Romiplostim and Marrow Fibrosis
Romiplostim and Marrow Fibrosis
Abstract & Commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Thrombopoietin receptor agonists such as romiplostim and eltrombopag have recently been approved to raise platelet counts in patients with immune thrombocytopenic purpura (ITP). One unusual side effect has been increased bone marrow reticulin fibrosis. The authors showed that romiplostim-induced fibrosis in rats was dose-dependent and resolved after drug withdrawal. Among 271 patients on romiplostim clinical trials, fibrosis developed in 10 patients, which often resolved on drug discontinuation. In some patients, romiplostim leads to reversible bone marrow reticulin fibrosis.
Source: Kuter D, et al. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood. 2009;114:3748-3756.
Immune thrombocytopenic purpura (ITP) in adults is often a chronic relapsing condition for which treatment may exact as many problems as the disease itself.1 Thrombopoietin stimulates platelet production through the thrombopoietin receptor c-MPL. Two new thrombopoietin-receptor agonists have been approved that improve platelet counts in chronic refractory ITP,2,3 romiplostim (AMG-531, Nplate), and Eltrombopag (SB-497115, Promacta). An increase in bone marrow reticulin fibrosis has been reported with eltrombopag (http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4366b1-02-GSK.pdf), prompting a thorough evaluation by Kuter et al of the impact of romiplostim on marrow reticulin fibrosis.
First, rats were treated with subcutaneous romiplostim for four weeks at three different doses and compared to placebo. Romiplostim caused a dose-dependent increase in platelet counts. Some rats were sacrificed to study bone-marrow changes. Romiplostim-treated rats revealed a dose-dependent increase in bone-marrow fiber content and hyperostosis, whereas the controls showed no marrow changes. Animals evaluated four weeks after drug discontinuation showed no marrow fibrosis or hyperostosis.
Results of romiplostim clinical trials were then reviewed. Kuter et al retrospectively reviewed data from 11 different romiplostim clinical trials involving 271 patients. From the retrospective series, 11 bone-marrow examinations were performed for select reasons. Ten of the 11 patients showed reticulin fibrosis. Reticulin fibrosis was graded by an expert panel for 8 of the 10 patients with reticulin fibrosis. Using a grade 1 to 4 scale, all but one had at grade 2 or greater reticulin fibrosis. For patients where both an on-treatment and after treatment bone-marrow sample were available, marrow changes improved or disappeared with time.
In addition, 10 subjects agreed to participate in a prospective trial in which baseline and follow-up bone marrows were performed. Bone marrow cellularity did not change during romiplostim treatment. Of eight patients with adequate staining at baseline and follow-up, all had normal reticulin staining of 0 to 1 at baseline. During treatment, two had reticulin greater than 0 to 1. One had involvement of B-cell lymphoma, potentially confounding reticulin changes. The other patient had an increase in reticulin, although it was still rated as 0 to 1. Off-treatment bone-marrow examinations were not performed.
Commentary
Satisfactory treatment is lacking for chronic refractory immune thrombocytopenic purpura (ITP). A host of immunosuppressive therapies or combination treatments may be used but may have considerable toxicity.1 The recognition that ITP often manifests inadequate endogenous thrombopoietin levels and suboptimal platelet production suggested megakaryocyte stimulation as a therapeutic approach. Initial studies with a thrombopoietin analog caused antibody formation that cross reacted against native thrombopoietin, halting clinical development.4 More recently developed thrombopoietin analogs have not shown antibody formation. Two drugs, romiplostim and eltrombopag, successful raised platelet counts in chronic refractory ITP, leading to FDA approval. One rarely reported potentially serious toxicity has been bone marrow fibrosis. As such, the authors evaluated the impact of romiplostim on bone marrow reticulin fibrosis and other changes.
Kuter et al first examined rats exposed to escalating doses of romiplostim or placebo. A dose dependent increase in bone marrow fibrosis and hyperostosis was found. After one month of treatment discontinuation, the marrow changes resolved. The authors reviewed 271 ITP patients treated with ITP in 11 different trials. Only 11 patients had a marrow examination performed, and ten showed some reticulin staining. Only half had pre-treatment marrows for comparison. Four of the five had an increase from baseline, supporting romiplostim-induced marrow fibrosis. Discontinuation in three patients led to improvement in marrow fibrosis. One patient continued drug with a slight decrease in reticulin fibrosis.
This report convincingly shows romiplostim can induce bone-marrow changes, including reticulin fibrosis. The data are not surprising, as preclinical models demonstrate that thrombopoietin overexpression can lead to a myeloproliferative disorder characterized by megakaryocyte proliferation and marrow fibrosis.5 Further, a recent FDA report indicated that among 117 ITP patients treated with eltrombopag, marrow fibrosis was identified in seven of 19 for whom a bone-marrow examination was performed. Fortunately, Kuter et al preclinical and clinical studies show that romiplostim-induced marrow fibrosis typically resolves after drug discontinuation.
The study affirms the need for long-term follow-up for patients receiving platelet growth factors. Risk factors for fibrosis have not been reported but, to the extent pre-clinical models showed dose-dependent marrow changes, one can anticipate higher doses may increase the chance of marrow fibrosis. Therefore, clinicians should use the lowest dose necessary of thrombopoietin-receptor analogs. The role, if any, of routine bone-marrow examination for patients on such drugs to evaluate for fibrosis is not clear.
In summary, romiplostim induced bone-marrow reticulin fibrosis in some patients that will likely resolve after drug discontinuation.
References
1. Boruchov DM, et al. Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood 2007;110: 3526-3531.
2. Bussel JB, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355: 1672-1681.
3. Bussel JB, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357:2237-2247.
4. Li J, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98: 3241-3248.
5. Yan XQ, et al: A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): Reversal of disease by bone marrow transplantation. Blood. 1996;88:402-409.
Thrombopoietin receptor agonists such as romiplostim and eltrombopag have recently been approved to raise platelet counts in patients with immune thrombocytopenic purpura (ITP). One unusual side effect has been increased bone marrow reticulin fibrosis.Subscribe Now for Access
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