Myeloproliferative Neoplasms

CME Haematology Clinical Medicine 2013, Vol 13, No 2: 188–92

tions are better defined for some condi- cythaemia (ET), polycythaemia vera (PV) Myeloproliferative tions than others. The more commonly and primary myelofibrosis (PMF) — are encountered MPN and their associated those associated with the Janus-associated neoplasms lesions are shown in Table 1. kinase 2 (JAK2) V617F mutation. JAK2 is a Of these, chronic myeloid leukaemia signalling protein whose normal role is to Amy Publicover, specialist registrar; Patrick (CML) is the best understood at a mole- activate cell proliferation following the Medd, consultant cular level. The translocation known as binding of erythropoietin to its receptor 1Department of Haematology, University Philadelphia chromosome t(9;22) results in (Fig 2). The activating V617F mutation Hospital Southampton. UK; 2Department of the ABL gene from chromosome 9 being leads to a constant ‘on switch’ that drives Haematology, Derriford Hospital, Plymouth, UK transferred to chromosome 22. The product proliferation of myeloid precursors. How a of this translocation (BCR-ABL) is an single mutation results in three clinical oncoprotein that has increased tyrosine phenotypes (and how some patients have The myeloproliferative neoplasms (MPN) kinase activity, which results in deregulated the disease without the mutation) is likely are a group of clonal haematological dis- proliferation of leukaemic myeloid cells. to depend on the roles of other, some as- eases, whose characteristic feature is prolif- Targeted treatment (with tyrosine kinase yet-unidentified, mutations and is cur- eration of one or more of the myeloid line- inhibitors such as imatinib) blocks rently under investigation.1 ages (Fig 1). The four disorders that are BCR-ABL and produces very durable most commonly included under MPN are remissions (now of more than 10 years) in Polycythaemia vera listed in Table 1. Evidence is emerging that the majority of patients with CML — a shows MPN is the result of various acquired huge improvement in outcome for this Polycythaemia refers simply to a raised hae- mutations, which permanently activate condition. matocrit (HCT). It is important to note that genes (often coding for tyrosine kinases) The MPN most commonly seen by non- the diagnosis is based on the haematocrit that regulate cell proliferation. These muta- haematologists — essential thrombo- and not the haemoglobin concentration.

CFU-Ba Basophil blast Basophil myelocyte Basophil Lymphoid stem cell Lymphoid

CFU-Eo Eosinophil blast Eosinophil myelocyte Eosinophil

Chronic myeloid leukaemia CFU-M Monoblast Promonocyte Monocyte

CFU-GM Pluripotent stem cell

Multipotent Myeloid stem cell Multipotent Myeloid CFU-G Myeloblast Neutrophil myelocyte Neutrophil

Essential thrombocythaemia and Primary myeloﬁbrosis CFU-Meg Megakaryoblast Megakaryocyte Platelets

Polycythaemia vera BFU-E CFU-E Erythroblast Normoblast Erythrocyte

Fig 1. Haematopoiesis and the lineages that are predominantly affected in MPN. Myeloid haematopoiesis derives from pluripotent myeloid stem cells in the marrow, which give rise to the erythroid, megakaryocyte (platelet), granulocyte (neutrophil, eosinophil and basophil) and monocyte lineages. The point in this hierarchy at which MPN-associated mutations occur could partially determine which cells are predominantly over-produced, giving rise to the different clinical phenotypes of the MPN. BFU burst-forming unit; CFU colony-forming unit; E erythroid; Meg megakaryocytic; GM granulocyte-monocyte; G granulocytic; M monocytic; Eo eosinophilic; Ba basophilic.

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In PV, the cause of the raised HCT is a pri- and splenomegaly. The major morbidity in thrombocytosis, systemic symptoms or mary marrow disorder resulting in red cell PV is the result of thrombosis (including symptomatic splenomegaly. First-line overproduction. mesenteric and hepato-portal thromboses). treatment is generally with interferon for Polycythemia might also be secondary or Splanchnic vein thrombosis is frequently those of <40 years old and with hydroxy- apparent. In secondary polycythemia, associated with PV and can occur before a carbamide for those >40 years old. excess red blood cells are produced in raised HCT is present. An unprovoked response to an increase in erythropoietin splanchnic vein thrombosis should prompt Prognosis concentrations in the blood. In turn, an JAK2 testing. increase in erythropoietin can be seen in In the past, many patients died within a few patients with chronic hypoxia (from con- Treatment years of diagnosis as a result of thrombotic genital cyanotic heart disease or severe complications. Median survival is now pulmonary disease) or, occasionally, First-line treatment for PV remains vene- greater than 10 years. The greatest risk is because of excess erythropoietin produc- section, with a target HCT of <0.45. still from thrombosis. Of patients treated tion resulting from a tumour, most com- Aspirin (75 mg) should be given pro- with venesection alone, 2–3% will progress monly renal cell cancer. viding there is no contraindication. to myelodysplastic syndrome (MDS) or In apparent or relative polycythemia the Cytoreduction should be considered when acute myeloid leukaemia (AML). The risk red cell mass is normal but the plasma the patient is aged >60 years or is unable of progression to myelofibrosis is 10–15% volume is reduced from causes such as to tolerate venesection, or where there is at 10 years. diuretic use, obesity, smoking or alcohol excess (Table 2). These alternative causes of polycythemia are not discussed further here. Distinguishing Table 1. Common mutations involved in MPN disorders. between PV and the other possible causes of Disease Incidence Genetic lesion % of those with the a raised haematocrit is important because disease carrying this the outcome in PV is improved by treatment lesion that reduces the haematocrit, whereas there Chronic myeloid 1–2 per 100,000 BCR-ABL 100% is little evidence for venesection in sec- leukaemia (CML) ondary polycythaemia. As almost 100% of Polycythaemia vera 0.7–2.6 per 100,000 JAK2 V617F 95–97% patients with PV are positive for a JAK2 (PV) JAK2 Exon 12 1–2% mutation, diagnosis has become much sim- TET2 10–20% pler in recent years. Essential 0.6–2.5 per 100,000 JAK2 V617F 60% The incidence of PV is 0.7–2.6 per thrombocythaemia MPL 3–5% 100,000 per year, with a slight male pre- (ET) dominance (M:F, 1.2:1) and a median age of 55–60 years. Primary myelofibrosis 0.5–1.5 per 100,000 JAK2 V617F 60% MPL 5–10% Investigation TET2 10–20% JAK2 Janus-associated kinase 2; MPL myeloproliferative leukemia. For a diagnosis of polycythemia, HCT should be >0.52 in men and >0.48 in Key points women. A careful history and examination are often sufficient to distinguish patients Myeloproliferative neoplasms (MPN) are primary, clonal expansions of myeloid lineage cells (erythrocytes, platelets and granulocytes) who are likely to have PV from those with a probable secondary cause. Initial investiga- MPN are often associated with mutations or translocations in the genes that regulate tions should include a full blood count cell proliferation (FBC) and film, a JAK2 V617F screen, fer- A mutation in the JAK2 gene is found in more than 97% of polycythaemia vera (PV) ritin level and basic biochemistry. and approximately 60% of essential thrombocythaemia (ET) and primary myelofibrosis (PMF) patients, and has revolutionised diagnosis of these conditions.

Clinical features and complications The major risk associated with PV and ET is arterial and venous thrombosis. Aspirin and control of the red cell and/or platelet count with venesection or cytoreductive Patients with PV might complain of pru- drugs greatly reduce the risk of thrombotic events. ritis (aquagenic, following a hot bath or shower), neurological symptoms (head- Inhibitors of JAK2 are showing early promise in the treatment of PMF, the most aches or drowsiness) or gout. Examination aggressive of the MPN. commonly reveals a plethoric appearance KEY WORDS: myeloproliferative, polycythaemia, thrombocytosis, myelofibrosis, JAK2

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MPL W515L TPO EPO MPL W515K MPL S505N TPO-R EPO-R

JAK2 V617F P JAK2 JAK2 P P JAK2 JAK2 JAK2 exon 12 P

P STATs P STATs

P STATs STATs P

Nucleus Transcription of genes driving cell proliferation

P STATs STATs P

Haematopoietic stem cell

Fig 2. Regulation of haematopoiesis by the erythropoietin (EPO) and thrombopoietin (TPO) receptors (EPO-R and TPO-R). The erythrocyte and platelet growth factors erythropoietin and thrombopoietin stimulate cell growth by binding cell surface receptors on haematopoietic progenitor cells. Receptor ligation leads to phosphorylation of the JAK2 tyrosine kinase and recruitment and activation of STATs. Activated, dimerised STATs pass into the nucleus, where they regulate the expression of genes that are required for cell-cycle activation and cell proliferation. Mutations in the JAK2 gene that result in constitutive activity are associated with PV, ET and PMF. Mutations in the MPL gene, coding for the TPO-R, are found in ET. CML chronic myeloid leukaemia; EPO erythropoietin; ET essential thrombocythaemia; JAK2 Janus- associated kinase 2; MPL myeloproliferative leukemia; P phosphorous; PMF primary myelofibrosis; PV polycythaemia vera; STAT signal transducers and activators of transcription; TPO thrombopoietin.

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Essential thrombocythaemia Table 2. Differential diagnosis of polycythaemia and thrombocytosis. Essential thrombocythaemia is a disorder Polycythaemia Thrombocytosis of the megakaryocyte lineage. Given the Reduced plasma volume (sometimes Iron deficiency prevalence of reactive thrombocytosis, resulting from diuretic use) Bleeding diagnosis is often difficult. In the absence Chronic hypoxia of the JAK2 V617F or other clonal muta- Elevated erythropoietin levels (endogenous Splenectomy or hyposplenism or exogenous), such as those secondary to tion, it is essentially one of exclusion. some renal tumours To meet the World Health Organisation High-affinity haemoglobins Inflammation or infection, malignancy, surgery (WHO) 2008 guidelines for diagnosis,2 the patient must meet all four of the following criteria: • Intermediate risk: aged 40–60 years, no especially platelet counts, can be high early other high-risk factors. in the disease). Abnormal, ineffective 1 sustained (during the time of investi- • Low risk: aged <40 years, no risk extramedullary haematopoiesis is probably ≥ 9 gation) platelet count 450 × 10 /l factors. a partial attempt to correct for the loss of 2 bone marrow biopsy showing proliferation marrow function and often leads to mas- of megakaryocytes with increased num- Other cardiovascular risk factors should sive splenomegaly. Systemic features, sec- bers of enlarged mature megakaryocytes be aggressively managed for all ET patients. ondary to cytokine release, are common 3 failure to meet the WHO criteria for First-line treatment for high-risk patients is and include fevers, weight loss, anorexia 4 other myeloproliferative neoplasms hydroxycarbamide and aspirin. PT-1, the and sweats. The replacement of the marrow 4 carry either the JAK2 V617F mutation largest randomised study of ET, showed by fibrosis results in the displacement of (present in about 50% of cases) or superiority for treatment with hydroxycar- immature cell forms, such as nucleated red another clonal marker, or have no bamide and aspirin over anagrelide and cells and myelocytes, into the peripheral evidence of reactive thrombocytosis aspirin in terms of a reduced risk of arterial blood (a leucoerythroblastic picture). The (see Table 2). thrombosis, major haemorrhage and trans- passage of normal erythrocytes through the formation to myelofibrosis, but not venous narrowed fibrotic marrow spaces distorts Incidence is estimated at 0.6–2.5 per thromboembolism. The benefit of treat- 100,000 per year. There is no sex predomi- them, generating the classic ‘tear-drop’- ment for the intermediate risk group is less shaped red cells. nance and the majority of cases present in clear. The majority of patients are treated patients aged 50–70 years. Incidence is equal in both sexes at 0.5–1.5 with hydroxycarbamide and aspirin. Low- per 100,000 per year and the most common risk patients can generally be managed with Clinical features age of onset is 50–60 years. In addition to the aspirin alone. primary disease, myelofibrosis can also Thrombosis is the major cause of morbidity occur secondary to ET or PV. Myelofibrosis and mortality for those with ET (the precise Prognosis can also be a feature of other malignancies, rate is not known, but has been estimated at such as Hodgkin lymphoma, when there is Most patients will have long, symptom-free approximately 25% at two years in untreated, marrow involvement. episodes, with the major risk being throm- high-risk patients) and can be either arterial bosis or haemorrhage. There is a risk of or venous. Age of more than 60 years and a transformation, to either myelofibrosis or previous history of thrombosis both further Investigation acute myeloid leukaemia (AML); risks at increase the thrombotic risk. Paradoxically, Full blood count and film are as described 10 years are <10% and approximately 3%, haemorrhage can also occur, especially in above. The JAK2 V617F mutation is present 9 respectively. Because of the usual age of those whose platelet count is >1,000 × 10 /l. in approximately 60% of patients. Liquid onset, however, life expectancy is often near Increased platelet numbers bind von bone marrow often cannot be aspirated normal. Willebrand’s factor, resulting in increased because of the fibrosis. Trephine biopsy clearance and a form of acquired von Primary myelofibrosis typically shows disorganisation of the Willebrand’s disease. normal marrow architecture, with increased In PMF, as in ET, the clonally proliferating numbers of morphologically abnormal Treatment cells are mostly abnormal megakaryocytes. megakaryoctyes. Reticulin staining identi- The release of cytokine derived from the fies the fibrous tissue and is increased Patients with ET can be stratified into clone causes reactive deposition of fibrous (especially later in the disease process). high-, intermediate- and low-risk groups, connective tissue, leading to the character- and their disease management is dependent istic features of the disease. Replacement of on risk.3 Treatment the normal bone marrow space with fibrous • High risk: aged >60 years or platelets tissue prevents normal haematopoiesis and The main treatment for PMF has been >1,500 × 109/l, an ET-related throm- leads to anaemia and, eventually, pancyto- supportive therapy (blood product botic or haemorrhagic event. penia (although peripheral blood counts, support, rapid treatment of infection).

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Hydroxycarbamide might be needed in clinical phenotype are still the subject of 4 Harrison CN, Campbell PJ, Buck G et al. the early proliferative phase to control research. As more than one mutation is Hydroxyurea compared with anagrelide in the white blood count or to reduce symp- involved, and as JAK2 has a necessary high-risk essential thrombocythemia. N Engl J Med 2005;353:33–45. tomatic splenomegaly. physiological role (unlike BCR-ABL), the 5 Campbell PJ, Green AR. Management of In younger patients who are fit for the development of targeted therapy remains a polycythaemia vera and essential thrombo- procedure, allogeneic stem cell transplan- challenge. Although new drugs are being cythaemia. In: Berliner N, Lee SJ, tation offers a potentially curative treat- developed, treatment at present is predomi- Linenberger M, Vogelsang GB (eds), ment by replacing the abnormal clonal nantly with agents that have been in use for Haematology 2005 — ASH Education Program Book. American Society of marrow with healthy donor haematopoi- many years. An understanding of the need Hematology: Washington DC, 2005: etic stem cells. Regression of bone marrow to control the thrombotic risk has, however, 201–8. fibrosis is observed (over time) following led to improved survival rates such that ET 6 Cortelazzo S, Finazzi G, Ruggeri M et al. successful allogeneic transplantation. For and PV can be seen as chronic diseases. Hydroxyurea for patients with essential patients who are unfit for transplant or thrombocythemia and a high risk of thrombosis, N Engl J Med 1995;332:1132–7. without a potential donor, the new JAK2 Acknowledgements 7 McMullin MF, Bareford D, Campbell P inhibitors (such as ruxolitinib) are showing et al. Guidelines for the diagnosis, investi- promise. We would like to thank Dr Andrew Duncombe gation and management of polycythaemia/ and Dr Nancy Colchester for helpful com- erythrocytosis. Br J Haematol ments on the manuscript, and Professor Nick 2005;130:174–95. Prognosis Cross for assistance with the figures. 8 McMullin MF, Reilly JT, Campbell P et al. Amendment to the guideline for the diag- PMF carries the poorest prognosis of the nosis and management of polycythaemia/ MPN. Median survival is estimated at References erythrocytosis. Br J Haematol 5–7 years, but is dependent on the stage at 2007;138:821–2. 1 Cross, NCP. Genetic and epigenetic com- which the disease is diagnosed, with some 9 Tefferi A. How I treat myelofibrosis. Blood plexity in myeloproliferative neoplasms. In: 2011:117;3494–504. patients surviving 10–15 years and others Burns LJ, Mikhael JR, Schwartz BS (eds), 10 Vassiliou G, Green AR. Myeloproliferative less than 12 months. Death results from Haematology 2011 — ASH Education disorders. In: Hoffbrand AV, Catovsky D, bone marrow failure (infection or bleeding), Program Book. American Society of Tuddenham EGD (eds), Postgraduate hae- thromboembolism, cardiac failure or trans- Hematology: Washington DC, 2011:208–14. matology, 5th edn. Oxford: Blackwell 2 Swerdlow SH, Campo E, Harris NL et al. formation to acute leukaemia. Publishing, 2005:761–82. (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. Lyon: International Agency for Research on Summary Address for correspondence: Cancer, 2008:31–65. Dr P Medd, Department of 3 Harrison CN, Bareford D, Butt N et al. The myeloproliferative neoplasms that are Haematology, Derriford Hospital, Guideline for investigation and manage- associated with the JAK2 mutation are a ment of adults and children presenting Plymouth heterogeneous group of disorders. The with a thrombocytosis. Br J Haematol PL6 8DH. 6YT, UK. additional mutations that result in the 2010;149:352–75. Email: [email protected]

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