Immunomodulation in Primary Immune Thrombocytopenia: A Possible Role of the Fc Fragment of Romiplostim?
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ABSTRACT:
SUBMITTER: Schifferli A
PROVIDER: S-EPMC6557984 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Immunomodulation in Primary Immune Thrombocytopenia: A Possible Role of the Fc Fragment of Romiplostim?
Schifferli Alexandra A Nimmerjahn Falk F Kühne Thomas T
Frontiers in immunology 20190604
Fc fusion proteins and Fc fusion peptides or peptibodies are chimeric molecules composed of an active pharmacological protein or peptide and the Fc fragment of an immunoglobulin. The primary aim of this drug construct is to prolong the half-life of the active component. This molecular architecture is seen in drugs, such as etanercept, romiplostim, and the recombinant factor VIII (efmoroctocog alfa). A considerable number of Fc fusion proteins and peptibodies are currently in pre-clinical and cli ...[more]
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Project description:"Immune thrombocytopenia" (ITP) is an autoimmune disorder that leads to peripheral destruction, as well as a decreased production of platelets. ITP most commonly presents as mild mucocutaneous bleeding. Though it is rare, the leading cause of mortality in persons with ITP is intracranial hemorrhage and those that do not respond to therapy are at increased risk. Our understanding of the pathophysiology of ITP has evolved immensely, especially over the last 60 years. The discovery of the platelet-production stimulator, thrombopoietin (TPO), lent clarity to an earlier hypothesis that inhibition of platelet production at the level of the megakaryocyte, at least in part, accounts for thrombocytopenia in adults with ITP. This facilitated the development of TPO-based therapies to treat ITP. Thrombopoietin receptor agonists are one of the most recent treatments to enter the landscape. Original production of a recombinant human TPO was halted after clinical trials revealed the untoward effect of autoantibodies to the recombinant human TPO with cross-reactivity to endogenous TPO. Next-step development focused on stimulation of the TPO receptor with fewer immunogenic agents. Currently, two such thrombopoietin receptor agonists, romiplostim and eltrombopag, are licensed in the USA to treat thrombocytopenia in adults with persistent or chronic ITP. Ongoing research will assess their efficacy in other immune-mediated and nonimmune-mediated primary and secondary thrombocytopenias.
| S-EPMC4304598 | biostudies-other
Project description: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 (≥50×109/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.
| S-EPMC5541869 | biostudies-literature
Project description:The effects of romiplostim on bone marrow morphology were evaluated in adults with immune thrombocytopenia (ITP). Patients with platelet counts <50 × 10(9)/L, ≥1 prior ITP therapies, and no collagen at baseline received weekly subcutaneous romiplostim starting at 1 μg/kg, adjusted to maintain platelet counts between 50 and 200 × 10(9)/L. Biopsies were scheduled after 1, 2, or 3 years of romiplostim (cohorts 1, 2, and 3, respectively). Irrespective of scheduled time, biopsies were performed earlier if patients discontinued or failed to achieve/maintain a response to romiplostim. Reticulin (silver stain) and collagen (trichrome stain) were graded by two hematopathologists using the modified Bauermeister scale (0-4). Of 169 patients, 131 had evaluable biopsies; 9/131 (6.9 %) had increases of ≥2 grades on the modified Bauermeister scale (cohort 1: 0/34; cohort 2: 2/39; cohort 3: 7/58), including two with collagen. Three of the nine patients had follow-up biopsies, including one patient with collagen; changes were reversible after romiplostim discontinuation. Of the nine patients, one had neutropenia detected by laboratory test and two had adverse events of anemia, both non-serious and not treatment-related. By actual exposure (as some biopsies did not occur as scheduled), the number of patients with grade increases ≥2 were year 1: 3/41, year 2: 1/38, year 3: 5/52. Twenty-four patients sustained platelet counts ≥50 × 10(9)/L for ≥6 months with no ITP medications after discontinuing romiplostim, i.e., they entered clinical remission of their ITP. In conclusion, in patients with ITP receiving romiplostim, bone marrow changes were observed in a small proportion of patients.ClinicalTrials.gov identifier: NCT#00907478.
| S-EPMC4889627 | biostudies-literature
Project description:BackgroundImmune thrombocytopenia (ITP) in dogs is analogous to that in humans. Romiplostim, a novel thrombopoietin receptor (TPO-R) agonist, is currently used for the treatment of refractory ITP in humans, but not in dogs. Here, we describe the response to romiplostim in five dogs with refractory ITP. Five dogs with severe and refractory ITP (three primary and two secondary) received romiplostim subcutaneously. Four dogs were administered 3-5 μg/kg and one dog received 10-13 μg/kg body weight once weekly.ResultsRomiplostim was well-tolerated and administration was associated with an increase in platelet counts in all five dogs. Four of the five dogs entered remission and relapses were not observed over a follow-up period of 3-10 months.ConclusionsRomiplostim is effective in the treatment of ITP in dogs at least as well as in humans. This finding may help to develop and use new therapeutics for ITP in dogs and humans.
| S-EPMC4901510 | biostudies-literature
Project description:PURPOSE:Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS:We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS:The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION:This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.
| S-EPMC6823892 | biostudies-literature
Project description:BackgroundMultiple trials have confirmed that romiplostim could increase platelet count in individuals with primary immune thrombocytopenia (ITP), but no related study has assessed Chinese patients.ObjectivesTo assess the effectiveness of romiplostim as a second-line treatment of persistent or chronic ITP in Chinese adults.MethodsThis phase III multicenter, randomized, placebo-controlled, double-blind, then open-label clinical trial (NCT02868099, CTR20150395) was conducted at 28 investigational sites in China. The patients were randomly assigned (3:1) to romiplostim (starting and maximum doses of 1 and 10 μg/kg, respectively) or placebo for 9 weeks (double-blind period), followed by the open-label period (both groups administered romiplostim) to week 22. The primary endpoint was the time (in weeks) during which platelet counts were ≥50 × 109/L in the double-blind period.ResultsIn this study, 202 patients (romiplostim, n = 151; placebo, n = 51) started the treatment. The median (range) numbers of weeks with platelet response after 6 weeks of treatment were 2 (0-6) and 0 (0-2) in patients administered romiplostim and placebo, respectively (P < .001). During the double-blind period, the proportions of patients with treatment-emergent adverse events were comparable between the romiplostim and placebo groups (82.8% vs 82.4%). The treatment-emergent adverse event with ≥10% difference in incidence between these 2 groups was injection site bleeding (1.3% vs 11.8%).ConclusionRomiplostim significantly increased the time with maintained platelet response in patients with persistent or chronic ITP in comparison with placebo. No new safety signal was observed.Trial registrationClinicalTrials.gov, NCT02868099. www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml, CTR20150395.
| S-EPMC10439391 | biostudies-literature
Project description:BackgroundRomiplostim, a thrombopoietin receptor agonist (TPOra), is a second-line medical treatment option for adults with chronic immune thrombocytopenia (ITP). Clinical trials have shown that romiplostim increases platelet counts, while reducing the risk of bleeding and, in turn, the need for costly rescue medications.AimsThe objective of this study was to assess the cost effectiveness of romiplostim in the treatment of adult ITP in Ireland, in comparison with eltrombopag and the medical standard of care (SoC).MethodsA lifetime treatment-sequence cost-utility Markov model with embedded decision tree was developed from an Irish healthcare perspective to compare romiplostim with eltrombopag and SoC. The model was driven by platelet response (platelet count ?50 × 10(9)/L), which determined effectiveness and progression along the treatment pathway, need for rescue therapy (e.g. intravenous immunoglobulin [IVIg] and steroids) and risk of bleeding. Probability of response, mean treatment duration, average time to initial response and utilities were derived from clinical trials and other published evidence. Treatment sequences and healthcare utilization practice were validated by Irish clinical experts. Costs were assessed in <euro> for 2011 and included drug acquisition costs and costs associated with monitoring patients and management of bleeding, as available from published Irish reimbursement lists and other relevant sources. Deterministic and probabilistic sensitivity analyses were conducted.ResultsRomiplostim treatment resulted in an average of 20.2 fewer administrations of rescue medication (IVIg or intravenous steroids) over a patient lifetime than eltrombopag, and 29.3 fewer rescue medication administrations than SoC. Romiplostim was dominant, with cost savings of <euro>13,258 and <euro>22,673 and gains of 0.76 and 1.17 quality-adjusted life-years (QALYs), compared with eltrombopag and SoC, respectively. Romiplostim remained cost effective throughout a variety of potential scenarios, including short-term TPOra treatment duration (1 year). One-way sensitivity analysis showed that the model was most sensitive to variation in the cost of IVIg and use of romiplostim and IVIg. Probabilistic sensitivity analysis showed that romiplostim was likely to be cost effective in over 90 % of cases compared with eltrombopag, and 96 % compared with SoC at a willingness-to-pay threshold of <euro>30,000 per QALY.ConclusionsUse of romiplostim in the ITP treatment pathway, compared with eltrombopag or SoC, is likely to be cost effective in Ireland. Romiplostim improves clinical outcomes by increasing platelet counts, reducing bleeding events and the use of IVIg and steroids, resulting in both cost savings and additional QALYs when compared with current treatment practices.
| S-EPMC3824633 | biostudies-literature
Project description:Romiplostim, a thrombopoietin-receptor agonist (TPO-ra), is a highly effective option in primary immune thrombocytopenia (ITP), with 80-90% of patients achieving platelet responses after few weeks of treatment. The evidence showing remissions, that is, sustained platelet counts after romiplostim discontinuation, in patients with ITP refractory to immunosuppressive therapy is steadily increasing. However, there is a lack of guidelines or recommendations addressing how and when to taper romiplostim in clinical practice in patients maintaining elevated and stable platelet counts. Furthermore, given the high heterogeneity of ITP patients, no associated predictive factors have been currently identified. Here, we present 4 representative clinical cases of the daily clinical practice in Spain comprising newly diagnosed, persistent, and both splenectomized and nonsplenectomized chronic ITP patients treated with romiplostim, achieving and maintaining clinical remission (platelet count ≥ 50 × 109/L for 24 consecutive weeks in the absence of any treatment for ITP) after treatment tapering and discontinuation, without observed safety concerns. Prospective studies identifying clinical and biological predictive factors of sustained response are warranted.
| S-EPMC5485313 | biostudies-other
Project description:Immune thrombocytopenia (ITP) is a prevalent autoimmune disease characterized by autoantibody-induced platelet clearance. Some ITP patients are refractory to standard immunosuppressive treatments such as intravenous immunoglobulin (IVIg). These patients often have autoantibodies that target the ligand-binding domain (LBD) of glycoprotein Ibα (GPIbα), a major subunit of the platelet mechanoreceptor complex GPIb-IX. However, the molecular mechanism of this Fc-independent platelet clearance is not clear. Here, we report that many anti-LBD monoclonal antibodies such as 6B4, but not AK2, activated GPIb-IX in a shear-dependent manner and induced IVIg-resistant platelet clearance in mice. Single-molecule optical tweezer measurements of antibodies pulling on full-length GPIb-IX demonstrated that the unbinding force needed to dissociate 6B4 from the LBD far exceeds the force required to unfold the juxtamembrane mechanosensory domain (MSD) in GPIbα, unlike the AK2-LBD unbinding force. Binding of 6B4, not AK2, induced shear-dependent unfolding of the MSD on the platelet, as evidenced by increased exposure of a linear sequence therein. Imaging flow cytometry and aggregometry measurements of platelets and LBD-coated platelet-mimetic beads revealed that 6B4 can sustain crosslinking of platelets under shear, whereas 6B4 Fab and AK2 cannot. These results suggest a novel mechanism by which anti-LBD antibodies can exert a pulling force on GPIb-IX via platelet crosslinking, activating GPIb-IX by unfolding its MSD and inducing Fc-independent platelet clearance.
| S-EPMC5814932 | biostudies-literature
Project description:BackgroundPopulation-based cohorts of immune thrombocytopenia (ITP) are useful for understanding occurrence, clinical characteristics and long-term clinical course. This paper describes the content of the Nordic Country Patient Registry for Romiplostim (NCPRR) and provides prevalence and incidence estimates of chronic ITP (cITP).MethodsThe NCPRR, a cohort study established in 2009, includes all adult (≥ 18 years) patients in Denmark, Sweden and Norway with cITP (defined as ITP lasting > 12 months and platelet count < 100 × 109/L), combining data from national health registries and medical records. The NCPRR currently includes prevalent cITP patients diagnosed before 2009 and incident cITP patients diagnosed during 2009-2016. The registry obtains clinical information for cITP patients, including comorbidities, treatments, laboratory values, and complete follow-up for various outcomes.FindingsThe NCPRR currently includes 3831 patients with cITP (1258 prevalent; 2573 incident). In 2009, the prevalence of registered cITP was 10 · 0/100,000 (95%CI:9 · 1-11 · 0) adult persons in Denmark and 10 · 7/100,000 (95% CI: 9 · 9-11 · 4) adults in Sweden. During 2009-2016, the incidence rates of cITP per 100,000 person-years were 2 · 8 (95%CI: 2 · 6-3 · 0), 1 · 8 (95%CI: 1 · 7-1 · 9) and 2 · 1 (95%CI: 1 · 9-2 · 2) in Denmark, Sweden and Norway, respectively. Fifty-eight percent of cITP patients were women. At NCPRR inclusion, 30.2% were aged ≥ 70 years, 23% had a platelet count < 50 × 109/L, 17.4% were splenectomized, 41% had prior ITP therapy, and 8.6% had severe comorbidity.InterpretationThe NCPRR provides population-based data on the epidemiology and characteristics of almost 4000 cITP patients and is a valuable resource for research.FundingThis study was partly funded by a research grant from Amgen to Aarhus University.
| S-EPMC6833351 | biostudies-literature