government site. There is no evidence-based knowledge and very limited experience on how to manage patients who develop increasing fibrosis during treatment with TPO-RA, although we believe that discontinuation of TPO-RA will allow the degree of reticulin deposition to decrease. None of the patients treated had any evidence of classic active graft-versus-host disease (GVHD), and evaluation of peripheral blood was negative for cytomegalovirus. Some patients had received previous treatment, such as romiplostim, that may have caused MF. Specimens were centrally processed, stained for reticulin and collagen, independently reviewed by 2 hematopathologists, and rated according to the European Consensus 0-3 scale of marrow fibrosis (MF). Some other studies have not clearly produced the same results; but this lower proportion of MF-2/3 could be explained by shorter observation times. Flow cytometric immunophenotyping of bone marrow aspirates was performed in 89 examinations. Last accessed: 06 June 2019. official website and that any information you provide is encrypted None of the bone marrow biopsies showed an increase in blasts. Authors Thirdly, the reference list of all identified reports and articles were searched for additional studies. In the study, eight clinical trials involving a total of 936 patients were reviewed; a number of points of contention regarding the trials were identified and some had limitations. Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, et al. Lakshmanan S, Cuker A. Gonzlez-Lpez TJ et al. BM: bone marrow; ITP: immune thrombocytopenia; KSA: Saudi Arabia; MF: myelofibrosis; TPO: thrombopoietin; TPORA: thrombopoietin receptor agonist; UK: United Kingdom; USA: United States of America. 19 Among 23 patients assessed, no increase in fibrosis or reticulin was noted on bone marrow . Other second-line treatments include azathioprine, cyclophosphamide, cyclosporine, danazol, mycophenolate mofetil, vincristine, and the novel medication fostamatinib. GlaxoSmithKline. Myelofibrosis often causes an enlarged spleen. Monitoring patients with the treatment of eltrombopag is a big concern. Yaman Y, Elli M, ahin , zdilli K, Bilgen H, Bayram N, Nepesov S, Anak S. Pediatr Transplant. Haematologica. Karata A, Gker H, Demirolu H, Malkan Y, Velet M, nar OE, Erdodu B, Karadeniz M, Saynalp N, Aksu S, Haznedarolu C, zcebe O, Bykak Y. Turk J Med Sci. MF was recorded using the European consensus on grading BM fibrosis and assessment of cellularity. Keywords: Sabnani I, Tsang P. Changing spectrum of chronic immune thrombocytopenic purpura: New face for an old disease. Eltrombopag, a potent stimulator of megakaryopoiesis. abnormal bone marrow or liver function tests. Cines DB. In a retrospective study of 27 patients, who received eltrombopag after allogeneic haematopoietic stem cell transplant (alloHCT), one patient [ age and sex not stated] was described, who developed bone marrow fibrosis during treatment with eltrombopag for secondary failure of platelet recovery (SFPR) or poor graft function (PGF). Cytomorphologic changes in bone marrow after eltrombopag administration are still unclear. Br J Haematol. Horikoshi M et al. These data provide evidence that the effects of TPO-RA are inconsistent but that TPO-RA treatment will generally increase the degree of fibrosis over time. Hyperuricaemia can also arise secondary to high cell turnover, in which a high white blood cell count and platelet count may be seen: these cells are needed to compensate the marrow underproduction. Drugs that are substrates . Bone marrow biopsies will be performed at screening, after 1-year and 2-years of eltrombopag treatment, and at early withdrawal of treatment. Accessibility Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Rutstein M. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. In the first trial, the authors studied 117 patients treated with eltrombopag for 5.5 years. No baseline for BMB was found before launching eltrombopag. Haematologica. Although these results are reassuring, the exposure time may have been too short to induce clonal abnormalities; longer follow-up is needed to ensure the safety of these agents in this regard as well. Bookshelf The initial search resulted in a total of 201 articles, which included records identified through searching various databases: 161 from Google Scholar, 27 from PubMed, 2 articles related to the Cochran database, and an additional 11 from article reference lists, relevant organisations such as ASH and the FDA, plus conference proceedings that included references identified through other sources. Epub 2022 Apr 14. The reviewers read the full articles to make the final decision as to whether they should be chosen for inclusion in the review. Before 2012;10(10):1988-98. Female patients mostly have no obvious conscious symptoms, but have leucorrhea. Patients with chronic ITP under TPORA treatment may be on these agents for as long as 510 years, meaning observational follow-up is needed to find out whether prolonged exposure to TPORA would lead to relevant grades of MF in many patients. Cytogenetic analysis was performed on 72 bone marrow biopsies. 2021 Jul;81(11):1285-1305. doi: 10.1007/s40265-021-01553-7. Any study design (retrospective or prospective). Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. The trial conducted by Gonzlez-Lpez et al.17 in 2017 studied 87 patients. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. 2010. In the study, three case reports of MF that was induced by eltrombopag were included. Drug Des Devel Ther. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022291REMS.pdf. In contrast, three reviews by Cook and Cooper,21 Rank et al.,22 and Bascianoa and Bussel24 concluded that there was no evidence of clinically relevant BM abnormalities or MF with long-term eltrombopag use, and that the significance of reticulin and MF accumulation in BM is unclear. Abstract: http://www.ncbi.nlm.nih.gov/nlmcatalog/9002563, Travlos GS. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study. Avatrombopag (Doptelet ) is an orally administered drug that mimics the natural compound (thrombopoietin) responsible for stimulating the production of platelets, an essential component of the clotting process that prevents excessive bleeding. Blood is composed of plasma and various types of cells. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study. 13 previous studies from our group suggested that the grade of reticulin might increase after initiation of tpo-ra in patients with itp. The proportion of bone marrow biopsies showing no fibrosis (myelofibrosis grade 0) decreased from 67% pre-treatment to 22% at last biopsy, of which 59% had grade 1 myelofibrosis and 18% had grade 2 myelofibrosis. At the time of the first, second, third and fourth on-treatment biopsies, median romiplostim dosages were 9, 9, 7.5, and 8 g/kg/week and median eltrombopag dosages were 63, 75, 75, and 75 mg/day, respectively. 2009;3:151-7. One patient in the placebo group experienced grade 3 bone marrow fibrosis. One patient returned to normal after discontinuing eltrombopag whereas the other patient had persistent MF. Ghanima W et al. Fibrosis, A guide for standardizing terminology in toxicologic pathology for rodents, Bain BJ, Clark DM, Lampert IA, Wilkins BS. 2014;25(8):777-80. Bone marrow fibrosis has been reported in patients receiving thrombopoietin-receptor agonists. 2015;90(7):598-601. The authors believe that degree of fibrosis may depend on specific factors, including dose of medicine, duration of disease, platelet number and immature fraction, splenectomy, and age at time of starting TPORA agent. Two recently published long-term studies of the use of romiplostim and eltrombopag in ITP also considered this topic although the romiplostim study only had bone marrow data for 40 out of more than 200 patients.20 The long-term study on safety and efficacy of eltrombopag (the EXTEND study) reported findings in which the initial results were in line with ours after 1 year of treatment (first set of bone marrow biopsies, Table 2), showing that 92% of patients had MF-0/MF-1 and 8% had MF-2.13 Also similar to our findings, Brynes et al., in a study of 45 patients in which pre-treatment biopsies were compared to those conducted after 1 and 2 years of treatment with eltrombopag, found a decrease in the proportion of MF-0 marrows from 90% in pre-treatment biopsies to 60% after 1 year of treatment; however, unlike the study reported here, the proportion of MF-0 increased again to just over 80% after 2 years of treatment.21 One difference between these studies and ours is that the duration of ITP before the first set of bone marrow biopsies was much longer in our study. Immune thrombocytopenic purpura is a clinical syndrome of thrombocytopenia that manifests as a bleeding tendency, typical skin rashes, easy bruising, or extravasation of blood from the capillaries. The ePub format uses eBook readers, which have several "ease of reading" features 2016;29(12):59-63. 2019;133(7):628-9. One patient developed MF-3 after 11 months of being on eltrombopag administration, but after cessation of eltrombopag this decreased to MF-1. Oncol Res Treat. Although not statistically significant, hemoglobin concentration tended to be lower in patients at the time of bone marrow biopsies showing MF-2/3, and platelet counts tended to be higher (Table 3). Bussel JB et al. The functionality is limited to basic scrolling. Received 2013 Sep 30; Accepted 2014 Jan 20. Eltrombopag: (Moderate) Eltrombopag is an inhibitor of OATP1B1 and Breast Cancer Resistance Protein (BCRP). Eltrombopag is an effective medication for treatment of ITP; however, the development of BM fibrosis is an immense concern and the authors will spotlight this issue in this scoping review. Home 2010;4:139-45. Moderate fibrosis or any cirrhosis should lead to discontinuation of the methotrexate; mild fibrosis normally suggests a repeat biopsy at 6 months. official website and that any information you provide is encrypted Schmitt A et al. All control cases were graded as either MF-0 (54%) or MF-1 (46%). Copyright 2022 European Medical Group LTD trading as European Medical Journal. Elbedewy TA, Elsebaey MA, Elkholy RA, Tahoon DM, Elshweikh SA. This study has some limitations. Two prospective trials were completed by Ghanima et al. First, as discussed, it appears that continuous exposure to therapeutic doses of TPO-RA induces fibrosis in a subset of patients and, once induced, fibrosis may progress. The authors recommend discontinuing the medication if this side effect occurs. Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist (TPO-RA) which stimulates the proliferation and differentiation of bone marrow megakaryocytes and increases platelet production. This study determined the extent of myelofibrosis, its clinical relevance, and incidence of phenotypic or karyotypic abnormalities in patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists. For most patients with chronic ITP, eltrombopag is not associated with clinically relevant increases in BM reticulin or collagen formation. Only the articles that met the inclusion and exclusion criteria were studied. 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