Abstract

Introduction: Romiplostim is an investigational Fc-peptide fusion protein (peptibody) that stimulates platelet production by a mechanism similar to endogenous thrombopoietin and is being investigated for its ability to treat patients with chronic ITP. Some degree of reticulin deposition is often a normal finding in bone marrow, and increased reticulin has been detected in patients treated with thrombopoietin mimetics (Kuter et al, Br J Haem 2007). We analyzed bone marrow biopsy samples from ITP patients at baseline and after romiplostim treatment for the presence and degree of reticulin.

Methods: Baseline and post-treatment samples were analyzed from two sets of bone marrow data: (1) a prospective study in which both baseline (pre-treatment) and follow-up (post-treatment) samples were taken, and (2) a retrospective study of spontaneously reported observations of reticulin occurring across all romiplostim clinical trials. Assessments were made from aspirate smears, core biopsies, reticulin stains, trichrome stains, and written reports. Only patients with evaluable baseline and post-treatment samples are included in this report. Reticulin was graded according to the following scale: 0 (absent), 1 (fine fibers), 2 (diffuse fine fiber network), 3 (diffuse fiber network with scattered coarse fibers), and 4 (areas of collagen). Grade 0–2 reticulin can be found in bone marrow from healthy individuals, and reticulin grades 1 to 2 have been described in the bone marrow of 66% of ITP patients (Mufti et al, ASH 2006).

Results: Six of 10 prospective study patients had both evaluable baseline and follow-up samples. Reticulin grades in all 6 samples at baseline were 0–1. Only 1 patient demonstrated an increase in reticulin (from 0–1 to 1–2 after 3 months of romiplostim). Higher degrees of reticulin deposition (grades >2) were not observed, and trichrome staining demonstrated absence of collagen in all 6 cases. Baseline and follow-up bone marrow samples were available in 5 of 9 retrospective study patients, including one patient from the prospective study in whom reticulin was also spontaneously reported following romiplostim administration. In these 5 patients, the baseline reticulin grade was 0 to 1 in all cases and increased after treatment in all but one case. Reticulin typically decreased soon after discontinuation of romiplostim. Two patients were exposed to drug doses exceeding those used in current clinical studies (≥ 10 μg/kg). One patient showed minimal collagen deposition (reticulin grade 4) that was absent in a further follow-up sample after treatment discontinuation.

Conclusion: Increased reticulin was observed in the bone marrow of some romiplostim-treated patients and typically decreased soon after drug withdrawal. There was no evidence that romiplostim exposure led to development of chronic idiopathic myelofibrosis or other clonal disorders in this small sample of patients.

Table 1. Reticulin scores in bone marrow samples from ITP patients before and following romiplostim therapy

   Reticulin Assessment (Weeks after initiating romiplostim) 
    Follow-up during treatment Follow-up after treatment discontinuation 
Age, Years Prior Splenectomy, Y/N Max Dose, μg/kg Baseline (prior to romiplostim treatment) 
A Reticulin in this patient was also spontaneously reported and included in the retrospective analysis 
B A focal area of possible collagen deposition was seen on trichrome stain. 
Prospective study cases 
70 0–1 1–2 (wk 15) 
43 0–1 0–1 (wk 37) 
42 0–1 1 (wk 13) 
55 0–1 0–1 (wk 34) 
83 0–1 0–1 (wk 13) 
53 0–1A 0–1A (wk 35) 
Retrospective study cases of spontaneously reported reticulin 
40 0–1, focal 2 3 (wk 5) 1–2 (wk 17) 
31 18 2–3 (wk 26) 1–2 (wk 34) 1 (wk 46) 
58 15 0–1 1–3B (wk 31) 2–3 (wk 51) 1–2 (wk 67) 
37 4 (wk 26) 1–2 (wk 38) 
   Reticulin Assessment (Weeks after initiating romiplostim) 
    Follow-up during treatment Follow-up after treatment discontinuation 
Age, Years Prior Splenectomy, Y/N Max Dose, μg/kg Baseline (prior to romiplostim treatment) 
A Reticulin in this patient was also spontaneously reported and included in the retrospective analysis 
B A focal area of possible collagen deposition was seen on trichrome stain. 
Prospective study cases 
70 0–1 1–2 (wk 15) 
43 0–1 0–1 (wk 37) 
42 0–1 1 (wk 13) 
55 0–1 0–1 (wk 34) 
83 0–1 0–1 (wk 13) 
53 0–1A 0–1A (wk 35) 
Retrospective study cases of spontaneously reported reticulin 
40 0–1, focal 2 3 (wk 5) 1–2 (wk 17) 
31 18 2–3 (wk 26) 1–2 (wk 34) 1 (wk 46) 
58 15 0–1 1–3B (wk 31) 2–3 (wk 51) 1–2 (wk 67) 
37 4 (wk 26) 1–2 (wk 38) 

Disclosures: Kuter:Amgen Inc.: Consultancy, Research Funding; Glaxo-Smith-Kline: Consultancy, Research Funding; Ligand: Consultancy, Research Funding; MGI Pharma: Consultancy, Research Funding. Mufti:Celgene: Honoraria, Speakers Bureau; Johnson and Johnson: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Bain:Amgen Inc.: Consultancy. Hasserjian:Amgen Inc.: Consultancy. Rutstein:Amgen Inc.: Employment, Equity Ownership.

Author notes

Corresponding author