Evaluation of Bone Marrow Reticulin in Patients with Chronic Immune Thrombocytopenic Purpura (ITP) Treated with Eltrombopag – Data From the EXTEND Study

Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) that increases platelet counts in patients with chronic ITP. The potential association of TPO-RA and increased bone marrow reticulin fibrosis is currently under investigation. The EXTEND study, an open-label extension study of eltrombopag, enrolled patients with heavily pre-treated chronic ITP who had received eltrombopag or placebo in a previous eltrombopag study. In EXTEND, patients underwent bone marrow biopsies at 12 months (+/− 2 months) after the first dose of eltrombopag, and thereafter annually (+/− 2 months) while on study. Methods: In order to reduce pre-analytic variables and standardize the analysis, a central laboratory processed specimens, except when only pre-stained slides were available. Morphology review was carried out by two hematopathologists, blinded to clinical information, who assessed specimens for cellularity, megakaryocyte, erythroid, and myeloid quantity and appearance, trabecular bone changes, and scored for reticulin and collagen deposition (European Consensus Classification). Results: In the EXTEND study, 301 patients with chronic ITP have been treated with eltrombopag for up to 4.5 years. 185 specimens from 110 patients, collected up to February 2011, were reviewed (Table). 156 of 185 could be reviewed for all parameters (154 for trabecular bone). Cellularity was within the normal range (40-60%) in 142 specimens (91.0%). 146 specimens (93.6%) demonstrated megakaryocytic hyperplasia. Megakaryocyte morphology was normal in 148 (94.9%) specimens. Six specimens had megakaryocytes reminiscent of those seen with polycythemia vera or essential thrombocythemia, and 2 of 6 were associated with increased reticulin fibers. Erythroid hyperplasia was observed in 35 (22.4%) and granulocytic maturation was hyperplastic in 9 (5.8%) specimens. Trabecular bone thinning was found in 62/154 (40.3%) of specimens, the majority collected from patients with prior exposure to steroids. Reticulin fibers were increased (MF ≥2) in 4/156 (2.6%) of specimens. Three of 4 specimens with MF ≥2 were positive for collagen. All 4 specimens with increased reticulin fibers were judged as hypercellular, and 2 of 4 contained megakaryocytes with myeloproliferative neoplasm-like features as described above. These 4 specimens were collected from 3 patients: 2 patients had reticulin documented after 763 and 970 days of treatment, and were preemptively withdrawn from the study. One of these two patients had an MF-0 and negative collagen 7-months following withdrawal. The third patient had MF-2 at Day 415 and MF-3 at Day 772, with presence of collagen, and is still on treatment almost one year after the last biopsy. None of these 3 patients experienced any adverse events or abnormality in hematologic parameters potentially related to impaired bone marrow function. Discussion: Reticulin fibrosis has been described as a rare adverse event in chronic ITP patients receiving TPO-RA. In this evaluation of EXTEND study specimens, reticulin was within the normal range in 152/156 (97.4%) of specimens collected from 102 patients, after a median of 25 months of treatment. None of the patients with reticulin or collagen findings showed clinical signs or symptoms indicative of bone marrow dysfunction. No pattern of increasing reticulin deposition with longer treatment periods is apparent based on bone marrow biopsy data available to date. These data suggest that for most patients treatment with eltrombopag is not associated with the development of bone reticulin or collagen fibrosis; however, the potential association of TPO-RA and increased bone marrow fibrosis still needs to be better understood.

Brynes:GlaxoSmithKline: Consultancy, Research Funding. Brainsky:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment.