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Originally published as JCO Early Release 10.1200/JCO.2009.23.7776 on August 24 2009 © 2009 American Society of Clinical Oncology.
Reply to K.N. NareshDepartment of Haematology, University of Cambridge, Cambridge, United Kingdom
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
Department of Haematology, Russells Hall Hospital, Dudley, Birmingham, United Kingdom
Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
Department of Histopathology, St Thomas' Hospital, London, United Kingdom
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Clinical Trial Service Unit, Oxford, United Kingdom
Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom
Department of Haematology, St Thomas' Hospital, London, United Kingdom We welcome Naresh's contribution1 to the ongoing debate about the notion of so-called prefibrotic myelofibrosis, diagnostic algorithms for essential thrombocythaemia (ET), and the distinction of ET from primary myelofibrosis (PMF). We will reply to his comments on each of these three points in turn. Our experience in the PT-1 trial does not support the concept of prefibrotic myelofibrosis and so-called true ET as biologically distinct entities.2,3 First, three experienced hematopathologists showed poor interobserver reliability for the histological diagnosis of prefibrotic myelofibrosis, suggesting that the criteria are not sufficiently robust for reproducible diagnosis.3 Second, patients labeled by any one of the hematopathologists as having prefibrotic myelofibrosis on the basis of bone marrow features showed no biologic, laboratory, or clinical features to distinguish them from other patients with ET.3 In particular, the JAK2 and MPL mutation proportions were equivalent in the two groups, diagnostic clinical and laboratory features were indistinguishable, and patients labeled as having prefibrotic myelofibrosis showed no differences in the rate of disease complications during long-term, prospective follow-up compared to patients with ET.3 Naresh1 questions the validity of these results because 11 of the 16 criteria we assessed related to megakaryocyte morphology and uncertainty about the scoring of erythrocyte and granulocyte cellularity. The choice of these criteria was determined by the histological features described in the original WHO monograph and accompanying publications.4–6 Indeed, the poor reproducibility of the prefibrotic myelofibrosis concept probably reflects the reliance of the diagnostic criteria on individual megakaryocyte appearances which we found to have low interobserver reliability. In contrast, erythrocyte and granulocytic cellularity, assessed on a semiquantitative scale from the H&E stain, showed strong interobserver reliability, making Naresh's contention that this was somehow responsible for the poor reproducibility of prefibrotic myelofibrosis difficult to sustain. On the basis of immunohistochemical staining for erythroid and granulocytic cellularity in bone marrow trephine specimens, Naresh1 proposes a new diagnostic algorithm for patients presenting with suspected ET. Such approaches may have diagnostic utility, although it is unclear whether the use of special stains would improve the already strong concordance we observed for assessing lineage-specific celularity.3 Furthermore, we have observed that bone marrow cellularity shows a strong relationship with the molecular status of the patient because, compared with JAK2/MPL-negative patients, JAK2 V617F-positive patients show increased, and MPL-positive patients decreased, granulocytic, and erythroid cellularity.7,8 Thus, it is unclear whether detailed immunohistochemical assessment of bone marrow cellularity adds anything beyond careful assessment of the hematoxylin and eosin stain and routine molecular testing. Nonetheless, ongoing assessment of the role of such diagnostic tests must be encouraged, although we stress that implementation of modifications to existing algorithms should only follow careful evaluation of interobserver reproducibility and diagnostic utility in the setting of carefully conducted, prospective cohort studies. In our follow-up paper assessing the prognostic significance of bone marrow histology in ET, we find that higher bone marrow reticulin levels at diagnosis of ET independently predict poorer outcome during follow-up, including increased rates of myelofibrotic transformation.2 Naresh uses this fact to suggest that such patients therefore had prefibrotic myelofibrosis all along, not ET. The circularity of this argument bedevils much of the discussion about the distinction between ET and PMF, and is worsened by the semantic loading of the oxymoronic term prefibrotic myelofibrosis. In fact, patients with reticulin levels of 2, and even 3, in our PT-1 study typically did not have any clinical features of established myelofibrosis and generally experienced a benign clinical course. Certainly, their prognosis was worse, but 85% to 90% were free of overt myelofibrotic transformation at 6 years after trial entry. Our data support a different model for the relationship between ET and PMF. We have found a gradation of increasingly disturbed blood counts and higher risk of clinical complications in association with greater reticulin levels at diagnosis.2 We believe that variable degrees of reticulin accumulation, and the accompanying association with ongoing clinical complications, are likely to reflect the interplay between genetic background, disease duration, clonal burden, therapy and the acquisition of additional genetic lesions. Indeed, we found that patients randomized to anagrelide therapy showed substantially greater subsequent increases in reticulin than those randomly assigned to hydroxyurea.2,9 The natural accumulation of reticulin over time in ET should be clearly distinguished from the clinical syndrome of myelofibrotic transformation, which represents accelerated-phase disease and presumably reflects the accumulation of additional genetic lesions. Because myelofibrotic transformation is essentially indistinguishable from PMF, we suggest that at least some cases currently labeled as PMF in fact represent patients presenting in an accelerated phase of undiagnosed ET. The concept of prefibrotic myelofibrosis should be removed from our lexicon, to be replaced by a more nuanced understanding of the complex biologic, histologic, and clinical factors underlying the phenotypic overlap between ET and PMF. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Claire N. Harrison, Shire Pharmaceuticals Expert Testimony: None Other Remuneration: None REFERENCES
1. Naresh KN: Classification of Philadelphia translocation–negative myeloproliferative neoplasms: Its impact on data from clinical trials. J Clin Oncol 27:e175–e176, 2009. 2. Campbell PJ, Bareford D, Erber WN, et al: Reticulin accumulation in essential thrombocythemia: Prognostic significance and relationship to therapy. J Clin Oncol 27:2991–2999, 2009. 3. Wilkins BS, Erber WN, Bareford D, et al: Bone marrow pathology in essential thrombocythemia: Interobserver reliability and utility for identifying disease subtypes. Blood 111:60–70, 2008. 4. Thiele J, Kvasnicka HM, Zankovich R, Diehl V: Relevance of bone marrow features in the differential diagnosis between essential thrombocythemia and early stage idiopathic myelofibrosis. Haematologica 85:1126–1134, 2000. 5. Thiele J, Kvasnicka HM: Diagnostic differentiation of essential thrombocythaemia from thrombocythaemias associated with chronic idiopathic myelofibrosis by discriminate analysis of bone marrow features: A clinicopathological study on 272 patients. Histol Histopathol 18:93–102, 2003.[Medline] 6. Thiele J, Kvasnicka HM: Chronic myeloproliferative disorders with thrombocythemia: A comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann Hematol 82:148–152, 2003.[Medline] 7. Beer PA, Campbell PJ, Scott LM, et al: MPL mutations in myeloproliferative disorders: Analysis of the PT-1 cohort. Blood 112:141–149, 2008. 8. Campbell PJ, Scott LM, Buck G, et al: Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: A prospective study. Lancet 366:1945–1953, 2005.[CrossRef][Medline] 9. Harrison CN, Campbell PJ, Buck G, et al: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353:33–45, 2005.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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