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Davi D J Kuter - One of the best experts on this subject based on the ideXlab platform.
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a multicenter study of Romiplostim for chemotherapy induced thrombocytopenia in solid tumors and hematologic malignancies
Haematologica, 2020Co-Authors: Hanny Alsamkari, Aric Parnes, Katayoon Goodarzi, James I. Weitzman, Jean M. Connors, Davi D J KuterAbstract:Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy delays, dose reductions, and discontinuation. There is no FDA-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional Romiplostim treatment pathways at 4 U.S. centers. The primary outcome was achievement of a Romiplostim response [median on-Romiplostim platelet count (Plt) ≥75x109/L and ≥30x109/L above baseline]. Secondary outcomes included time to Plt≥100x109/L and rates of the following: Plt
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assessment of Romiplostim immunogenicity in adult patients in clinical trials and in a global postmarketing registry
British Journal of Haematology, 2020Co-Authors: Daniel T Mytych, Vibha Jawa, Joseph Park, Troy E Barger, Andy Boshier, Davi D J KuterAbstract:: Antibodies to first-generation recombinant thrombopoietin (TPO) neutralized endogenous TPO and caused thrombocytopenia in some healthy subjects and chemotherapy patients. The second-generation TPO receptor agonist Romiplostim, having no sequence homology to TPO, was developed to avoid immunogenicity. This analysis examined development of binding and neutralising antibodies to Romiplostim or TPO among adults with immune thrombocytopenia (ITP) in 13 clinical trials and a global postmarketing registry. 60/961 (6·2%) patients from clinical trials developed anti-Romiplostim-binding antibodies post-baseline. The first positive binding antibody was detected 14 weeks (median) after starting Romiplostim, at median Romiplostim dose of 2 µg/kg and median platelet count of 29.5 × 109 /l; most subjects had ≥98·5% of platelet assessments showing response. Neutralising antibodies to Romiplostim developed in 0·4% of patients, but were unrelated to Romiplostim dose and did not affect platelet count. Thirty-three patients (3·4%) developed anti-TPO-binding antibodies; none developed anti-TPO-neutralising antibodies. In the global postmarketing registry, 9/184 (4·9%) patients with spontaneously submitted samples had binding antibodies. One patient with loss of response had anti-Romiplostim-neutralising antibodies (negative at follow-up). Collectively, anti-Romiplostim-binding antibodies developed infrequently. In the few patients who developed neutralising antibodies to Romiplostim, there was no cross-reactivity with TPO and no associated loss of platelet response.
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safety and efficacy of self administered Romiplostim in patients with immune thrombocytopenia results of an integrated database of five clinical trials
American Journal of Hematology, 2020Co-Authors: Davi D J Kuter, Dominik Selleslag, Francesco Rodeghiero, Adrian C. Newland, Ann Janssens, Kejia Wang, Robert Bird, Donald M Arnold, Jiri Mayer, Robert OlieAbstract:Romiplostim self-administration by patients or caregivers may offer time/cost savings to healthcare professionals (HCPs) and convenience for patients who avoid weekly clinic visits. We performed an integrated analysis of five clinical trials to evaluate the efficacy and safety of Romiplostim self-administration. Data were analyzed from adults with immune thrombocytopenia (ITP) who received weekly Romiplostim via self-administration or from an HCP. Patients who achieved a stable Romiplostim dose for ≥3 weeks (HCP group ≥5 weeks to provide an appropriate index date to enable comparisons with the self-administration group) with platelet counts ≥50 × 109 /L were eligible. In the self-administration (n = 621) vs HCP (n = 133) groups, respectively, median age was 53 vs 58 years, median time since primary ITP diagnosis was 3.7 vs 2.5 years, and median baseline platelet count at ITP diagnosis was 19.0 vs 20.0 × 109 /L. In the self-administration and HCP-dosed groups, median Romiplostim treatment duration was 89 vs 52 weeks and median total number of doses was 81 vs 50, respectively. In the self-administration and HCP groups, respectively: 95.0% and 100.0% of patients achieved ≥1 platelet response (defined as weekly platelet count ≥50 × 109 /L without rescue medication in previous 4 weeks); the median percentage of weeks with a response was 94.5% and 95.9%; and rescue medication was used in 36.7% and 39.8% of patients. Self-administration did not adversely affect safety; duration-adjusted rates for all treatment-emergent adverse events (TEAEs) and bleeding TEAEs were numerically lower with self-administration. Romiplostim self-administration appears effective and well tolerated in eligible patients with ITP.
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A Multicenter Study of Romiplostim to Treat Chemotherapy-Induced Thrombocytopenia in Solid Tumors and Lymphoid Malignancies
Blood, 2019Co-Authors: Hanny Al-samkari, Aric Parnes, Katayoon Goodarzi, James I. Weitzman, Jean M. Connors, Davi D J KuterAbstract:Introduction : Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients causing chemotherapy treatment delays, dose reductions, and discontinuation. A major unmet clinical need, there is no FDA-approved agent available to manage CIT. Given this, we developed clinical pathways to treat CIT at 4 large academic hospitals. Data using Romiplostim to manage CIT is limited to small single-center studies and case series of solid tumor patients only. We performed the first large multicenter study of Romiplostim for CIT, including both solid tumor and non-myeloid hematologic malignancy patients. Methods : We retrospectively collected demographics, cancer and chemotherapy data, Romiplostim dosing, weekly platelet counts (Plt), and outcomes of Romiplostim support for patients treated on institutional Romiplostim CIT pathways from 2009-2019. For solid tumor patients, 2 institutions utilized intracycle dosing (Romiplostim administered on average twice monthly on chemotherapy-off weeks) and 2 utilized standard weekly Romiplostim dosing, facilitating comparison of dosing strategies. Romiplostim response was defined as a median on-Romiplostim Plt of ≥75×109/L and at least 30×109/L higher than baseline. Baseline characteristics were analyzed for predictors of Romiplostim non-response using multivariate logistic regression. Wilcoxon signed-rank and Mann-Whitney U tests compared paired and unpaired groups and Chi square and Fisher's exact tests compared categorical outcomes. Results : 173 patients (153 solid tumor, 20 lymphoid malignancy) were treated for CIT with Romiplostim to facilitate ongoing chemotherapy administration, with 170 (98%) receiving a median (range) of 4 (1-36) additional chemotherapy cycles over 10 (2-125) weeks of Romiplostim support. A total of 61.3 patient-years of Romiplostim treatment of CIT were analyzed for effectiveness and safety. Table 1 lists baseline patient characteristics and Table 2 details chemotherapy regimens precipitating CIT and supported on Romiplostim. Median per-patient Plt on Romiplostim was significantly higher than baseline (all patients, 112×109/L vs. 54×109/L, P<0.001; solid tumor patients, 116×109/L vs. 60×109/L, P<0.001), Figure 1. Median Romiplostim starting dose was 3 µg/kg/week, which was also the median optimized Romiplostim dose (dose achieving Plt >100×109/L). While on Romiplostim, bleeding occurred in 7.5% of patients and venous thromboembolism occurred in 4.6% (at Plt 65-306×109/L). Compared with intracycle Romiplostim dosing, weekly Romiplostim dosing resulted in higher median Plt (Figure 2) and fewer chemotherapy delays/dose reductions with no difference in bleeding or thrombotic events (Table 3). Characteristics of solid tumor patients predicting non-response to Romiplostim per multivariate regression included biopsy-proven bone marrow invasion by tumor (P<0.001), prior pelvic irradiation (P=0.029), and prior temozolomide (P=0.031) (Figure 3), with only 23%, 20%, and 46% of patients, respectively, achieving a Romiplostim response compared with 82% of all other solid tumor patients. Plt improvement with Romiplostim was modest in patients with myeloma (N=7, median per-patient Plt 39×109/L with Romiplostim vs. 19×109/L at baseline, P=0.078) and aggressive lymphoma (N=13, 47×109/L with Romiplostim vs. 23×109/L at baseline, P=0.033), Figure 3, with only 35% receiving more than 1 additional chemotherapy cycle on Romiplostim. All myeloma and lymphoma patients were dosed weekly and had extensive bone marrow involvement by malignancy. Conclusions : We present results of Romiplostim treatment of CIT in a large cohort of 173 cancer patients, including lymphoid malignancies. Dosing strategies were compared and predictors of non-response were evaluated. Romiplostim was highly effective in solid tumor patients with CIT, allowing chemotherapy administration. Bleeding and thrombosis rates were similar to the general cancer patient population. Both weekly and intracycle dosing were effective and equally safe, but weekly dosing maintained higher Plt overall and higher Plt nadirs with fewer chemotherapy dose reductions or treatment delays. Bone marrow invasion, pelvic irradiation, and prior temozolomide predicted Romiplostim non-response. Romiplostim had modest effectiveness to manage CIT in lymphoid malignancy patients with underlying bone marrow involvement. Disclosures Al-Samkari: Moderna: Consultancy. Parnes:Sunovion: Consultancy, Other: Safety monitoring board; Hoffman LaRoche: Research Funding; Genentech: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Geron Corporation: Other: owning stock . Connors:Portola: Other: scientific ad boards; Abbott: Consultancy; Bristol Myer-Squibb: Consultancy, Other: Scientific Ad boards; Eli Lilly: Consultancy. Kuter:Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Shinogi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kezar: Research Funding. OffLabel Disclosure: Off-label use of the thrombopoietin receptor agonist Romiplostim to treat chemotherapy-induced thrombocytopenia is discussed.
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Romiplostim in adult patients with newly diagnosed or persistent immune thrombocytopenia itp for up to 1 year and in those with chronic itp for more than 1 year a subgroup analysis of integrated data from completed Romiplostim studies
British Journal of Haematology, 2019Co-Authors: Davi D J Kuter, Francesco Rodeghiero, Beng H. Chong, Ingrid Pabinger, Adrian C. Newland, Monica T Romero, Yuqi Chen, Kejia Wang, Bhakti Mehta, Melissa EisenAbstract:: The thrombopoietin receptor agonist Romiplostim is approved for second-line use in chronic immune thrombocytopenia (ITP), but its effects in patients with ITP for ≤1 year are not well characterized. This analysis of pooled data from 9 studies included patients with ITP for ≤1 year (n = 311) or >1 year (n = 726) who failed first-line treatments and received Romiplostim, placebo or standard of care. In subgroup analysis by ITP duration, patient incidences for platelet response at ≥75% of measurements were higher for Romiplostim [ITP ≤1 year: 74% (204/277); ITP >1 year: 71% (450/634)] than for placebo/standard of care [ITP ≤1 year: 18% (6/34); ITP >1 year: 9% (8/92)]. Of patients with ≥9 months on study, 16% with ITP ≤1 year and 6% with ITP >1 year discontinued Romiplostim and maintained platelet counts ≥50 × 109 /l for ≥6 months without ITP treatment (treatment-free remission). Independent of ITP duration, rates of serious adverse events and bleeding were lower with Romiplostim than placebo/standard of care and thrombotic events occurred at similar rates. In this analysis, Romiplostim and placebo/standard of care had similar safety profiles and Romiplostim increased platelet counts in patients with either ITP ≤1 year or ITP >1 year, with more treatment-free remission in those with ITP ≤1 year.
Dietmar Berger - One of the best experts on this subject based on the ideXlab platform.
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Subcutaneous or intravenous administration of Romiplostim in thrombocytopenic patients with myelodysplastic syndrome (MDS)
Journal of Clinical Oncology, 2016Co-Authors: M.a. Sekeres, Kuolung Hu, Janet Franklin, H. M. Kantarjian, Pierre Fenaux, Pamela S. Becker, Adam Boruchov, Agnes Guerci-bresler, Dietmar BergerAbstract:7009 Background: Thrombocytopenia is common in patients (pts) with MDS, and treatment options are currently limited to platelet (plt) transfusions. Romiplostim is an Fc-peptide fusion protein (peptibody) that stimulates plt production by the same mechanism as thrombopoietin. Methods: This was a phase II, multicenter, single arm, open-label study. Eligibility criteria included IPSS low or intermediate-1 risk MDS and a mean baseline plt count ≤50x109/L. Safety and efficacy of Romiplostim were evaluated in pts receiving 750μg Romiplostim according to one of 3 schedules: weekly or biweekly subcutaneous injections (QWSC or Q2WSC), or biweekly intravenous injections (Q2WIV). Plt responses were measured per IWG 2006 criteria. Results: Of the 28 pts enrolled, 17 (61%) completed the study; 22 (79%) were male and the mean (±SD) baseline plt count was 29 (±10) x 109/L. The mean age was 71 years and 19 pts (68%) had received plt transfusions in the past year. Mean duration of exposure to Romiplostim was 12 (±8) weeks...
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Romiplostim or standard of care in patients with immune thrombocytopenia
The New England Journal of Medicine, 2010Co-Authors: Davi D J Kuter, Mathias J Rummel, Ralph V Boccia, Gail B Macik, Dominik Selleslag, Xuena Wang, Francesco Rodeghiero, Beng H. Chong, Ingrid Pabinger, Dietmar BergerAbstract: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. (Funded by Amgen; ClinicalTrials.gov number, NCT00415532.)
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phase 2 study of Romiplostim in patients with low or intermediate risk myelodysplastic syndrome receiving azacitidine therapy
Blood, 2010Co-Authors: H. M. Kantarjian, Kuolung Hu, Guillermo Garciamanero, Peter L. Greenberg, Janet Franklin, Janice Gabrilove, Francis J Giles, Ron Paquette, Eunice S Wang, Dietmar BergerAbstract:We evaluated the efficacy and safety of Romiplostim, a thrombopoietin mimetic, in patients with low- or intermediate-risk myelodysplastic syndromes (MDS) receiving azacitidine therapy. Forty patients with low- or intermediate-risk MDS were stratified by baseline platelet counts (< 50 vs ≥ 50 × 109/L) and randomized to Romiplostim 500 μg or 750 μg or placebo subcutaneously once weekly during 4 cycles of azacitidine. The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined by grade 3 or 4 thrombocytopenia starting on day 15 of the first cycle or platelet transfusion at any time during the 4-cycle treatment period. No formal hypothesis testing was planned. The incidence of clinically significant thrombocytopenic events in patients receiving Romiplostim 500 μg, Romiplostim 750 μg, or placebo was 62%, 71%, and 85%, respectively. The incidence of platelet transfusions was 46%, 36%, and 69%, respectively. These differences were not statistically significant with the small numbers in each group. Romiplostim 750 μg significantly raised median platelet counts during cycle 3 on day 1 ( P = .0373) and at the nadir ( P = .0035) compared with placebo. Grade 3 rash and arthralgia each were reported in 1 Romiplostim-treated patient (4%). This study suggests Romiplostim may provide clinical benefits in MDS patients during azacitidine therapy. This study was registered at [www.clinicaltrials.gov][1] as #[NCT00321711][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00321711&atom=%2Fbloodjournal%2F116%2F17%2F3163.atom
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Assessment of immunogenicity of Romiplostim in clinical studies with ITP subjects
Annals of Hematology, 2010Co-Authors: Vibha Jawa, Dietmar Berger, Martha Hokom, Zheng Hu, Naglaa El-abaadi, Yao Zhuang, Shalini Gupta, Steven J. Swanson, Narendra ChirmuleAbstract:Romiplostim is an Fc-peptide fusion protein that activates intracellular transcriptional pathways via the thrombopoietin (TPO) receptor leading to increased platelet production. Romiplostim has been engineered to have no amino acid sequence homology to endogenous TPO. Recombinant protein therapeutics can be at a risk of development of an antibody response that can impact efficacy and safety. Hence, a strategy to detect potential antibody formation to the drug and to related endogenous molecules can be useful. The immunogenicity assessment strategy involved both the detection and characterization of binding and neutralizing antibodies. The method for detection was based on a surface plasmon resonance biosensor platform using the Biacore 3000. Samples that tested positive for binding antibodies in the Biacore immunoassay were then tested in a neutralization assay. Serum samples from 225 subjects with immune thrombocytopenic purpura (ITP) dosed with Romiplostim and 45 ITP subjects dosed with placebo were tested for Romiplostim and TPO antibodies. Prior to Romiplostim treatment, 17 subjects (7%) tested Romiplostim antibody positive and 12 subjects (5%) tested TPO antibody positive for pre-existing binding antibodies. After Romiplostim exposure, 11% of the subjects exhibited binding antibodies against Romiplostim and 5% of the subjects with ITP showed binding antibodies against TPO. The antibodies against Romiplostim did not cross-react with TPO and vice versa. No cases of anti-TPO neutralizing antibodies were detected in Romiplostim-treated subjects. The incidence of anti-Romiplostim neutralizing antibodies to Romiplostim was 0.4% (one subject); this subject tested negative at the time of follow-up 4 months later. No impact on platelet profiles were apparent in subjects that had antibodies to Romiplostim to date. In summary, administration of Romiplostim in ITP subjects resulted in the development of a binding antibody response against Romiplostim and TPO ligand. One subject developed a neutralizing antibody response to Romiplostim that impacted the platelet counts of this subject. No neutralizing antibodies to endogenous TPO were observed.
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randomized phase ii study evaluating the efficacy and safety of Romiplostim treatment of patients with low or intermediate risk myelodysplastic syndrome mds receiving lenalidomide
Blood, 2009Co-Authors: Roger M Lyons, Janet Franklin, Richard A Larson, Michael A Kosmo, Sunil Gandhi, Marc Chernoff, Luke Dreisbach, Carmen Matei, Kuolong Hu, Dietmar BergerAbstract:Abstract 1770 Poster Board I-796 Introduction Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor. Low platelet counts in patients with myelodysplastic syndromes (MDS) may be due to the underlying disease or to treatment with disease-modifying agents, and platelet transfusions are often the only treatment for clinically significant thrombocytopenia (CST) or bleeding. This was a phase 2 multi-center, randomized, double-blind, placebo-controlled, dose-finding study that evaluated the effect of Romiplostim on the incidence of clinically significant thrombocytopenic events (grade 3 or 4 thrombocytopenia and/or receipt of platelet transfusions) and the safety of Romiplostim in patients with low or intermediate risk MDS receiving lenalidomide. Patients and Methods Patients who were ≥18 years old, had MDS by bone marrow exam and WHO criteria, had low or Intermediate-1 risk category MDS using the IPSS, and were planning to receive lenalidomide were eligible. Patients were randomized 1:1:1 into treatment groups receiving placebo, 500 μg Romiplostim, or 750 μg Romiplostim by weekly subcutaneous injections in combination with lenalidomide (one 10 mg capsule by mouth daily for each 28-day cycle). Treatments continued for a total of four cycles. Results The median age of the 39 randomized patients was 74 years (range, 39 to 90); 15 (39%) had platelet counts Conclusions Romiplostim appeared to be well-tolerated in low and intermediate risk MDS patients receiving lenalidomide. This preliminary information suggests that Romiplostim may reduce the rate of clinically significant thrombocytopenic events in these patients while increasing platelet counts and decreasing the incidence of lenalidomide dose reductions and delays due to thrombocytopenia Disclosures Lyons:GlaxoSmithKline: Consultancy, Speakers Bureau; JohnsonJ Celgene: Consultancy; Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Use of Romiplostim to treat Thrombocytopenia in MDS. Larson:Amgen Inc.: Equity Ownership, Research Funding. Liu:Amgen Inc.: Honoraria, Research Funding. Hu:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.
Janet Franklin - One of the best experts on this subject based on the ideXlab platform.
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Subcutaneous or intravenous administration of Romiplostim in thrombocytopenic patients with myelodysplastic syndrome (MDS)
Journal of Clinical Oncology, 2016Co-Authors: M.a. Sekeres, Kuolung Hu, Janet Franklin, H. M. Kantarjian, Pierre Fenaux, Pamela S. Becker, Adam Boruchov, Agnes Guerci-bresler, Dietmar BergerAbstract:7009 Background: Thrombocytopenia is common in patients (pts) with MDS, and treatment options are currently limited to platelet (plt) transfusions. Romiplostim is an Fc-peptide fusion protein (peptibody) that stimulates plt production by the same mechanism as thrombopoietin. Methods: This was a phase II, multicenter, single arm, open-label study. Eligibility criteria included IPSS low or intermediate-1 risk MDS and a mean baseline plt count ≤50x109/L. Safety and efficacy of Romiplostim were evaluated in pts receiving 750μg Romiplostim according to one of 3 schedules: weekly or biweekly subcutaneous injections (QWSC or Q2WSC), or biweekly intravenous injections (Q2WIV). Plt responses were measured per IWG 2006 criteria. Results: Of the 28 pts enrolled, 17 (61%) completed the study; 22 (79%) were male and the mean (±SD) baseline plt count was 29 (±10) x 109/L. The mean age was 71 years and 19 pts (68%) had received plt transfusions in the past year. Mean duration of exposure to Romiplostim was 12 (±8) weeks...
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Development of Romiplostim for Treatment of Primary Immune Thrombocytopenia From a Pharmacokinetic and Pharmacodynamic Perspective
Clinical Pharmacokinetics, 2016Co-Authors: Bing-bing Yang, Janet Franklin, Sameer Doshi, Karen Arkam, Andrew T. ChowAbstract:Romiplostim is a novel thrombopoiesis-stimulating peptibody consisting of a carrier Fc domain and a peptide domain that binds to the thrombopoietin receptor (TPOR) on platelets and platelet precursors. Similar to endogenous thrombopoietin, Romiplostim activates the TPOR to stimulate the growth and maturation of megakaryocytes, resulting in increased production of platelets in the circulation. Binding of Romiplostim to TPOR on the platelets and megakaryocytes presumably triggers subsequent internalization and degradation. Therefore, increased platelet counts following Romiplostim treatment results in increased elimination of the drug. The TPOR target-mediated process is saturable, resulting in nonlinear volume of distribution and clearance of Romiplostim. Therefore, target-mediated disposition plays a decreasing role in drug elimination with increasing Romiplostim serum concentration. Conversely, nonspecific elimination processes such as renal clearance play an increasing role with increasing Romiplostim serum concentration. Limited pharmacokinetics data demonstrated that the exposure to Romiplostim was lower after multiple dose administrations than after the first dose, although large inter-subject variability was observed. Large inter- and intra-subject variability in the platelet response was also observed at a given dose. These findings suggest considerable heterogeneity of disease in patients with primary immune thrombocytopenia and support the need for individual dose adjustments based on platelet counts.
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changes in bone marrow morphology in adults receiving Romiplostim for the treatment of thrombocytopenia associated with primary immune thrombocytopenia
Annals of Hematology, 2016Co-Authors: Ann Janssens, Xuena Wang, Francesco Rodeghiero, Beng H. Chong, Ingrid Pabinger, Deirdra R. Terrell, David Anderson, Z Boda, Libor Cervinek, Janet FranklinAbstract:The effects of Romiplostim on bone marrow morphology were evaluated in adults with immune thrombocytopenia (ITP). Patients with platelet counts <50 × 109/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 × 109/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 × 109/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.
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safety and efficacy of long term open label dosing of Romiplostim in thrombocytopenic pediatric patients pts with immune thrombocytopenia itp
Blood, 2014Co-Authors: James B Bussel, Janet Franklin, Michael D Tarantino, Amy E Geddis, Michael F Guerrera, Alan K Ikeda, Melissa EisenAbstract:Background: Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim, a TPO receptor agonist that stimulates platelet production, increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 study. Pts who completed that study or an ongoing phase 3 study could roll over into this open-label long-term extension; data from up to 4.2 years of Romiplostim in this extension are described here. Objectives: To describe the safety and efficacy of long-term use of Romiplostim in pediatric ITP. Methods: All pts received SC Romiplostim weekly (QW); the starting dose was the last dose given in the parent study or 1 μg/kg (for those who had previously received only placebo or who had not received Romiplostim for >24 wk). Doses could be adjusted up to 10 µg/kg to achieve target platelet counts in the range of 50-200×10 9 /L. The primary endpoint was incidence of adverse events (AEs). Assessments of AEs, concomitant medications, and local platelet counts were performed QW. For pts who maintained platelet counts of ≥50×10 9 /L for ≥4 consecutive wk at a stable Romiplostim dose, they or their caregivers, if deemed appropriate by the investigator, could learn to self-administer subsequent Romiplostim doses. Pts who self-administered Romiplostim had monthly assessments (not QW). Pts and/or their caregivers recorded dosing date, time, volume administered, and any dosing errors. Pts who turned 18 years of age were permitted to remain on study. Results: 40 pts (12 from the phase 1/2 study and 28 from the phase 3 study) entered the extension; 39 received Romiplostim for up to 217 wk (4.2 yrs); 1 pt withdrew consent before receiving Romiplostim. At extension study baseline, median age was 11 years (range 3-16), 55% were female, and 12.5% had prior splenectomy. Median (range) Romiplostim treatment duration was 40 wk (5–217); median total number of doses was 37 (5–216); median average QW Romiplostim dose was 6 µg/kg (1–10 µg/kg), including dose escalation to achieve a stable dose; median maximum dose was 8 µg/kg (1–10 µg/kg). 10 pts discontinued the study: consent withdrawn (n=5), noncompliance (2), administrative decision (2), and non-response (1). No pts withdrew due to AEs and 30 continued on study. After the first wk of the extension, which for some pts was their first wk of Romiplostim, median platelet counts remained >50×10 9 /L and were in the target range of 50-200×10 9 /L, except for wk 76 and 156, when they were just above 200×10 9 /L (Figure). Q1 platelet counts were >50×10 9 /L from wk 16 on. The median (Q1, Q3) Romiplostim dose was 5 (1, 9) µg/kg at wk 1 and 5 (1, 6) µg/kg at wk 216 (Figure). The median dose fell from 6 µg/kg to 3 µg/kg; from Week 172 on (n≤8), it started to rise and fluctuate. 11 pts received rescue medications (for platelet counts 9 /L, bleeding/wet purpura, or investigator decision), including IV immunoglobulin (n=4), tranexamic acid (2), prednisone (3), platelet transfusion (1), and aminocaproic acid (1). The 21 instances of rescue treatment for 11 pts occurred: in the first 3 months (12 instances), >3–6 months (4), >6–12 months (4), and after 1 year (1) of Romiplostim treatment. 7 pts had 13 serious AEs (asthma, epistaxis, gastroenteritis, gastrointestinal infection, hemangioma, infection, mouth hemorrhage, pain, pharyngitis, pyrexia, tachycardia, transfusion reaction, and viral infection) and 3 had life-threatening AEs (infection, n=1, thrombocytopenia, n=2); none were fatal. None of the serious or life-threatening AEs were deemed treatment-related by the investigators. 30 pts had bleeding AEs, which were deemed treatment-related in 2 pts (gingival bleeding and petechiae). Bleeding AEs occurring in ≥2 pts included contusion (n=11), epistaxis (9), petechiae (8), gingival bleeding (7), ecchymosis (3), hemorrhage (3), injection site bruising (3), mouth hemorrhage (3), and injection site hemorrhage (2). No bone marrow biopsies were performed and no thrombotic events were reported. Conclusion: In this open-label extension, long-term treatment with Romiplostim (up to 4.2 yrs) maintained platelet counts in pediatric pts with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of Romiplostim in children with chronic ITP. Disclosures Bussel: Cangene: Research Funding; GlaxoSmithKline: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy; Amgen Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Off Label Use: Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Use of Romiplostim in pediatric patients is under investigation.. Tarantino: Baxter: Membership on an entity9s Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity9s Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Cangene: Research Funding; UptoDate, Inc.: Patents & Royalties; Amgen Inc.: Membership on an entity9s Board of Directors or advisory committees. Nie: Amgen Inc.: Employment, Equity Ownership. Franklin: Amgen Inc.: Employment, Equity Ownership. Eisen: Amgen Inc.: Employment, Equity Ownership.
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a randomized controlled trial of Romiplostim in patients with low or intermediate risk myelodysplastic syndrome receiving decitabine
Leukemia & Lymphoma, 2013Co-Authors: Peter L. Greenberg, Allen S. Yang, Lloyd Earl Damon, Kuolung Hu, Michael R. Moore, Gail J Roboz, Guillermo Garciamanero, Janet FranklinAbstract:AbstractPatients with myelodysplastic syndrome (MDS) receiving hypomethylating agents commonly develop thrombocytopenia. This double-blind study evaluated the efficacy and safety of Romiplostim, a peptibody protein that increases platelets, in patients with MDS receiving decitabine. Patients received Romiplostim 750 μg (n = 15) or placebo (n = 14) and decitabine. Median platelet counts at the beginning of each decitabine cycle trended lower in placebo-treated than in Romiplostim-treated patients. Bleeding events occurred in 43% of placebo-treated and 27% of Romiplostim-treated patients, and platelet transfusions were administered to 57% of placebo-treated and 47% of Romiplostim-treated patients. Overall clinical therapeutic response was achieved by 21% of placebo-treated and 33% of Romiplostim-treated patients. Treatment was generally well tolerated. Progression to acute myeloid leukemia (AML) occurred in one patient per group. Adding Romiplostim to decitabine treatment is well tolerated and may be benefi...
Xuena Wang - One of the best experts on this subject based on the ideXlab platform.
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changes in bone marrow morphology in adults receiving Romiplostim for the treatment of thrombocytopenia associated with primary immune thrombocytopenia
Annals of Hematology, 2016Co-Authors: Ann Janssens, Xuena Wang, Francesco Rodeghiero, Beng H. Chong, Ingrid Pabinger, Deirdra R. Terrell, David Anderson, Z Boda, Libor Cervinek, Janet FranklinAbstract:The effects of Romiplostim on bone marrow morphology were evaluated in adults with immune thrombocytopenia (ITP). Patients with platelet counts <50 × 109/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 × 109/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 × 109/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.
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efficacy and safety of the thrombopoietin receptor agonist Romiplostim in patients aged 65 years with immune thrombocytopenia
Annals of Hematology, 2015Co-Authors: Marc Michel, Louis M Aledort, Bertrand Godeau, Jeffrey S. Wasser, Yoshiaki Tomiyama, Nichola Cooper, M Khellaf, Xuena WangAbstract:Thrombopoietin receptor agonists increase platelet counts and reduce bleeding risk in patients with immune thrombocytopenia (ITP). Studies have reported that these agents may represent a risk factor for thromboembolic events, especially in the elderly, who are at increased risk for such complications relative to younger patients. In this retrospective analysis, efficacy and safety data for Romiplostim in patients with ITP aged ≥65 years versus those aged <65 years are described. Data from 3 studies (N = 159; 24.5% ≥65 years of age) were analyzed for efficacy. Data from 13 studies (N = 1037; 28.4% ≥65 years of age) were analyzed for adverse events (AEs). Relative risk (RR) ratios with 95% CIs were calculated for duration-adjusted incidences of AEs for Romiplostim versus placebo/standard of care (SOC) in patients ≥65 and <65 years. Slightly higher platelet response rates were seen among Romiplostim-treated patients ≥65 versus <65 years. In the safety analyses, 65 (6.3%) received placebo/SOC, 69 (6.7%) received placebo/SOC and then Romiplostim, and 903 (87.1%) received Romiplostim only. Duration-adjusted AE rates were similar for Romiplostim versus placebo/SOC in older and younger patients. The risks for grade ≥3 bleeding (RR 1.92; 95% CI, 0.47–7.95) and thromboembolic events (RR 3.85; 95% CI, 0.53–27.96) were numerically but not significantly higher for Romiplostim versus placebo/SOC in patients ≥65 years. Romiplostim is effective and, with the exception of nonsignificant trends showing increased risks of grade ≥3 bleeding and thromboembolic events (a trend observed in other studies), generally well tolerated in older patients with ITP.
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Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist Romiplostim
International Journal of Hematology, 2015Co-Authors: Douglas B. Cines, Xuena Wang, Terry Gernsheimer, Drew Provan, Jeffrey Wasser, Bertrand Godeau, Roger Lyons, Ivy Altomare, Angela LopezAbstract:A safety analysis of pooled data from clinical studies of Romiplostim, a thrombopoietin (TPO) receptor agonist, in which patients with immune thrombocytopaenia (ITP) received Romiplostim, placebo, or medical standard of care (SOC) Rodeghiero et al. (Eur J Haematol 91:423–436, 2013 ), has been updated. Included are data from 14 trials spanning 2002–2011; placebo- and SOC-arm data are pooled. Most patients ( n = 1059) were female (61 %) and Caucasian (85 %); 38 % had undergone splenectomy; 23 were children. Mean (SD) baseline platelet count was 20.6 (16.5) × 10^9/L. Mean (SD) weekly dose of Romiplostim was 4.2 (2.8) µg/kg; total exposure was 1520 patient-years. Overall, 921 patients received Romiplostim only, 65 received placebo/SOC only, and 73 received placebo/SOC followed by Romiplostim. Rates of haemorrhage (Romiplostim, 205/100 patient-years; placebo/SOC, 263/100), thrombosis (both, 5.5/100 patient-years), haematological malignancy/myelodysplastic syndrome (Romiplostim, 0.5/100 patient-years; placebo/SOC, 2.7/100), and non-haematological tumours (Romiplostim, 2.2/100 patient-years; placebo/SOC, 3.6/100) were comparable among groups. Bone marrow reticulin was reported in 17 patients and collagen in one patient receiving Romiplostim; one patient receiving placebo/SOC had reticulin reported. Three patients developed neutralizing antibodies to Romiplostim, but not to endogenous TPO. This integrated analysis of the safety profile of Romiplostim in patients with ITP is consistent with previously reported studies; no new safety concerns emerged.
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results from a phase iv open label study evaluating changes in bone marrow morphology in adult immune thrombocytopenia itp patients receiving Romiplostim analysis of the 1 and 2 year Romiplostim cohorts
Blood, 2013Co-Authors: Francesco Rodeghiero, Xuena Wang, Beng H. Chong, Ingrid Pabinger, David Anderson, Z Boda, Libor Cervinek, Angela LopezAbstract:Introduction Reticulin is a normal and common component of the bone marrow stroma. In clinical trials of adults with chronic ITP treated with the thrombopoietin mimetic Romiplostim, a small number of cases of reticulin and/or collagen in bone marrow were reported. However, bone marrow biopsies were not systematically performed in these trials. Here, we report a multicenter study of adult ITP patients that evaluated bone marrow biopsies for reticulin and collagen pre- and post-treatment with Romiplostim. Methods Eligible ITP patients had platelet counts <50x109/L, received ≥1 prior ITP therapy, and no collagen in baseline bone marrow biopsies (ie, before Romiplostim). Three cohorts of patients were scheduled for biopsies after 1 (Cohort 1), 2 (Cohort 2), or 3 years of Romiplostim, dosed to maintain platelet counts at 50–200x109/L. Bone marrow biopsies were also performed if patients discontinued early or failed to achieve/maintain a response to Romiplostim, defined as platelet counts ≤20x109/L for 4 consecutive weeks at the maximum Romiplostim dose of 10 µg/kg. Reticulin and collagen formation were measured using the modified Bauermeister scale (0 no reticulin; 1 occasional fine fibers/foci fine fiber network; 2 fine fiber network; 3 diffuse fiber network, scattered coarse fibers; 4 diffuse coarse fiber network with areas of collagenization). Collagen was detected by trichrome staining and reticulin by silver staining. Cohort 1 biopsy samples were reread as the modified Bauermeister scale had not been applied as specified in the study protocol. All samples were read by 2 hematopathologists at a central bone marrow laboratory with grading discrepancies reviewed by an independent bone marrow panel. Data cutoff for this analysis was August 10, 2012. Results Of the 50 patients enrolled in Cohort 1 (54% female, mean age 55.5 years, range 20–86 years), 39 patients received Romiplostim and had bone marrow biopsies ([Table][1]). Mean (SD) dose was 3.8 (2.9) µg/kg. No patients with evaluable results developed collagen. No patients had an increase ≥2 grades from baseline in reticulin. Of the 50 patients enrolled in Cohort 2 (76% female, mean age 48.6 years, range 19–83 years), 39 patients received Romiplostim and had bone marrow biopsies ([Table][1]). Mean (SD) dose was 4.1 (3.2) µg/kg. Again, of the patients with evaluable results, none developed collagen. Two patients had a 2-grade increase in reticulin (1 patient: baseline grade 0 to 2 at year 2; 1 patient: baseline grade 1 to 3 at end of treatment). The safety profile was similar to previous trials. In Cohort 1, 3 patients died (not attributed to Romiplostim); causes were fungal sepsis in a patient with longstanding corticosteroid use, cerebral hemorrhage, and pulmonary hemorrhage in a patient with pulmonary thrombosis treated with acenocumarol. In Cohort 2, 2 patients died (not attributed to Romiplostim); causes were acute renal failure, in a patient with a medical history of chronic renal insufficiency, and suicide. There were no neutralizing antibodies to Romiplostim or thrombopoietin in the 2 cohorts. View this table: Table 2 Romiplostim Cohort Results Summary/Conclusion There was no evidence of collagen formation after 2 years of Romiplostim treatment. The incidence of increase in reticulin was low, consistent with results of previous Romiplostim studies. This ongoing study will provide additional data on bone marrow changes with up to 3 years of Romiplostim treatment. At completion of year 1 treatment, discontinuations included withdrew consent (n=5), non-responders (n=4), died (n=3), adverse event (n=1, severe joint pain), administration decision (n=1). At completion of year 2 treatment, discontinuations included withdrew consent (n=6), non-responders (n=2), declined biopsy (n=2), adverse events (n=2, dermatitis and suspected non-Hodgkins lymphoma), died (n=1), required alternate therapy (n=1). Disclosures: Janssens: Amgen, GSK, Mundipharma, Roche: Membership on an entity’s Board of Directors or advisory committees. Rodeghiero: Amgen, GSK: Honoraria; Amgen, Eisai, GSK, LFB, Suppremol: Membership on an entity’s Board of Directors or advisory committees. Chong: Amgen, GSK: Research Funding. Pabinger: CSL Behring: Research Funding; Amgen, Baxter, Bayer, Boehringer Ingelheim, CSL Behring, Pfizer: Honoraria; Amgen, Baxter, Bayer, Boehringer Ingelheim, CSL Behring, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Cervinek: Alexion, Amgen, GSK: Consultancy. Wang: Amgen: Employment, Equity Ownership. Lopez: Amgen: Employment, Equity Ownership. [1]: #T1
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long term safety and tolerability of Romiplostim in patients with primary immune thrombocytopenia a pooled analysis of 13 clinical trials
European Journal of Haematology, 2013Co-Authors: Francesco Rodeghiero, Xuena Wang, Ingrid Pabinger, Douglas B. Cines, Bertrand Godeau, Roberto Stasi, Aristoteles Giagounidis, Howard A. Liebman, J F Viallard, Paul WoodardAbstract:Background and objectives Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo-controlled trials is available. We sought to determine the long-term tolerability of the TPOra Romiplostim, with a particular focus on thrombosis, bleeding, bone marrow (BM) reticulin, neoplasms/haematological malignancies and fatal events. Methods Data from 13 Romiplostim clinical trials in which 653 patients with ITP received Romiplostim for up to 5 yr (921.5 patient-years) were pooled; subject incidence rates and exposure-adjusted event rates (per 100 patient-years) were calculated. Results The rate of thrombotic events (6% of patients, 7.5 events per 100 patient-years) did not appear to increase over time; 9 events were associated with platelet counts >400 × 109/L and 10 with Romiplostim doses exceeding current recommendations. Serious and grade ≥3 bleeding each occurred in approximately 8% of patients (~11 events per 100 patient-years). Adverse events of BM reticulin were recorded for 12 patients (1.8%, 1.3 events per 100 patient-years, confirmed by bone biopsy in ten patients) and BM collagen for one patient (0.2%, 0.1 event per 100 patient-years, confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events per 100 patient-years). Fatal events occurred in 3.7% of patients (2.6 events per 100 patient-years, four events treatment-related). Conclusions Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term Romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr.
James B Bussel - One of the best experts on this subject based on the ideXlab platform.
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long term treatment with Romiplostim and treatment free platelet responses in children with chronic immune thrombocytopenia
Haematologica, 2019Co-Authors: Michael D Tarantino, James B Bussel, Victor S Blanchette, Bhakti Mehta, Jenny M Despotovic, Donald Beam, Nancy Carpenter, Melissa EisenAbstract:Children with immune thrombocytopenia for ≥6 months completing a Romiplostim study received weekly subcutaneous Romiplostim (1-10 μg/kg targeting platelet counts of 50-200×109/L) in this extension to examine Romiplostim’s long-term safety and efficacy. Sixty-five children received Romiplostim for a median of 2.6 years (range: 0.1-7.0 years). Median baseline age was 11 years (range: 3-18 years) and platelet count was 28×109/L (range: 2-458×109/L). No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 mg/kg (range: 0.1-10 mg/kg); median platelet counts remained >50×109/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50×109/L, no rescue medication in the previous 4 weeks), 72% had responded at ≥75% of visits, and 58% had responded at ≥90% of visits. Treatment-free response (platelets ≥50×109/L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15 of 65 patients while withholding Romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of four years (range: 1-12 years) and had received Romiplostim for two years (range: 1-6 years). At last observation, treatment-free responses lasted for a median of one year (range: 0.4-2.1 years), with 14 of 15 patients still in treatment-free response. Younger age at first dose and platelet count >200×109/L in the first four weeks were associated with treatment-free responses. In this 7-year open-label extension, three-quarters of the patients responded ≥75% of the time, and Romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding Romiplostim and all other immune thrombocytopenia medications for ≥6 months. (Registered at clinicaltrials.gov identifier: 01071954)
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platelet count control in immune thrombocytopenic purpura patient optimum Romiplostim dose profile
Journal of Process Control, 2016Co-Authors: Chiahung Tsai, James B Bussel, Allison Imahiyerobo, Stanley I Sandler, Babatunde A OgunnaikeAbstract:Abstract Patients with immune thrombocytopenic purpura (ITP), a disease featuring abnormally low platelet count, are susceptible to excessive bleeding. One of the more effective treatment regimens is to increase platelet production with Romiplostim. However, current Romiplostim treatment strategies tend to produce undesirable responses where platelet count oscillates between dangerously low and extremely high values, as a consequence of the complex nonlinear dynamics associated with platelet production. This study aims to determine the optimum Romiplostim dose profile required to maintain a stable platelet count for a specific ITP patient. Using the specific patient’s platelet count data obtained in response to a series of Romiplostim doses, a pharmacokinetics/pharmacodynamics model was developed, validated, and analyzed to obtain insight into the patient’s physiological characteristics. The model was subsequently used to investigate the performance of three control strategies for weekly and bi-weekly treatment regimens. A stable platelet count is more likely to be achieved in the specific patient with weekly treatments. Bi-weekly treatments are less effective because fundamental characteristics of Romiplostim make oscillations in platelet count unavoidable at this treatment frequency. Model-based decisions determined using patient-specific mathematical models are potentially useful for designing better treatment regimens for ITP patients. The strategies developed in this work provide potential solutions to the highly variable responses observed among ITP patients undergoing Romiplostim treatment. The approach can also be applied to other diseases with complex system dynamics.
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Romiplostim in children with immune thrombocytopenia a phase 3 randomised double blind placebo controlled study
The Lancet, 2016Co-Authors: Michael D Tarantino, James B Bussel, Melissa J Rose, Victor S Blanchette, Jenny M Despotovic, Carolyn M Bennett, Bronwyn Williams, Donald Beam, Jaime Morales, Nancy CarpenterAbstract:Summary Background The thrombopoietin receptor agonist Romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether Romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months' duration. Methods In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10 9 /L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10 9 /L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly Romiplostim or placebo for 24 weeks stratified by age (1 year to 9 /L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10 9 /L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18–25). This study is registered with ClinicalTrials.gov, NCT 01444417. Findings Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to Romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the Romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9–43·2]). Durable platelet response rates with Romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the Romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the Romiplostim group, were considered treatment related. No patients withdrew due to adverse events. Interpretation In children with chronic immune thrombocytopenia, Romiplostim induced a high rate of platelet response with no new safety signals. Ongoing Romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia. Funding Amgen Inc.
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long term use of the thrombopoietin mimetic Romiplostim in children with severe chronic immune thrombocytopenia itp
Pediatric Blood & Cancer, 2015Co-Authors: James B Bussel, Loan Hsieh, George R Buchanan, Kimo C Stine, Ram Kalpatthi, David J Gnarra, Richard H Ho, Melissa EisenAbstract:Background Treatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12–16-week study, 15/17 Romiplostim-treated patients achieved platelet counts ≥50 × 109/L, and Romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received Romiplostim; all achieved platelet counts >50 × 109/L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of Romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term Romiplostim treatment in chronic severe pediatric ITP.
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safety and efficacy of long term open label dosing of Romiplostim in thrombocytopenic pediatric patients pts with immune thrombocytopenia itp
Blood, 2014Co-Authors: James B Bussel, Janet Franklin, Michael D Tarantino, Amy E Geddis, Michael F Guerrera, Alan K Ikeda, Melissa EisenAbstract:Background: Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim, a TPO receptor agonist that stimulates platelet production, increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 study. Pts who completed that study or an ongoing phase 3 study could roll over into this open-label long-term extension; data from up to 4.2 years of Romiplostim in this extension are described here. Objectives: To describe the safety and efficacy of long-term use of Romiplostim in pediatric ITP. Methods: All pts received SC Romiplostim weekly (QW); the starting dose was the last dose given in the parent study or 1 μg/kg (for those who had previously received only placebo or who had not received Romiplostim for >24 wk). Doses could be adjusted up to 10 µg/kg to achieve target platelet counts in the range of 50-200×10 9 /L. The primary endpoint was incidence of adverse events (AEs). Assessments of AEs, concomitant medications, and local platelet counts were performed QW. For pts who maintained platelet counts of ≥50×10 9 /L for ≥4 consecutive wk at a stable Romiplostim dose, they or their caregivers, if deemed appropriate by the investigator, could learn to self-administer subsequent Romiplostim doses. Pts who self-administered Romiplostim had monthly assessments (not QW). Pts and/or their caregivers recorded dosing date, time, volume administered, and any dosing errors. Pts who turned 18 years of age were permitted to remain on study. Results: 40 pts (12 from the phase 1/2 study and 28 from the phase 3 study) entered the extension; 39 received Romiplostim for up to 217 wk (4.2 yrs); 1 pt withdrew consent before receiving Romiplostim. At extension study baseline, median age was 11 years (range 3-16), 55% were female, and 12.5% had prior splenectomy. Median (range) Romiplostim treatment duration was 40 wk (5–217); median total number of doses was 37 (5–216); median average QW Romiplostim dose was 6 µg/kg (1–10 µg/kg), including dose escalation to achieve a stable dose; median maximum dose was 8 µg/kg (1–10 µg/kg). 10 pts discontinued the study: consent withdrawn (n=5), noncompliance (2), administrative decision (2), and non-response (1). No pts withdrew due to AEs and 30 continued on study. After the first wk of the extension, which for some pts was their first wk of Romiplostim, median platelet counts remained >50×10 9 /L and were in the target range of 50-200×10 9 /L, except for wk 76 and 156, when they were just above 200×10 9 /L (Figure). Q1 platelet counts were >50×10 9 /L from wk 16 on. The median (Q1, Q3) Romiplostim dose was 5 (1, 9) µg/kg at wk 1 and 5 (1, 6) µg/kg at wk 216 (Figure). The median dose fell from 6 µg/kg to 3 µg/kg; from Week 172 on (n≤8), it started to rise and fluctuate. 11 pts received rescue medications (for platelet counts 9 /L, bleeding/wet purpura, or investigator decision), including IV immunoglobulin (n=4), tranexamic acid (2), prednisone (3), platelet transfusion (1), and aminocaproic acid (1). The 21 instances of rescue treatment for 11 pts occurred: in the first 3 months (12 instances), >3–6 months (4), >6–12 months (4), and after 1 year (1) of Romiplostim treatment. 7 pts had 13 serious AEs (asthma, epistaxis, gastroenteritis, gastrointestinal infection, hemangioma, infection, mouth hemorrhage, pain, pharyngitis, pyrexia, tachycardia, transfusion reaction, and viral infection) and 3 had life-threatening AEs (infection, n=1, thrombocytopenia, n=2); none were fatal. None of the serious or life-threatening AEs were deemed treatment-related by the investigators. 30 pts had bleeding AEs, which were deemed treatment-related in 2 pts (gingival bleeding and petechiae). Bleeding AEs occurring in ≥2 pts included contusion (n=11), epistaxis (9), petechiae (8), gingival bleeding (7), ecchymosis (3), hemorrhage (3), injection site bruising (3), mouth hemorrhage (3), and injection site hemorrhage (2). No bone marrow biopsies were performed and no thrombotic events were reported. Conclusion: In this open-label extension, long-term treatment with Romiplostim (up to 4.2 yrs) maintained platelet counts in pediatric pts with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of Romiplostim in children with chronic ITP. Disclosures Bussel: Cangene: Research Funding; GlaxoSmithKline: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy; Amgen Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Off Label Use: Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Use of Romiplostim in pediatric patients is under investigation.. Tarantino: Baxter: Membership on an entity9s Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity9s Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Cangene: Research Funding; UptoDate, Inc.: Patents & Royalties; Amgen Inc.: Membership on an entity9s Board of Directors or advisory committees. Nie: Amgen Inc.: Employment, Equity Ownership. Franklin: Amgen Inc.: Employment, Equity Ownership. Eisen: Amgen Inc.: Employment, Equity Ownership.
