Thrombopoietin Receptor (TPO-R) Agonist Induced Myelofibrosis: Comparison of Pre-Treatment and Post-Treatment Bone Marrow Biopsies
M Arabadjief, JT Geyer, S Barouk, DM Knowles, I Ouansafi, JB Bussel, A Orazi. Weill Cornell Medical College, New York
Background: Thrombopoietin receptor (TPO-R) agonists are a recent advance in the treatment of chronic idiopathic thrombocytopenia purpura (ITP). Increase in bone marrow reticulin was seen in 8 of 142 patients during evaluation of long-term treatment with romiplostim. However, the true incidence of this event is unknown. The goal of our study is to investigate this finding and elucidate the fibrogenetic mechanisms.
Design: Seven patients from ongoing TPO-R studies had both baseline and follow-up bone marrow examinations. The biopsies were stained with reticulin, trichrome, collagen IV, laminin and smooth muscle actin (SMA) to investigate the extracellular matrix characteristics and presence of myofibroblastic differentiation. Degree of reticulin (0 to 3+) was graded according to the European Consensus Methods for measuring bone marrow fibrosis. A trichrome stain was used to assess for the presence of collagen fibrosis (result expressed as + or -). Collagen IV, laminin and SMA were determined semiquantitatively as focally positive, positive, or strongly positive.
Results: Mean time between baseline and follow-up marrow examination with treatment initiation was 42.6 mo (baseline to treatment range, 6 to 26 mo; treatment to follow-up range, 2 to 56 mo). Mean baseline and follow-up patient age was 38.3 years and 41.6 years, respectively (range, 11 to 70 years and 13 to 72 years, respectively). Five cases showed an increase in reticulin fibrosis in comparison to baseline: from 0 to 1+ in 3 cases, from 0 to 2+ in 1 case; from 2 to 3+ in an additional case. The one patient with moderate increase (0 to 2+) in marrow fibrosis in the post-treatment sample showed megakaryocytes with features usually seen in cases of essential thrombocythemia (hyperlobulation and clustering). Collagen fibrosis was not observed in any of the cases. Immunostaining for SMA, collagen IV and laminin also showed no difference.
Conclusions: Five of 7 patients showed an increase in reticulin fibrosis; in 4 patients this was mild and may not be relevant clinically. None of the patients showed collagen positivity or immunohistochemical changes seen in myelofibrotic myeloproliferative neoplasms (MPN). However, 1 case with a moderate increase in reticulin fibrosis after TPO-R agonist therapy developed morphologic features usually seen in essential thrombocythemia (ET), a less aggressive MPN subtype. This raises the possibility that hypersensitivity to TPO may play a role in a subset of ET patients.
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 196, Wednesday Afternoon