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      Correlation of the Plasma Concentration of Eltrombopag With Efficacy in the Treatment of Refractory Aplastic Anemia: A Single-Centre Study in China

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          Abstract

          Background and purpose: Eltrombopag (ELT) can be effective in the treatment of relapse/refractory aplastic anemia (AA) patients. Responses and adverse drug reactions (ADRs) differed greatly among individuals treated at the same dosage of ELT.

          Methods: Patients diagnosed with nonsevere aplastic anemia (NSAA) between January 2018 and January 2019 in Peking Union Medical Colleague Hospital who were refractory to immunosuppressive therapy were treated with ELT and followed up for at least 6 months. Plasma concentrations of ELT were detected by high-performance liquid chromatography-mass spectrometry after at least two months of ELT treatment and treatment at the same dosage for at least 2 weeks. The dose-concentration, concentration-response and concentration-ADR relationships were evaluated.

          Results: Among the 72 patients treated with ELT during the study period, 44 patients with complete data were enrolled. Six (13.6%) were males, and 38 were females (86.4%), with a median age of 54 years [interquartile range (IQR): 38.5–63]. At the time the ELT plasma concentration was detected, the median dosage of ELT was 75 (IQR 50–100) mg/d, the median time of total ELT exposure was 3 (IQR 2.0–6.0) months, and 37 (70.5%) patients had responded to ELT. The median concentration of ELT was 10.4 μg/ml (IQR 3.7–24.4 μg/ml). The concentration of ELT was positively correlated with the daily dose of ELT ( r = 0.68, p < 0.001). Multivariate logistic regression analysis showed that the risk of inefficacy of ELT at a concentration between 11.2 and 15.2 μg/ml was 0.028-fold (95% CI: 0.001–0.864; p = 0.041) of that at a concentration between 3.2 and 7.2 μg/ml. The cutoff value for the concentration of ELT showing efficacy was 12.50 μg/ml according to the receiver operation characteristic curve. A higher risk of ADR was related to a longer total exposure to ELT ( p = 0.012). Although the correlation was not significant, the odds ratio increased with the ELT concentration, suggesting that it was possible that an elevated risk of ADR was correlated with the ELT blood concentration.

          Conclusion: ELT is effective for the treatment of NSAA and has acceptable side effects. The plasma concentration of ELT was correlated with the dose and the effects of ELT.

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          Guidelines for the diagnosis and management of aplastic anaemia.

          N. C. Edwards, Judith C W Marsh, Jane Mercieca … (2009)
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            Eltrombopag and improved hematopoiesis in refractory aplastic anemia.

            Matthew J. Olnes, Phillip Scheinberg, Katherine Calvo … (2012)
            Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells. We conducted a phase 2 study involving patients with aplastic anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag. Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes. Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00922883.).
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              Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug.

              Ronan Desmond, Danielle M Townsley, Bogdan Dumitriu … (2014)
              About a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy. We have previously demonstrated that eltrombopag has efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. We now report safety and efficacy data on a further 18 patients and long-term follow-up on the entire cohort of 43 patients. The overall response rate was 17 of 43 patients (40%) at 3 to 4 months, including tri- and bilineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. Eltrombopag is efficacious in a subset of patients with aplastic anemia refractory to immunosuppressive therapy, with frequent multilineage responses and maintenance of normalized hematopoiesis off treatment. This study is registered at www.clinicaltrials.gov as #NCT00922883.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Pharmacol
                Journal ID (iso-abbrev): Front Pharmacol
                Journal ID (publisher-id): Front. Pharmacol.
                Title: Frontiers in Pharmacology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1663-9812
                Publication date (Electronic): 16 November 2020
                Publication date Collection: 2020
                Volume: 11
                Electronic Location Identifier: 582625
                Affiliations
                [ 1 ]Department of Pharmacy, Peking Union Medical Colleague Hospital, Chinese Academy of Medical Science, Beijing, China
                [ 2 ]Department of Hematology, Peking Union Medical Colleague Hospital, Chinese Academy of Medical Science, Beijing, China
                Author notes

                Edited by: Robert L. Lins, Independent Researcher, Antwerp, Belgium

                Reviewed by: Etienne Lengline, Assistance Publique Hopitaux De Paris, France

                Tomás José González-López, Burgos University Hospital, Spain

                * Correspondence: Bing Han, hanbing_li@ 123456sina.com
                [†]

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology

                Article
                Publisher ID: 582625
                DOI: 10.3389/fphar.2020.582625
                PMC ID: 7751734
                PubMed ID: 33364958
                SO-VID: 4430e2a8-6fe8-45be-baaa-bd7bbc0dd976
                Copyright © Copyright © 2020 Zuo, Zhang, Ruan, Chen and Han
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 13 July 2020
                Date accepted : 15 October 2020
                Page count
                Pages: 0
                Categories
                Subject: Pharmacology
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: eltrombopag,non-severe aplastic anemia,refractory,plasma concentration,efficacy
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: eltrombopag, non-severe aplastic anemia, refractory, plasma concentration, efficacy

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