an 11-year period. The median follow-up period was 25 months; patients with follow-up of &lt;1 month were excluded. The outcomes of splenectomy were compared in HIV-positive v. HIV-negative patients. The rate of complete response was 83%, and response was sustained for at least 1 year or until latest follow-up in 80% of patients. Twelve patients were HIV-positive. Splenectomy was laparoscopic in 43 patients (62%) with an overall 16% complication rate. The 90-day mortality rate was 1.38%. There was no statistically significant difference in response or complication rate in the HIV-positive patients. There was a statistically significant (p=0.003) poorer response to splenectomy in the patients with steroid-resistant ITP. Splenectomy is effective and safe irrespective of HIV status and remains an appropriate second-line treatment for ITP. Further research is needed to corroborate our finding of lower response in patients who are steroid-resistant, as this might be a subgroup of patients who may benefit from thrombopoietin agonists as second line therapy.