correspondence

Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia

The diagnosis of the myeloproliferative neoplasms (MPN)‒ essential thrombocythaemia (ET) and primary myelofibrosis (PMF) ‒ in patients lacking a molecular marker is challenging. Recently, mutations in exon 9 of the calreticulin gene (CALR) have been described in around one-third of ET and MF patients (Klampfl et al, 2013a; Nangalia et al, 2013). Notably, these mutations are almost always seen in JAK2

V617F-negative and MPL-non-mutated patients and account for the majority of these cases. Such is the prevalence of these mutations we suggest that they are added to the British Committee for Standards in Haematology criteria for the diagnosis of ET and also PMF (Harrison et al, 2010; Reilly et al, 2012) (evidence grade 1A). The modified diagnostic criteria and algorithms are shown in

Platelet Count ≥450x109/l

Review blood film Acute phase reactants (e.g. CRP; ESR) Iron status

Acute phase response

Iron deficiency

Normal

Reactive thrombocytosis

Treat

Repeat blood count

Repeat blood count

Persistent unexplained thrombocytosis

Further investigation † Molecular genetics - JAK2 V617F; MPL exon 10; CALR - BCR-ABL1 if above negative and/or if positive and there are atypical features eg basophilia

Fig 1. (†) Diagnostic pathway for the investigation of thrombocytosis. (*) Bone marrow examination is recommended to confirm the diagnosis, as per the World Health Organization Classification. In some circumstances this may not be clinically indicated. (x) The need for cytogenetic analysis on the bone marrow should be guided by the blood and bone marrow morphology.

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

* Bone marrow examination - aspirate and trephine biopsy

x

Cytogenetic analysis

Diagnosis (See text for diagnostic features)

doi:10.1111/bjh.12986

Correspondence Table I. Proposed diagnostic criteria for essential thrombocythaemia. Diagnosis requires A1–A3 or A1 + A3–A5 A1 A2 A3 A4 A5

Sustained platelet count ≥450 9 109/l Presence of an acquired pathogenetic mutation (e.g. in the JAK2, CALR or MPL genes) No other myeloid malignancy, especially PV*, PMF†, CML‡ or MDS§ No reactive cause for thrombocytosis and normal iron stores Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm. Reticulin is generally not increased (grades 0–2/4 or grade 0/3)

*Polycythaemia vera; excluded by a normal haematocrit in an ironreplete patient. †Primary myelofibrosis; indicated by presence of significant marrow bone marrow fibrosis (greater or equal to 2/3 or 3/4 reticulin) AND palpable splenomegaly, blood film abnormalities (circulating progenitors and tear-drop cells) or unexplained anaemia (Barosi, 1999; Mesa et al, 2007). ‡Chronic myeloid leukaemia; excluded by absence of BCR-ABL1 fusion from bone marrow or peripheral blood. §Myelodysplastic syndrome; excluded by absence of dysplasia on examination of blood film and bone marrow aspirate.

application of IPS ET results in re-allocation of large proportions of patients from high risk into low and intermediate and vice versa. The management of intermediate risk ET is uncertain and has only been tested in the PT-1 intermediate risk study, which has not yet been reported and uses a different definition of intermediate risk.

Conflict of interest The authors have no conflicts of interest to disclose. All authors have contributed equally to this document. Claire N. Harrison1 Nauman Butt2 Peter Campbell3 Eibhlin Conneally4 Mark Drummond5 Anthony R. Green6 Richard Murrin7 Deepti H. Radia1 Adam Mead8 John T. Reilly9 Nicholas C. P. Cross10 Mary F. McMullin11 1

Table I and Fig 1. Some initial reports suggest that the presence of a CALR mutation is associated with greater longevity and lower risk of thrombosis in ET patients (Klampfl et al, 2013b) (Rotunno et al, 2014). However the utility of incorporating CALR mutation status into current risk stratification is not yet tested and therefore is not recommended. Furthermore, the guideline writing group also considers the utility of the proposed International Prognostic Score for ET (IPS ET) to be limited and does not recommend its incorporation into standard practice (Barbui et al, 2012; Passamonti et al, 2012). The reasons for this decision are that the score was tested upon retrospective selected groups of patients who were already receiving treatment. The

References Barbui, T., Finazzi, G., Carobbio, A., Thiele, J., Passamonti, F., Rumi, E., Ruggeri, M., Rodeghiero, F., Randi, M.L., Bertozzi, I., Gisslinger, H., Buxhofer-Ausch, V., De Stefano, V., Betti, S., Rambaldi, A., Vannucchi, A.M. & Tefferi, A. (2012) Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSETthrombosis). Blood, 120, 5128–5133. Barosi, G. (1999) Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. Journal of Clinical Oncology, 17, 2954–2970.

2

Department of Haematology, Guy’s and St Thomas, Hospitals’ NHS Foundation Trust, London, 2Department of Haematology, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, 3

Welcome Trust Sanger Institute, Cambridge, 4Department of Haema-

tology, St James’ Hospital, Dublin, 5Beatson Oncology Centre, Glasgow, 6

Univeristy of Cambridge, Cambridge, 7Department of Haematology,

City Hospital, Birmingham, 8Department of Haematology, Royal Hallamshire Hospital, Sheffield, 9University of Oxford, Oxford,

10

Wessex

Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, and 11Department of Haematology, Queen’s University, Belfast, UK E-mail: [email protected]

Keywords: myeloproliferative neoplasms, thrombocytosis, calreticulin gene

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ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Correspondence Mesa, R.A., Verstovsek, S., Cervantes, F., Barosi, G., Reilly, J.T., Dupriez, B., Levine, R., Le Bousse-Kerdiles, M.C., Wadleigh, M., Campbell, P.J., Silver, R.T., Vannucchi, A.M., Deeg, H.J., Gisslinger, H., Thomas, D., Odenike, O., Solberg, L.A., Gotlib, J., Hexner, E., Nimer, S.D., Kantarjian, H., Orazi, A., Vardiman, J.W., Thiele, J. & Tefferi, A. (2007) Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leukemia research, 31, 737–740. Nangalia, J., Massie, C.E., Baxter, E.J., Nice, F.L., Gundem, G., Wedge, D.C., Avezov, E., Li, J., Kollmann, K., Kent, D.G., Aziz, A., Godfrey, A.L., Hinton, J., Martincorena, I., Van Loo, P., Jones, A.V., Guglielmelli, P., Tarpey, P., Harding, H.P., Fitzpatrick, J.D., Goudie, C.T.,

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Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia.

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