Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
2015; Elsevier BV; Volume: 26; Linguagem: Inglês
10.1093/annonc/mdv203
ISSN1569-8041
AutoresAlessandro M. Vannucchi, Tiziano Barbui, Francisco Cervantes, Claire Harrison, Jean‐Jacques Kiladjian, Nicolaus Kröger, J. Thiele, Christian Buske,
Tópico(s)Eosinophilic Disorders and Syndromes
ResumoAccording to the 2008 World Health Organization (WHO) classification, classical Philadelphia chromosome/BCR-ABL negative chronic myeloproliferative neoplasms (MPNs) include polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]. The reported worldwide annual incidence rate of MPNs ranges from 0.44 to 5.87/105, with the lowest incidence being reported in Japan and Israel [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar]. These great ranges may reflect racial/geographic differences as well as differences in study design, diagnostic criteria and methods of reporting, among others. The estimated incidence rate in Europe is 0.4–2.8 × 105/year for PV, 0.38–1.7 × 105/year for ET and 0.1–1 × 105/year for PMF [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar]. There are few reliable estimates of the prevalence [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar, 3.Titmarsh G.J. Duncombe A.S. McMullin M.F. et al.How common are myeloproliferative neoplasms? A systematic review and meta-analysis.Am J Hematol. 2014; 89: 581-587Crossref PubMed Scopus (123) Google Scholar]. The last is likely to be rising due to earlier diagnosis and trends towards prolonged survival [4.Cervantes F. Dupriez B. Passamonti F. et al.Improving survival trends in primary myelofibrosis: an international study.J Clin Oncol. 2012; 30: 2981-2987Crossref PubMed Scopus (95) Google Scholar]. The reported median age at diagnosis ranges from 65–74 years for PV, 64–73 years for ET, and 69–76 years for PMF [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar]. To achieve the most accurate diagnosis possible, the 2008 WHO classification is recommended. It is based upon standardised morphological features, ideally using specimens obtained before treatment, and is integrated with haematological, molecular and clinical diagnostic criteria (Table 1). For full details and images of classical morphological features, the reader is referred to the WHO publication [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]. European consensus-based criteria for grading of cellularity and bone marrow (BM) fibrosis should be followed (Table 2) [6.Thiele J. Kvasnicka H.M. Facchetti F. et al.European consensus on grading bone marrow fibrosis and assessment of cellularity.Haematologica. 2005; 90: 1128-1132PubMed Google Scholar].Table 1The WHO diagnostic criteria for Philadelphia chromosome-negative chronic myeloproliferative neoplasms [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]Polycythaemia vera (PV)Essential thrombocythaemia (ET)Primary myelofibrosis (PMF)Major criteria1. Haemoglobin>18.5 g/dl (men)>16.5 g/dl (women)or a any other evidence of increased red cell volume1. Platelet count ≥450 × 109/l1. Megakaryocyte proliferation and atypiab accompanied by either reticulin and/or collagen fibrosis, or c2. Megakaryocyte proliferation with large and mature morphology2. Presence of JAK2V617F or JAK2 exon 12 mutation3. Not meeting WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm2. Not meeting WHO criteria for CML, PV, MDS or other myeloid neoplasm4. Demonstration of JAK2V617F orother clonal marker orno evidence of reactive thrombocytosis3. Demonstration of JAK2V617F orother clonal marker orno evidence of reactive BM fibrosisMinor criteria1. BM trilineage myeloproliferation1. Leukoerythroblastosis2. Sub-normal sEPO level2. Increased serum LDH level3. Endogenous erythroid colony growth3. Anaemia4. Palpable splenomegalyaHb or HCT >99th percentile of reference range for age, sex or altitude of residence or red cell mass >25% above mean normal predicted or Hb >17 g/dl (men)/>15 g/dl (women) if associated with a sustained increase of ≥2 g/dl from baseline that cannot be attributed to correction of iron deficiency.bSmall to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.cIn the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF).PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria.Note: mutations in calreticulin (CALR) will be included as major diagnostic criteria for ET and PMF in the upcoming (2015) revised WHO classification [5.Tefferi A. Thiele J. Vannucchi A.M. Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms.Leukemia. 2014; 28: 1407-1413Crossref PubMed Scopus (172) Google Scholar].BM, bone marrow; WHO, World Health Organization; CML, chronic myelogenous leukaemia; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase; sEPO, serum erythropoietin; Hb, haemoglobin; HCT, haematocrit. Open table in a new tab Table 2European consensus on the grading of myelofibrosis (MF) [6.Thiele J. Kvasnicka H.M. Facchetti F. et al.European consensus on grading bone marrow fibrosis and assessment of cellularity.Haematologica. 2005; 90: 1128-1132PubMed Google Scholar]Republished with permission. Obtained from the Haematologica Journal website http://www.haematologica.org.MF—0 Scattered linear reticulin with no intersection (cross-overs) corresponding to normal bone marrowMF—1 Loose network of reticulin with many intersections, especially in perivascular areasMF—2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosisMF—3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosisFibre density should be assessed in haematopoietic (cellular) areas. Open table in a new tab aHb or HCT >99th percentile of reference range for age, sex or altitude of residence or red cell mass >25% above mean normal predicted or Hb >17 g/dl (men)/>15 g/dl (women) if associated with a sustained increase of ≥2 g/dl from baseline that cannot be attributed to correction of iron deficiency. bSmall to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering. cIn the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF). PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria. Note: mutations in calreticulin (CALR) will be included as major diagnostic criteria for ET and PMF in the upcoming (2015) revised WHO classification [5.Tefferi A. Thiele J. Vannucchi A.M. Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms.Leukemia. 2014; 28: 1407-1413Crossref PubMed Scopus (172) Google Scholar]. BM, bone marrow; WHO, World Health Organization; CML, chronic myelogenous leukaemia; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase; sEPO, serum erythropoietin; Hb, haemoglobin; HCT, haematocrit. Fibre density should be assessed in haematopoietic (cellular) areas. In PV, classical BM features are a moderate to overt increase in age-matched cellularity, due to a trilineage proliferation (panmyelosis) of erythroid and granulocytic precursors and megakaryocytes in variable proportions. Megakaryocytes are characterised by a pleomorphic appearance due to the variability in sizes, from small to giant cells, without gross abnormalities of maturation. There may be minimal (grade 1) reticulin fibrosis, which is very rarely grade 2. In ET, age-adjusted cellularity is normal or sometimes slightly increased; there is no left-shifted neutrophil granulopoiesis. Any case with a mild to moderate panmyelosis is suspicious for early PV rather than ET. Megakaryocytes have increased in number and are randomly distributed within the BM, with scattered forms or a few loose clusters. Large to giant mature megakaryocytes with extensively folded (staghorn-like) nuclei and mature cytoplasm are in the majority. Gross disturbances of the histologic topography or extensive dense clustering of megakaryocytes should not be detectable. There is no substantial increase of reticulin fibres. The WHO classification suggests that these features clearly distinguish ET from pre-fibrotic/early PMF; however, minor diagnostic criteria should also be present in order to assign this diagnosis (Table 1). In the initial phases of PMF, the BM is often hypercellular with prominent granulocytic and megakaryocytic proliferation, frequently with a reduction of erythroid precursors. If reticulin fibrosis is present, grade 1 is allocated. Megakaryopoiesis is characterised by the extensive formation of loose to dense clusters of megakaryocytes, with abnormal localisation toward the endosteal borders. Megakaryocyte anomalies include a high degree of cellular atypia (from small to giant forms), abnormal nuclear folding and an aberrant nuclear cytoplasmic ratio created by large, bulbous and hyperchromatic cloud-shaped nuclei. Naked (bare) megakaryocytic nuclei are often visible. Overall, the megakaryocytes in PMF show a more pronounced degree of atypia than in other MPN subtypes. The more advanced fibro-osteosclerotic phases of PMF are characterised by grade ≥2 reticulin deposition, and the appearance of coarse bundles of collagen fibres. Additional features include endophytic bone formation (osteosclerosis) associated with extension of adipose tissue. Dilated marrow sinuses with intraluminal haematopoiesis, especially made up of megakaryocytes, are often seen. The morphological hallmark of post-polycythaemia vera myelofibrosis (PPV-MF) and post-essential thrombocythaemia myelofibrosis (PET-MF) is overt reticulin and collagen fibrosis of the BM. Cellularity varies, but hypocellularity is common. Clusters of megakaryocytes (often with hyperchromatic and abnormal nuclei) are prominent, while erythropoiesis and granulopoiesis are decreased. Osteosclerosis may occur. However, these findings must be integrated with other features to achieve a diagnosis (Table 3).Table 3Diagnostic criteria for post-polycythaemia vera myelofibrosis (PPV-MF) and post-essential thrombocythaemia myelofibrosis (PET-MF) according to the International Working Group for Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) [7.Barosi G. Mesa R.A. Thiele J. et al.Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment.Leukemia. 2008; 22: 437-438Crossref PubMed Scopus (375) Google Scholar]Reprinted by permission from Macmillan Publishers Ltd.: Leukemia [7.Barosi G. Mesa R.A. Thiele J. et al.Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment.Leukemia. 2008; 22: 437-438Crossref PubMed Scopus (375) Google Scholar], copyright 2008.PPV-MFPET-MFRequired criteria (both required):1. Documentation of a previous diagnosis of PV as defined by the 2008 WHO criteria2. Bone marrow fibrosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale)1. Documentation of a previous diagnosis of ET as defined by the 2008 WHO criteria2. Bone marrow fibrosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale)Additional criteria (≥2 required):Anaemia or sustained loss of requirement for phlebotomy in the absence of cytoreductive therapyAnaemia and a Hb ≥2 g/dl decrease from baseline Hb levelLeukoerythroblastic peripheral blood pictureLeukoerythroblastic peripheral blood pictureIncreasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm from the LCM, or the appearance of a newly palpable splenomegalyIncreasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm from the LCM, or the appearance of a newly palpable splenomegalyDevelopment of ≥1 of the constitutional symptoms (>10% weight loss in 6 months, night sweats, unexplained fever >37.5°C)Development of >1 of the constitutional symptoms (>10% weight loss in 6 months, night sweats, unexplained fever >37.5°C)Increased lactate dehydrogenaseWHO, World Health Organization; LCM, left costal margin; Hb, haemoglobin; PV, polycythaemia vera; ET, essential thrombocythaemia. Open table in a new tab WHO, World Health Organization; LCM, left costal margin; Hb, haemoglobin; PV, polycythaemia vera; ET, essential thrombocythaemia. Although a number of clinicopathological studies have demonstrated that a reliable morphological differentiation can be achieved with high consensus rates [8.Thiele J. Kvasnicka H.M. Müllauer L. et al.Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification.Blood. 2011; 117: 5710-5718Crossref PubMed Scopus (132) Google Scholar, 9.Gianelli U. Bossi A. Cortinovis I. et al.Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms.Mod Pathol. 2014; 27: 814-822Crossref PubMed Scopus (34) Google Scholar, 10.Madelung A.B. Bondo H. Stamp I. et al.World Health Organization-defined classification of myeloproliferative neoplasms: morphological reproducibility and clinical correlations—the Danish experience.Am J Hematol. 2013; 88: 1012-1016Crossref PubMed Scopus (41) Google Scholar], both the reproducibility and the clinical usefulness of the WHO classification of MPNs remain controversial issues, especially concerning the distinction between ET and pre-fibrotic/early myelofibrosis (MF) as well as initial cases of PV from ET or even PMF [11.Thiele J. Kvasnicka H.M. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis.Curr Hematol Malig Rep. 2009; 4: 33-40Crossref PubMed Scopus (69) Google Scholar, 12.Barbui T. Thiele J. Vannucchi A.M. Tefferi A. Problems and pitfalls regarding WHO-defined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia.Leukemia. 2013; 27: 1953-1958Crossref PubMed Scopus (60) Google Scholar]. To avoid incorrect classification, comprehensive evaluation and, if necessary, re-evaluation of patients are suggested. This also ensures that the patient is not unnecessarily diagnosed as ‘MPN-unclassified’. MPNs are characterised by somatic recurrent mutations and are included as the main criteria in the 2008 WHO classification (Table 1), for which a further revision is expected in the future due to the newly discovered calreticulin (CALR) mutations [5.Tefferi A. Thiele J. Vannucchi A.M. Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms.Leukemia. 2014; 28: 1407-1413Crossref PubMed Scopus (172) Google Scholar]. These mutations include the Janus kinase (JAK) 2V617F mutation, found in ≥95% of PV and ∼60% of ET and PMF patients. 3%–5% of ET and 5%–8% of PMF patients have point mutations at codon 515 of the gene encoding the thrombopoietin receptor MPL (W>L, K or A). Abnormalities (deletions/duplications/substitutions) located in exon 12 of JAK2 are detected exclusively in 2%–4% of PV. About 60%–80% of JAK2 and MPL un-mutated patients with ET and PMF have mutations in the exon 9 of CALR. Therefore, virtually all patients with PV have a mutation in JAK2. Conversely, 10%–15% of ET and PMF patients remain molecularly uncharacterised, and are operationally defined as ‘triple negative’ for the three phenotypic driver mutations. The presence of any of these mutations excludes reactive forms of erythrocytosis, thrombocytosis and MF, but does not indicate a specific MPN subtype. These mutations can be found using methods such as conventional sequencing, qualitative and quantitative polymerase chain reaction (PCR) and high-resolution melting analysis (may have a sensitivity of 1% and higher). Whole blood or purified granulocytes are harvested and tested; the latter is preferred in cases with low mutation burden, as is often the case with JAK2 exon12 mutations. Genotyping should be obtained at diagnosis. It is not recommended to measure the mutation burden serially during follow-up or to assess response to treatment, except following allogeneic stem-cell transplantation (alloSCT) and, possibly, interferon (IFN) treatment. In such instances, a detection limit of JAK2V617F allele burden of ≤0.1% is recommended [13.Jovanovic J.V. Ivey A. Vannucchi A.M. et al.Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.Leukemia. 2013; 27: 2032-2039Crossref PubMed Scopus (84) Google Scholar]. Accurate differentiation among the three unique MPN subtypes as well as the exclusion of reactive conditions (in mutation-negative patients only) and disorders such as myelodysplasia and chronic myeloid leukaemia (CML) are critical for appropriate prognosis and therapy decision making. It is not acceptable to use the generic diagnostic label ‘MPN’ alone [I, A]. The 2008 WHO diagnostic criteria for MPN outlined in Table 1 should be followed strictly [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]. Any patient with suspected MPN should be tested for the three driver mutations [I, B]. A simplified diagnostic algorithm is presented in Figure 1. A diagnosis of PPV-MF or PET-MF is made using the criteria described by the International Working Group for Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) (Table 3). Any patient newly diagnosed with MPN should be categorised at baseline according to the risks associated with the disease [I, B]. It must be realised that the prognostic scoring systems used for risk-adapted therapy in PV and ET are based on the likelihood of patients developing thrombotic complications. These complications are the leading cause of morbidity and mortality in PV and ET patients. Scores predicting for overall survival in PV and ET are also available, yet considering the long survival of these disorders, they do not currently impact treatment decisions [14.Passamonti F. Thiele J. Girodon F. et al.A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment.Blood. 2012; 120: 1197-1201Crossref PubMed Scopus (188) Google Scholar, 15.Tefferi A. Rumi E. Finazzi G. et al.Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.Leukemia. 2013; 27: 1874-1881Crossref PubMed Scopus (430) Google Scholar]. The recommended prognostic scoring system for PV and ET is based upon two variables: age >60 years and previous history of thrombosis. These variables separate patients into low- or high-risk categories (Table 4). In ET, an intermediate-risk group is sometimes advocated. However, this group is variably defined and there is no clear evidence of how to manage patients in this category. Thrombocytosis (>1000 × 109/l) is a risk factor for haemorrhage, and advocates caution for the use of aspirin. Extreme thrombocytosis (>1500 × 109/l) is regarded as an indication for therapy in ET, and less frequently in PV. Improved risk stratification is desirable, but any new risk stratification should be robust, easily measurable and ideally validated in a prospective manner.Table 4Risk stratification and risk-adapted therapy in polycythaemia vera (PV) and essential thrombocythaemia (ET) [16.Barbui T. Barosi G. Birgegard G. et al.Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.J Clin Oncol. 2011; 29: 761-770Crossref PubMed Scopus (631) Google Scholar, 17.Marchioli R. Finazzi G. Landolfi R. et al.Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.J Clin Oncol. 2005; 23: 2224-2232Crossref PubMed Scopus (524) Google Scholar]Risk categoryRisk variablesTherapyPVETLow•Age <60 years•No thrombosis history•Phlebotomy, and•Correction of CV risk factors, and•Low-dose aspirina•Correction of CV risk factors, and•Low-dose aspirinaHigh•Age ≥60 yearsand /or•Thrombosis history•Cytoreduction, and•Correction of CV risk factors, and•Low-dose aspirina•Phlebotomy if required•Cytoreduction, and•Correction of CV risk factors, and•Low-dose aspirinaaDepending on the thrombosis type, oral anti-coagulation instead of low-dose aspirin.CV, cardiovascular. Open table in a new tab aDepending on the thrombosis type, oral anti-coagulation instead of low-dose aspirin. CV, cardiovascular. Since the median survival in PMF is ∼6 years, ranging from 10 years, the relevant end point for current prognostic scoring systems in PMF is represented by survival (Table 5). The International Prognostic Scoring System (IPSS) [18.Cervantes F. Dupriez B. Pereira A. et al.New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.Blood. 2009; 113: 2895-2901Crossref PubMed Scopus (945) Google Scholar] is used at the time of diagnosis to outline four risk categories (low, intermediate-1, intermediate-2 and high risk), with median survival of 135, 95, 48 and 27 months, respectively. The ‘dynamic’ IPSS (DIPSS) [19.Passamonti F. Cervantes F. Vannucchi A.M. et al.A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment).Blood. 2010; 115: 1703-1708Crossref PubMed Scopus (672) Google Scholar], which utilises the same variables as the IPSS, is employed during follow-up. A refinement is represented by DIPSS-plus score [20.Gangat N. Caramazza D. Vaidya R. et al.DIPSS Plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.J Clin Oncol. 2011; 29: 392-397Crossref PubMed Scopus (711) Google Scholar] that incorporates thrombocytopaenia, transfusion requirements and abnormal cytogenetics (Table 5). The role of CALR [21.Rumi E. Pietra D. Pascutto C. et al.Clinical effect of driver mutations of JAK2, CALR or MPL in primary myelofibrosis.Blood. 2014; 124: 1062-1069Crossref PubMed Scopus (298) Google Scholar] and other mutations (i.e. EZH2, ASXL1, SRSF2, IDH1/2 mutations), comprising a high-molecular risk category in PMF [22.Vannucchi A.M. Lasho T.L. Guglielmelli P. et al.Mutations and prognosis in primary myelofibrosis.Leukemia. 2013; 27: 1861-1869Crossref PubMed Scopus (552) Google Scholar], has been underscored but has yet to be incorporated in an updated prognostic score. Appropriate risk stratification in PMF has relevance for risk-adapted therapy, particularly for alloSCT. These scores are commonly used for PPV-MF and PET-MF. It should be underlined that they have not been validated in such a context, and their appropriateness has been questioned [23.Hernández-Boluda J.C. Pereira A. Gómez M. et al.The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis.Haematologica. 2014; 99: e55-e57Crossref PubMed Scopus (47) Google Scholar].Table 5Risk stratification in primary myelofibrosis (MF)VariableIPSS [18.Cervantes F. Dupriez B. Pereira A. et al.New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.Blood. 2009; 113: 2895-2901Crossref PubMed Scopus (945) Google Scholar]DIPSS [19.Passamonti F. Cervantes F. Vannucchi A.M. et al.A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment).Blood. 2010; 115: 1703-1708Crossref PubMed Scopus (672) Google Scholar]DIPSS-plus [20.Gangat N. Caramazza D. Vaidya R. et al.DIPSS Plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.J Clin Oncol. 2011; 29: 392-397Crossref PubMed Scopus (711) Google Scholar]Age >65 years✓✓✓Constitutional symptoms✓✓✓Haemoglobin (Hb) 25 × 109/l✓✓✓Circulating blasts >1%✓✓✓Platelet count <100 × 109/l✓RBC transfusion need✓Unfavourable karyotypea✓1 point each1 point each but Hb = 2Calculated by the DIPSS score (Int 1 = 1, Int 2 = 2, High = 3) plus one additional point for each of the three additional variablesRisk groupPointsMedian survival (years)PointsMedian survival (years)PointsMedian survival (years)Low011.30n.r.015.4Intermediate-117.91–214.216.5Intermediate-224.03–442–32.9High≥32.35–61.5≥41.3aUnfavourable karyotype includes +8, –7/7q–, i(17q), inv(3), –5/5q–, 12p–, 11q23 rearrangements.IPSS, International Prognostic Scoring System; DIPSS, dynamic International Prognostic Scoring System; RBC, red blood cell; Int, intermediate; n.r., not reached. Open table in a new tab aUnfavourable karyotype includes +8, –7/7q–, i(17q), inv(3), –5/5q–, 12p–, 11q23 rearrangements. IPSS, International Prognostic Scoring System; DIPSS, dynamic International Prognostic Scoring System; RBC, red blood cell; Int, intermediate; n.r., not reached. Treatment aims are to reduce the risk of thrombosis and haemorrhage, control symptoms and perhaps reduce the risk of progression (Figure 2). Cure is not presently possible, except in selected MF patients who are successfully receiving alloSCT. All patients should be informed regarding the disease course, and vascular risk factors such as smoking should be aggressively managed. PV therapy should address both short- and long-term objectives (Figure 2A). In the short-term, therapeutic aims are to reduce the risk of occurrence and recurrence of thrombosis. The long-term objective is to reduce the risk of evolution to MF, myelodysplastic syndrome (MDS) and/or acute myeloid leukaemia (AML) [16.Barbui T. Barosi G. Birgegard G. et al.Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.J Clin Oncol. 2011; 29: 761-770Crossref PubMed Scopus (631) Google Scholar]. Risk stratification (Table 4) aims at selecting the patients with a low risk of vascular events. PV is associated with elevated haematocrit (HCT); with these patients, phlebotomy is carried out to control the HCT and low-dose aspirin is used, as it may delay the need for cytoreductive therapy. Phlebotomy can be an emergency therapy at diagnosis, in patients presenting with very high HCT and clinical signs of hyperviscosity, as well as a long-term maintenance therapy to control the HCT [I, A]. The optimal target of HCT levels for reducing vascular events was a matter of debate, but, a recent multicentre, randomised clinical trial (CYTO-PV) showed that the HCT should be maintained strictly below 45% to efficiently reduce the risk of thrombotic events [I, A] [24.Marchioli R. Finazzi G. Specchia G. et al.Cardiovascular events and intensity of treatment in polycythemia vera.N Engl J Med. 2013; 368: 22-33Crossref PubMed Scopus (506) Google Scholar]. Low-dose aspirin is the second cornerstone of PV therapy [I, A]. It has been shown in the European Collaboration on Low-dose Aspirin in Polycythaemia Vera (ECLAP) study, a large European double-blind, placebo-controlled, randomised trial, to significantly reduce a primary combined end point, including: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and major venous thromboembolism [25.Landolfi R. Marchioli R. Kutti J. et al.Efficacy an
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