Bone Marrow Fibrosis in 66 Patients with Immune Thrombocytopenia Treated with Thrombopoietin-receptor Agonists: a Single-center, Long-term Follow-up

Overview

Journal Haematologica

Specialty Hematology

Date 2014 Jan 28

PMID 24463212

Citations 27

Authors

Waleed Ghanima

Julia Turbiner Geyer

Christina S Lee

Leonardo Boiocchi

Allison A Imahiyerobo

Attilio Orazi

James B Bussel

Affiliations

Soon will be listed here.

Abstract

Thrombopoietin-receptor agonists increase platelet counts by stimulating the thrombopoietin receptor. Bone marrow fibrosis has been reported in patients receiving thrombopoietin-receptor agonists. 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. The grade of myelofibrosis was assessed before (n=15), during (n=117) and after (n=9) treatment in bone marrow biopsies from 66 patients. 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. The median duration of treatment with thrombopoietin-receptor agonists to last bone marrow biopsies was 29 months; patients who had two or more biopsies significantly more frequently had myelofibrosis grades 2/3 in the last bone marrow biopsies as compared to the first. Older age was associated with higher grades of fibrosis. No differences in blood counts or lactate dehydrogenase levels were found between patients with myelofibrosis grades 0/1 and those with grade 2. No clonal karyotypic or immunophenotypic abnormalities emerged. This study found that thrombopoietin-receptor agonists induce myelofibrosis grades 2/3 in approximately one-fifth of patients with immune thrombocytopenia, increasingly with >2 years of treatment with thrombopoietin-receptor agonists. Annual/biannual follow-up with bone marrow biopsies is, therefore, recommended in patients being treated with thrombopoietin-receptor agonists in order to enable prompt discontinuation of these drugs should grades 2/3 myelofibrosis develop. Discontinuation of thrombopoietin-receptor agonists may prevent development of clinical manifestations by stopping progression of fibrosis in grade 2/3.

Citing Articles

Safety analysis of romiplostim, eltrombopag, and avatrombopag post-market approval: a pharmacovigilance study based on the FDA Adverse Event Reporting System.

Wang X, Li Y, Zhuang W BMC Pharmacol Toxicol. 2025; 26(1):46.

PMID: 40016824 PMC: 11869546. DOI: 10.1186/s40360-025-00873-8.

Let It Grow: The Role of Growth Factors in Managing Chemotherapy-Induced Cytopenia.

Alyamany R, Alnughmush A, Alzahrani H, Alfayez M Curr Oncol. 2024; 31(12):8094-8109.

PMID: 39727719 PMC: 11675056. DOI: 10.3390/curroncol31120596.

Current state and potential applications of neonatal Fc receptor (FcRn) inhibitors in hematologic conditions.

Jacobs J, Booth G, Raza S, Clark L, Fasano R, Gavriilaki E Am J Hematol. 2024; 99(12):2351-2366.

PMID: 39324647 PMC: 11560617. DOI: 10.1002/ajh.27487.

Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.

Barrachina M, Pernes G, Becker I, Allaeys I, Hirsch T, Groeneveld D Nat Cardiovasc Res. 2024; 2(8):746-763.

PMID: 39195958 PMC: 11909960. DOI: 10.1038/s44161-023-00305-y.

Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options.

Mititelu A, Onisai M, Rosca A, Vladareanu A Int J Mol Sci. 2024; 25(4).

PMID: 38396839 PMC: 10889445. DOI: 10.3390/ijms25042163.

References

Cheng G, Saleh M, Marcher C, Vasey S, Mayer B, Aivado M . Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2010; 377(9763):393-402. DOI: 10.1016/S0140-6736(10)60959-2. View

Bussel J, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L . Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009; 373(9664):641-8. DOI: 10.1016/S0140-6736(09)60402-5. View

Kuter D, Gminski D, Rosenberg R . Transforming growth factor beta inhibits megakaryocyte growth and endomitosis. Blood. 1992; 79(3):619-26. View

Bauermeister D . Quantitation of bone marrow reticulin--a normal range. Am J Clin Pathol. 1971; 56(1):24-31. DOI: 10.1093/ajcp/56.1.24. View

Bussel J, Kuter D, George J, McMillan R, Aledort L, Conklin G . AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006; 355(16):1672-81. DOI: 10.1056/NEJMoa054626. View

Ghanima W, Junker P, Hasselbalch H, Boiocchi L, Geyer J, Feng X . Fibroproliferative activity in patients with immune thrombocytopenia (ITP) treated with thrombopoietic agents. Br J Haematol. 2011; 155(2):248-55. DOI: 10.1111/j.1365-2141.2011.08845.x. View

Ghanima W, Bussel J . Thrombopoietic agents in immune thrombocytopenia. Semin Hematol. 2010; 47(3):258-65. DOI: 10.1053/j.seminhematol.2010.03.003. View

Kuter D, Rummel M, Boccia R, Macik B, Pabinger I, Selleslag D . Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010; 363(20):1889-99. DOI: 10.1056/NEJMoa1002625. View

Bussel J, Kuter D, Pullarkat V, Lyons R, Guo M, Nichol J . Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2008; 113(10):2161-71. DOI: 10.1182/blood-2008-04-150078. View

10.

Thiele J, Kvasnicka H, Facchetti F, Franco V, van der Walt J, Orazi A . European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005; 90(8):1128-32. View

11.

Kuter D, Bain B, Mufti G, Bagg A, Hasserjian R . Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol. 2007; 139(3):351-62. DOI: 10.1111/j.1365-2141.2007.06807.x. View

12.

Cines D, Bussel J, Liebman H, Luning Prak E . The ITP syndrome: pathogenic and clinical diversity. Blood. 2009; 113(26):6511-21. PMC: 2710913. DOI: 10.1182/blood-2009-01-129155. View

13.

Kuter D, Bussel J, Lyons R, Pullarkat V, Gernsheimer T, Senecal F . Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008; 371(9610):395-403. DOI: 10.1016/S0140-6736(08)60203-2. View

14.

Kuter D, Bussel J, Newland A, Baker R, Lyons R, Wasser J . Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013; 161(3):411-23. DOI: 10.1111/bjh.12260. View

15.

Bussel J, Cheng G, Saleh M, Psaila B, Kovaleva L, Meddeb B . Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007; 357(22):2237-47. DOI: 10.1056/NEJMoa073275. View

16.

Boiocchi L, Orazi A, Ghanima W, Arabadjief M, Bussel J, Geyer J . Thrombopoietin receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities. Mod Pathol. 2011; 25(1):65-74. DOI: 10.1038/modpathol.2011.128. View

17.

Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M . Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011; 29(6):761-70. PMC: 4979120. DOI: 10.1200/JCO.2010.31.8436. View

18.

Saleh M, Bussel J, Cheng G, Meyer O, Bailey C, Arning M . Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2012; 121(3):537-45. DOI: 10.1182/blood-2012-04-425512. View

19.

Chagraoui H, Komura E, Tulliez M, Giraudier S, Vainchenker W, Wendling F . Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood. 2002; 100(10):3495-503. DOI: 10.1182/blood-2002-04-1133. View

20.

Kuter D . Biology and chemistry of thrombopoietic agents. Semin Hematol. 2010; 47(3):243-8. PMC: 2904343. DOI: 10.1053/j.seminhematol.2010.02.005. View