Originally published as JCO Early Release 10.1200/JCO.2008.20.3174 on April 13 2009

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Reticulin Accumulation in Essential Thrombocythemia: Prognostic Significance and Relationship to Therapy

Peter J. Campbell, David Bareford, Wendy N. Erber, Bridget S. Wilkins, Penny Wright, Georgina Buck, Keith Wheatley, Claire N. Harrison, Anthony R. Green

From the Department of Haematology, University of Cambridge; Departments of Haematology and Histopathology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton; Department of Haematology, Russells Hall Hospital, Dudley; Birmingham Clinical Trials Unit, University of Birmingham, Birmingham; Departments of Histopathology and Haematology, St Thomas' Hospital, London; and the Clinical Trial Service Unit, Oxford, United Kingdom.

Corresponding author: Anthony Green, FRC Path, F Med Sci, Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Rd, Cambridge CB2 2XY, United Kingdom; e-mail: arg1000{at}cam.ac.uk.

Purpose Essential thrombocythemia (ET) manifests substantial interpatient heterogeneity in rates of thrombosis, hemorrhage, and disease transformation. Bone marrow histology reflects underlying disease activity in ET but many morphological features show poor reproducibility.

Patients and Methods We evaluated the clinical significance of bone marrow reticulin, a measure previously shown to have relatively high interobserver reliability, in a large, prospectively-studied cohort of ET patients.

Results Reticulin grade positively correlated with white blood cell (P = .05) and platelet counts (P = .0001) at diagnosis. Elevated reticulin levels at presentation predicted higher rates of arterial thrombosis (hazard ratio [HR], 1.8; 95% CI, 1.1 to 2.9; P = .01), major hemorrhage (HR, 2.0; 95% CI, 1.0 to 3.9; P = .05), and myelofibrotic transformation (HR, 5.5; 95% CI, 1.7 to 18.4; P = .0007) independently of known risk factors. Higher reticulin levels at diagnosis were associated with greater subsequent falls in hemoglobin levels in patients treated with anagrelide (P < .0001), but not in those receiving hydroxyurea (P = .9). Moreover, serial trephine specimens in patients randomly assigned to anagrelide showed significantly greater increases in reticulin grade compared with those allocated to hydroxyurea (P = .0003), and four patients who developed increased bone marrow reticulin on anagrelide showed regression of fibrosis when switched to hydroxyurea. These data suggest that patients receiving anagrelide therapy should undergo surveillance bone marrow biopsy every 2 to 3 years and that those who show substantially increasing reticulin levels are at risk of myelofibrotic transformation and may benefit from changing therapy before adverse clinical features develop.

Conclusion Our results demonstrate that bone marrow reticulin grade at diagnosis represents an independent prognostic marker in ET, reflecting activity and/or duration of disease, with implications for the monitoring of patients receiving anagrelide.

D.B., W.N.E., and B.S.W. contributed equally to the manuscript.

Supported by the Leukemia Research Fund, Cancer Research United Kingdom, the Wellcome Trust, the Medical Research Council, United Kingdom, the National Institute for Health Research Cambridge Biomedical Research Centre, and the Leukemia and Lymphoma Society of. America. P.J.C. is a Kay Kendall Leukemia Fund intermediate fellow.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00175838 [ClinicalTrials.gov] .

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				P. J. Campbell, D. Bareford, W. N. Erber, B. S. Wilkins, P. Wright, G. Buck, K. Wheatley, C. N. Harrison, and A. R. Green Reply to K.N. Naresh J. Clin. Oncol., November 1, 2009; 27(31): e177 - e178. [Full Text] [PDF]