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Introduction : Three distinct phases are recognized in immune thrombocytopenia (ITP): newly diagnosed (≤3 months after diagnosis), persistent (>3-12 months after diagnosis), and chronic (>12 months). Several international guidelines/expert recommendations have been released in the past 2 years regarding the treatment of newly diagnosed/persistent ITP. Areas covered : Across the guidelines/expert recommendations, thrombopoietin receptor agonists (TPO-RAs), including romiplostim (the focus of this review), are recommended in newly diagnosed or persistent ITP for patients who fail to respond to corticosteroids or intravenous immunoglobulin (or where these are contraindicated). To identify data relating to romiplostim in adults with newly diagnosed or persistent ITP, we conducted a search of PubMed (with no time limit applied) and abstracts from 2019 EHA/ASH meetings using the term 'romiplostim.' Expert opinion : The findings from nine clinical trials, six real-world studies and ten case reports provide insight into the early use of romiplostim, which could help to reduce exposure to the adverse effects associated with prolonged corticosteroid use, as well as reduce the risk of severe bleeding. Additionally, given the durable responses observed in patients with newly diagnosed/persistent ITP, as well as the potential for treatment-free responses following discontinuation, romiplostim might help to avoid the need for subsequent treatment.

: Thrombopoietin receptor agonists (TPO-RA) are currently approved to treat chronic immune thrombocytopenia (ITP) but there is increasing interest in considering these drugs earlier during the course of the disease. We present six patients with primary ITP resistant to corticosteroids and intravenous immunoglobulins, who received TPO-RA in the persistent phase and then underwent splenectomy in the chronic phase. Eltrombopag was administered as a second-line therapy in four patients, whereas two patients received romiplostim. Five out of six patients rapidly reached response or complete response (four and one, respectively) and steroid suspension. In one case, remission was obtained with steroid and TPO-RA. No significant side effects were reported. After splenectomy, complete response and response was reached in four and two patients, respectively. One relapse was recorded, rescued by steroid and eltrombopag. Postsplenectomy complication was registered in one patient (grade 4 intra-abdominal bleeding). TPO-RA could be a valuable choice in ITP patients in persistent phase candidates to splenectomy.

A proportion of patients with immune thrombocytopenic purpura are refractory to multiple therapies including thrombopoietin-receptor agonists (TPO-RA). We report 10 patients who did not respond to a TPO-RA until the addition of a glucocorticoid. These patients were previously treated with a median of 6 therapies. One patient elected to discontinue both medications despite persistent thrombocytopenia. The remaining 9 patients continued on the combination of prednisone (doses 5 mg every other day to 10 mg daily) and a TPO-RA. Combination therapy with low dose glucocorticoid and a TPO-RA may be an option for patients unresponsive to a TPO-RA alone.

Management of patients with corticosteroid-refractory immune thrombocytopaenia (ITP) possesses a significant challenge to practitioners. Until recently, options included splenectomy and immunosuppression. With improved knowledge of both thrombopoiesis and the pathophysiology of ITP, novel drug development with thrombopoietin-receptor agonists (TPO-RAs) was undertaken. Two agents, romiplostim and eltrombopag, are currently approved for use in patients with chronic ITP. Both agents have been shown to increase the platelet count, improve health-related quality of life and reduce bleeding symptoms and concomitant medication use. This review will highlight the discovery of TPO-RA agents, appraise key clinical trials and explore future directions., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To assess long-term treatment patterns and outcomes in patients with persistent or chronic immune thrombocytopenia (ITP), also considering the impact of the treatment with thrombopoietin receptor agonists (TPO-RAs) prior to splenectomy., Methods: Medical records of all patients with persistent or chronic ITP seen at our institution between January 1985 and December 2016 were reviewed. Data on demographic and clinical characteristics were analyzed using descriptive statistics. Wilcoxon rank-sum test was used to compare medians between groups of patients., Results: Among 80 patients with persistent or chronic ITP, 34 underwent splenectomy and 59 were treated with TPO-RAs. Twenty patients were both splenectomized and treated with TPO-RAs; among them, 9 received TPO-RAs before splenectomy. Median time to splenectomy from diagnosis of ITP was 25 months in the group of patients pretreated with TPO-RAs vs 14.5 months in the group of splenectomized patients. These differences were not statistically significant., Conclusions: Our study provides some initial data on the potential benefits of the treatment with TPO-RAs that may allow splenectomy to be safely deferred for prolonged periods. More research is needed to evaluate the impact of the treatment with TPO-RAs prior to splenectomy., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Primary immune thrombocytopenia is an autoimmune disorder characterized by increased platelet destruction and insufficient platelet production without another identified underlying disorder. Splenectomy may alter responsiveness to treatment and/or increase the risk of thrombosis, infection, and pulmonary hypertension. The analysis herein evaluated the safety and efficacy of the thrombopoietin receptor agonist romiplostim in splenectomized and nonsplenectomized adults with primary immune thrombocytopenia. Data were pooled across 13 completed clinical studies in adults with immune thrombocytopenia from 2002-2014. Adverse event rates were adjusted for time of exposure. Results were considered different when 95% confidence intervals were non-overlapping. Safety was analyzed for 1111 patients (395 splenectomized; 716 nonsplenectomized) who received romiplostim or control (placebo or standard of care). At baseline, splenectomized patients had a longer median duration of immune thrombocytopenia and a lower median platelet count, as well as a higher proportion with >3 prior immune thrombocytopenia treatments versus nonsplenectomized patients. In each treatment group, splenectomized patients used rescue medications more often than nonsplenectomized patients. Platelet response rates (≥50×10 9 /L) for romiplostim were 82% (310/376) for splenectomized and 91% (592/648) for nonsplenectomized patients ( P <0.001 by Cochran-Mantel-Haenszel test). Platelet responses were stable over time in both subgroups. Exposure-adjusted adverse event rates were higher for control versus romiplostim for both splenectomized (1857 versus 1226 per 100 patient-years) and nonsplenectomized patients (1052 versus 852 per 100 patient-years). In conclusion, responses to romiplostim were seen in both splenectomized and nonsplenectomized patients, and romiplostim was not associated with an increase in the risk of adverse events in splenectomized patients. clinicaltrials.gov Identifier: 00111475(A)(B), 00117143, 00305435, 01143038, 00102323, 00102336, 00415532, 00603642, 00508820, 00907478, 00116688, and 00440037 ., (Copyright© 2017 Ferrata Storti Foundation.)

Background: Immune thrombocytopenia (ITP) in adulthood is characterized by chronic relapsing course. Despite the efficacious first line treatment (corticosteroid, intravenous immunoglobulin), majority of patients will enter the chronic phase warranting another treatment approach. Until recently, splenectomy performed in ITP chronic phase represented the standard of care with longterm remissions in more than 70% of patients, but it has never been tested in clinical trials. However, with the advances of our understanding of ITP pathophysiology and the shifting focus on megakaryocyte impairment, novel drugs were introduced in the treatment paradigm, mainly trombopoietin receptor agonists (TPO-RAs); romiplostim and eltrombopag., Methods: These TPO-RAs were tested in randomized controlled trials resulting in adequate platelet response with few side effects and less need for additional therapy leading to approval of corresponding regulatory agencies and wide acceptance by hematological community, but however TPO-RAs must be taken continuously to maintain the response. With their onset, the rate of splenectomy in chronic ITP has diminished in modern era., Conclusion: The main aim behind conducting this review is to evaluate the pros and cons of splenectomy compared to TPO-RAs treatment in order to provide the critical overview which may help the practicing clinician in managing often challenging cases of chronic ITP., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: Romiplostim has maintained long-term platelet counts in patients with immune thrombocytopenia (ITP) for up to 5 yr in clinical studies. This prospective observational study aimed to describe romiplostim utilisation and outcomes in European clinical practice., Methods: Adults with primary ITP who received romiplostim in routine care were eligible., Results: Three-hundred and forty patients were eligible for analysis, of whom 299 (88%) completed the 2-yr observation period. The median age was 62 yr, with 43% of patients aged ≥65 yr, and two-thirds of patients initiated romiplostim before splenectomy. The median average weekly dose of romiplostim was 2.8 μg/kg. The median baseline platelet count was 20 × 10 9 /L, which increased after 2 wk of romiplostim treatment and remained >50 × 10 9 /L thereafter. After romiplostim initiation, there was a decrease in rates of grade ≥3 bleeding events (from 12 to 2 per 100 patient-years) and ITP-related hospitalisations (from 87 to 33 per 100 patient-years). The rate of thrombotic events was 2 per 100 patient-years, and bone marrow fibrosis occurred in two patients., Conclusions: Romiplostim dosing, effectiveness and safety in an unselected real-world ITP population seemed comparable with that observed in clinical studies., (© 2016 Amgen Inc. European Journal of Haematology. Published by John Wiley & Sons Ltd.)

In patients with immune thrombocytopenia (ITP) refractory to corticosteroids and intravenous immunoglobulins (IVIG), splenectomy may result at higher risk of peri-operative complications and, for this reason, potentially contraindicated. The thrombopoietin receptor agonists (TPO-RAs) romiplostim and eltrombopag have shown high therapeutic activity in primary ITP, but data of efficacy and safety regarding their use in preparation for splenectomy are missing. Thirty-one adult patients, median age 50 years, with corticosteroids and/or IVIG refractory persistent and chronic ITP who were treated with TPO-RAs (romiplostim= 24; eltrombopag= 7) with the aim to increase platelet count and allow a safer execution of splenectomy were retrospectively evaluated. Twenty-four patients (77%) responded to the use of TPO-RAs with a median platelet count that increased from 11 × 10(9) /L before starting TPO-RAs to 114 × 10(9) /L pre-splenectomy, but a concomitant treatment with corticosteroids and/or IVIG was required in 19 patients. Twenty-nine patients underwent splenectomy while two patients who responded to TPO-RAs subsequently refused surgery. Post-splenectomy complications were characterized by two Grade 3 thrombotic events (1 portal vein thrombosis in the patient with previous history of HCV hepatitis and 1 pulmonary embolism), with a platelet count at the time of thrombosis of 260 and 167 × 10(9) /L, respectively and one Grade 3 infectious event. TPO-RAs may represent a therapeutic option to improve platelet count and reduce the risk of peri-operative complications in ITP candidates to splenectomy. An increased risk of post-splenectomy thromboembolic events cannot be ruled out and thromboprophylaxis with low-molecular weight heparin is generally recommended., (© 2016 Wiley Periodicals, Inc.)

Objective: This post hoc analysis evaluated romiplostim self-administration (SA group) vs. romiplostim administration by a healthcare provider in a clinical setting (HCP group) in patients with chronic immune thrombocytopenia (ITP)., Methods: Outcomes from 3 ITP trials allowing self-administration in patients achieving a stable romiplostim dose for ≥3 consecutive weeks were compared. Evaluations were conducted for 12-wk treatment intervals. Efficacy endpoints included percentage of patients and weeks with platelets within the target range of 50-200 × 10(9) /L and safety., Results: Baseline characteristics suggested less severe disease in the SA groups (n = 563) than in the HCP groups (n = 241). The SA groups had greater proportions of patients achieving the target platelet range (55-58% vs. 40-52%) and greater proportions of weeks with a platelet response (75-88% vs. 47-76%) than the HCP groups. The rate of romiplostim discontinuation was twofold to fivefold lower in the SA groups than in the HCP groups. Rates of duration-adjusted adverse events (AEs), serious AEs and treatment-related AEs were also lower in the SA groups., Conclusions: In conclusion, in adults with ITP receiving romiplostim, self-administration was comparable to healthcare provider administration in terms of efficacy and safety profiles, suggesting that self-administration of romiplostim is a feasible option for certain patients with ITP., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which the platelet count falls to <100 × 10(9)/L. Corticosteroids are recommended as the first-line treatment, splenectomy is recommended as the second-line treatment, and thrombopoietin receptor agonists (TPO-RAs) and rituximab are recommended as the third-line treatments for ITP in Japanese ITP treatment guidelines. However, in Japan, rituximab is not eligible for reimbursement for the treatment of ITP. The cost-effectiveness of ITP treatment has not been investigated in Japan. Therefore, in this study, the cost-effectiveness of adding rituximab treatment to the existing treatments indicated for ITP in Japan, namely splenectomy and the TPO-RA romiplostim, was investigated based on the scenario that rituximab is eligible for reimbursement in Japan as a treatment for ITP., Methods: The efficacy endpoint was set as the number of years with a platelet count ≥30 × 10(9)/L. The analysis was conducted from the healthcare payer's perspective. If the first treatment is ineffective or relapse occurs, then the patient is given the following treatment. The analyzed treatment order consisted of three patterns: splenectomy-romiplostim (sequence 1), splenectomy-romiplostim-rituximab (sequence 2), and splenectomy-rituximab-romiplostim (sequence 3). A Markov model was built for ITP, and the analysis period was set as 2 years. The discount rate was an annual rate of 2%. Sensitivity analyses of the efficacy of splenectomy, romiplostim, and rituximab; treatment cost; and romiplostim dose were performed., Results: The expected costs per patient over a 2-year period for sequences 1, 2, and 3 were USD 40,980, USD 39,822, and USD 33,551, respectively. The expected years with a platelet count ≥30 × 10(9)/L for the three sequences were 1.75, 1.79, and 1.78 years, respectively. The sensitivity analyses illustrated that the results of the base case analysis were robust., Conclusions: Adding rituximab to standard treatment for ITP (sequences 2-3) is less costly and marginally more effective than standard therapy in adults. According to the study results, if rituximab is reimbursed for the treatment of ITP in Japan, medical expenses are expected to decline.

Objective: To report a case of severe rebound thrombocytopenia after temporary discontinuation of romiplostim during splenectomy in the context of refractory immune (idiopathic) thrombocytopenic purpura (ITP)., Case Summary: A 65-year-old man with a history of severe refractory ITP failing multiple treatments was considered for romiplostim therapy. He was initiated on 1 µg/kg and titrated upward to 4 µg/kg to elevate and stabilize his platelet levels prior to splenectomy. On day 74 of his clinical course, his platelets increased to 434 × 10(9)/L, and his scheduled dose of romiplostim was withheld on day 75 for fear of romiplostim-induced postsplenectomy rebound thrombocytosis. On day 78, his platelets dropped precipitously to 9 × 10(9)/L, and he experienced multiple episodes of epistaxis. He was reinitiated at 5 µg/kg and soon recovered. He later missed a scheduled dose of romiplostim, and his platelets fell to 23 × 10(9)/L. After resuming romiplostim at 8 µg/kg, his platelets continued to recover., Discussion: Romiplostim, a thrombopoietin mimetic is directly regulated by megakaryocytes and existing circulating platelets via a negative feedback mechanism. This explains the theoretical risk of rapid clearance of romiplostim caused by an increased platelet pool. Clinically, alternative causes of his severe postoperative thrombocytopenia were considered and deemed unlikely. The rebound effect was observed after romiplostim was withdrawn on 2 occasions, and platelet counts improved after restarting romiplostim. The Naranjo Adverse Drug Reaction Probability Score of 7 suggests a probable adverse drug reaction., Conclusion: Physicians using romiplostim as a bridge to splenectomy should be cautious about withholding a scheduled dose around the time of surgery., (© The Author(s) 2014.)

Thrombopoietin-receptor agonists (Tpo-RAs) are highly effective in immune thrombocytopenia (ITP). Recently, cases of durable remission after Tpo-RA discontinuation in adult ITP have been reported. We aimed to describe the subset of patients in whom transient Tpo-RA therapy may induce a durable response. We studied all adults with primary ITP treated with at least one Tpo-RA over a 5-year period (n = 54) and seen at one of three participating referral centres in France. Tpo-RAs were discontinued in 20 of 28 patients who achieved a complete response. We excluded six patients because a previous treatment at the start of Tpo-RA treatment may have interfered with the response. Overall, eight patients with chronic ITP showed a sustained response [median follow-up: 13·5 months (range 5-27 months)]. We could not identify a predictive factor of sustained response. In conclusion, a substantial proportion of ITP patients receiving Tpo-RAs can maintain a durable response after treatment discontinuation., (© 2014 John Wiley & Sons Ltd.)

Romiplostim was effective, safe, and well-tolerated over 6-12 months of continuous treatment in Phase 3 trials in patients with immune thrombocytopenia (ITP). This report describes up to 5 years of weekly treatment with romiplostim in 292 adult ITP patients in a long-term, single-arm, open-label study. Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin/fibrosis), platelet response (platelet count >50 × 10(9) per litre), and the proportion of patients requiring rescue treatments. Treatment-related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6.5% of patients and were not associated with platelet count. Median platelet counts of 50-200 × 10(9) per litre were maintained with stable doses of romiplostim (mean 5-8 μg/kg; generally self-administered at home) throughout the study. A platelet response was achieved at least once by 95% of patients, with a platelet response maintained by all patients on a median 92% of study visits. There was a low rate of bleeding and infrequent need for rescue treatments. In conclusion, this study demonstrated that romiplostim was safe and well-tolerated over 614 patient-years of exposure in ITP patients, and that efficacy was maintained with stable dosing for up to 5 years of continuous treatment., (© 2013 Blackwell Publishing Ltd.)

Purpose: To develop a tool to assist the decision-making for selection of Thrombopoyetin Receptor Agonists of adult patients with chronic immune primary thrombocytopenia (PTI)., Methods: Stochastic cost-effectiveness analysis with a 6-Health- States Markov model: stable, bleeding type 2, 3 or 4, post-type 4 bleeding and death. Each simulation analyzes a randomly generated scenario that describes patients characteristics, results measured in quality adjusted life years (QALYs) and costs (in ?2011). Distributions were obtained from the Spanish data of the European health survey of 2009, the INE estimate of population for 2011 and the 6-months clinical studies for Eltrombopag and Romiplostim. Utility values were obtained from the literature and the costs from Spanish official rates lists. A set of 10.000 random scenarios were generated and the patients evolution of each scenario was simulated during a time horizon of five years (in 2-weeks cycles). National Health System Perspective was used and the annual discount rate was set at 3%., Results: Eltrombopag showed more effectiveness in 9.983 scenarios and there was no difference in 17. In 7.048 scenarios the alternative Eltombopag was dominant. It was cost-effective in another 19 (threshold 30,000 ??/AVAC)., Conclusions: Eltrombopag was the most cost-effective alternative in 70,67% of the simulated scenarios and its use could produce lower costs to the NHS., (Copyright © 2013 SEFH. Published by AULA MEDICA. All rights reserved.)

This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP), in which splenectomy was not possible due to the persistence of a low platelet count despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) and platelet transfusion treatment. As an attempt to increase platelet count prior to performing splenectomy, the thrombopoietin receptor agonist, romiplostim, was administered in combination with steroids and IVIG. A single administration of romiplostim was found to be markedly effective, allowing a rapid and notable platelet increase, required for a well tolerated splenectomy. This case confirms the potent activity of romiplostim in ITP, and indicates that patients with recurrent primary ITP who are unresponsive to conventional immunosuppressive therapy may benefit from the addition of a short course of romiplostim.

This study assessed the grade of bone marrow (BM) fibrosis and its association with a seromarker for collagen-III formation and fibrosis-related cytokines in 25 immune thrombocytopenia (ITP) patients treated with thrombopoietin receptor agonists (Tpo-RA) who had at least one BM biopsy. Assessment of 8 pre- and on-treatment BM biopsies revealed statistically significant increases in reticulin. Reticulin in biopsies performed after a median of 1·4 years of treatment was graded: MF-0 in 3 (12%), MF-1 in 19 (76%), MF-2 in 2 (8%) and MF-3 in 1 (4%). No cytogenetic or flow-cytometric abnormalities were detected. Median pretreatment Procollagen III N-propeptide (PIIINP) (6·6 μg/l) was significantly higher than on-treatment levels (5·6 μg/l); both were higher than controls (3·4 μg/l; P < 0·001). PIIINP was negatively correlated with treatment duration (r = -0·49) suggesting a decelerated reticulin production over time. There was a trend towards an association between grade of reticulin and PIIINP. Transforming growth factor (GF)-beta and basic-Fibroblast GF were not different between patients and controls but Hepatocyte GF (HGF), an anti-fibrotic cytokine, was significantly elevated in patients. In conclusion, low-grade BM reticulin fibrosis is seen in most ITP patients on Tpo-RA. The novel findings of decreasing PIIINP and elevated HGF need further investigation to explore their significance in BM fibrogenesis., (© 2011 Blackwell Publishing Ltd.)

Background: Romiplostim, a thrombopoietin mimetic, increases platelet counts in patients with immune thrombocytopenia, with few adverse effects., Methods: In this open-label, 52-week study, we randomly assigned 234 adult patients with immune thrombocytopenia, who had not undergone splenectomy, to receive the standard of care (77 patients) or weekly subcutaneous injections of romiplostim (157 patients). Primary end points were incidences of treatment failure and splenectomy. Secondary end points included the rate of a platelet response (a platelet count >50×10(9) per liter at any scheduled visit), safety outcomes, and the quality of life., Results: The rate of a platelet response in the romiplostim group was 2.3 times that in the standard-of-care group (95% confidence interval [CI], 2.0 to 2.6; P<0.001). Patients receiving romiplostim had a significantly lower incidence of treatment failure (18 of 157 patients [11%]) than those receiving the standard of care (23 of 77 patients [30%], P<0.001) (odds ratio with romiplostim, 0.31; 95% CI, 0.15 to 0.61). Splenectomy also was performed less frequently in patients receiving romiplostim (14 of 157 patients [9%]) than in those receiving the standard of care (28 of 77 patients [36%], P<0.001) (odds ratio, 0.17; 95% CI, 0.08 to 0.35). The romiplostim group had a lower rate of bleeding events, fewer blood transfusions, and greater improvements in the quality of life than the standard-of-care group. Serious adverse events occurred in 23% of patients (35 of 154) receiving romiplostim and 37% of patients (28 of 75) receiving the standard of care., Conclusions: Patients treated with romiplostim had a higher rate of a platelet response, lower incidence of treatment failure and splenectomy, less bleeding and fewer blood transfusions, and a higher quality of life than patients treated with the standard of care. ( ClinicalTrials.gov number, NCT00415532.).

Purpose: On August 22, 2008, Romiplostim (Nplate for Injection) received approval from the US Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. This report summarizes the FDA analyses of the clinical data supporting this approval., Experimental Design: The FDA reviewed data from two double-blind, placebo-controlled clinical studies, an uncontrolled extension study, and supportive studies. In the controlled studies, enrolled patients had completed at least one prior treatment for chronic ITP and had a platelet count < or = 30 x 10(9)/L. One study enrolled patients who had undergone splenectomy; the other enrolled patients who had not undergone splenectomy. The primary endpoint in both controlled studies was durable platelet response., Results: Overall, 125 patients were randomized in the controlled studies. A durable platelet response was observed in 61% of nonsplenectomized patients and 38% of patients who had undergone splenectomy. One placebo group patient achieved a durable platelet response. Serious hemorrhage events were reported in 10% of placebo recipients and 6% of romiplostim recipients. In the extension study, patients received romiplostim for a median of 60 weeks and a maximum of 96 weeks; the majority of patients maintained platelet counts > or = 50 x 10(9)/L throughout the study. Major safety findings pertained to a risk for bone marrow reticulin formation and worsened thrombocytopenia following romiplostim discontinuation., Conclusions: The FDA approved romiplostim for use among certain patients with chronic ITP. This approval included a Risk Evaluation and Mitigation Strategy to ensure that the benefits of the drug outweigh its risks.