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Myeloproliferative neoplasms
MARROW DISORDERS
Myeloproliferative neoplasms
(JAK2 V617F) gene occurs in most patients with PV and almost half of those with ET or PMF, and less prevalent mutations have been described in exon 12 of JAK2 and the transmembrane domain of the thrombopoietin receptor cMPL, as well as others.2,3 The JAK2 V617F mutation disrupts the secondary structure of the pseudokinase domain and then enables constitutive, cytokine-independent activation of signal transduction pathways, enhancing cell proliferation (Figures 1 and 2). This has revolutionized the investigation and diagnosis of these conditions. Four large clinical trials, ECLAP, PT1 and the COMFORT studies, have developed evidence-based management further, while current clinical trials focus upon such novel agents used alone and in combination.4e6
Claire N Harrison Clodagh Keohane
Abstract The Philadelphia-negative myeloproliferative neoplasms, polycythaemia vera, essential thrombocythaemia and myelofibrosis, are uncommon clonal haematological malignancies that are generally diagnosed from late middle age onwards, although they may occur in children and young adults. Each of these disorders has unique features but their clinical courses have similarities, including thrombosis, haemorrhage, a tendency for progressive myelofibrosis and the development of acute myeloid leukaemia. Myelofibrosis is associated with a much poorer prognosis than the other conditions, and death, usually due to progressive bone marrow failure or leukaemia. Recently, a mutation at position 617 in exon 14 of the JAK2 gene (JAK2 V617F) has been identified in the majority of patients with polycythaemia vera and half of those with essential thrombocythaemia or myelofibrosis. This has improved diagnostic pathways, but challenges their current classification as separate entities. Current treatment for these patients involves aggressive management of thrombotic risk factors, aspirin for most patients unless contraindicated, and cytoreductive agents such as hydroxycarbamide for patients at high risk of thrombosis. A new class of drugs, JAK inhibitors, has proven to be effective for symptomatic myelofibrosis and the first of these agents has recently been licensed.
Polycythaemia vera Clinical features PV is characterized by raised red cell number (erythrocytosis) and with thrombocytosis and/or neutrophilia; pruritus, gout and splenomegaly are classical clinical features. Median age at presentation is 55e60 years. Clinical events include arterial and to a lesser extent venous thromboses often at atypical sites (e.g. abdominal venous thrombosis) or rarely bleeding. Over 10e15 years, myelofibrosis occurs in 10e15% and acute myeloid leukaemia (AML) in 5e10%. Investigations A packed cell volume (PCV or haematocrit) persistently greater than 0.51 in a male, or 0.48 in a female, merits investigation (Table 1). Assessment includes a thorough history and examination, full blood count/film, haematinics, renal/liver profile, serum urate, JAK2 V617F screen, urinalysis and chest X-ray (especially for smokers). In the absence of an obvious secondary cause and no detectable JAK2 V617F mutation, a red cell mass may be required to identify an absolute erythrocytosis (i.e. a truly raised red cell count). Additional tests include serum erythropoietin (suppressed in PV), bone marrow biopsy, screening for mutations in exon 12 of JAK2, truncated erythropoietin receptor, proline dehydroxylase abnormalities, abdominal ultrasound scan, sleep studies and screening for a highaffinity haemoglobin.
Keywords erythrocytosis; essential thrombocythaemia; JAK inhibitors; myelofibrosis; myeloproliferative; polycythaemia vera; thrombocytosis
The myeloproliferative neoplasms (MPNs) are clonal haematological diseases characterized by overproduction of mature blood cells and a chronic course.1 The World Health Organization (WHO) has recently modified the nomenclature from myeloproliferative disorder to neoplasm to reflect the malignant nature of these diseases. MPNs include polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET), and the rarer entities, chronic neutrophilic leukaemia, chronic eosinophilic leukaemia and chronic myeloproliferative neoplasm (unclassifiable), as well as mast cell diseases. Here, we consider the commoner, so-called classical Philadelphia-negative MPNs: ET, PV and PMF. Proliferation of a single cell type defines disease phenotype: erythrocytes in PV, platelets in ET and fibroblasts in PMF. An acquired point mutation in the JAK2
Management and prognosis The risk of vascular events in treated PV patients remains raised, at approximately 1.6 times normal. Transformation to either myelofibrosis or AML following PV are treated supportively, as the outlook is extremely poor; stem cell transplantation is an option in a minority of suitably fit patients who transform. Reversible factors for cardiovascular disease should be managed aggressively, and low-dose aspirin considered unless contraindicated (e.g. by active or previous peptic ulcer disease, prominent bleeding symptoms or acquired von Willebrand’s disease). Treatment includes repeated venesection or cytoreductive therapy to keep PCV below 0.45 in males and females, and the platelet count, in some patients, below 400 109/litre. Hydroxycarbamide (HC) is the cytoreductive drug of first choice. Concern that it might increase the risk of leukaemia is not proven but the use of phosphorus-32 (P32) or busulfan is restricted because of their well-defined leukaemogenic potential.
Claire N Harrison DM FRCP FRCPath is a Consultant Haematologist at Guy’s and St Thomas’ Hospital, London, UK. Competing interests: none declared. Clodagh Keohane MRCPI FRCPath is a Clinical Research Fellow in Myeloproliferative Neoplasms at Guy’s and St Thomas’ Hospital, London, UK. Competing interests: none declared.
MEDICINE 41:5
265
Ó 2013 Elsevier Ltd. All rights reserved.
MARROW DISORDERS
Myeloproliferative neoplasms – clinical and common molecular features Clinical features of PV: • Raised haemoglobin (usually also white blood cells (WBC) and platelets) • Splenomegaly (in 10%) • Pruritus • Plethora • Tendency to thrombosis, haemorrhage • Long-term risk of marrow failure and leukaemia
Clinical features of PMF: • Normocytic normochromic anaemia • Sometimes raised WBC and/or platelets • Splenomegaly • Leukoerythroblastic blood film with tear drop cells • Tendency to thrombosis, haemorrhage • Reduced life expectancy due to marrow failure and acute leukaemia
Clinical features of ET: • Raised platelets (sometimes also WBC) • Splenomegaly • Tendency to thrombosis, haemorrhage • Long-term risk of marrow failure and leukaemia
JAK2 exon 12 mutations
V617F + PV
V617F + PMF
V617F-MPL -PMF
MPL W515
V617F + ET
V617F-MPL -ET
MPL W515 Less common TET2, ASXL1, EZH2, CBL, LNK, IDH1/IDH2, SF3B1 … Figure 1
Interferon a (IFN) is a non-leukaemogenic alternative and recent data suggest that pegylated IFN may reduce JAK2 V617F levels, potentially eradicating the abnormal clone. Investigational agents include JAK inhibitors and histone deacetylase inhibitors, which are currently being assessed in clinical trial. A current trial is directly comparing IFN and HC.
Investigations Differential diagnosis includes other MPNs and reactive thrombocytosis. Causes of a reactive thrombocytosis include iron deficiency anaemia, infection, chronic inflammation (e.g. rheumatoid arthritis or inflammatory bowel disease), splenectomy, acute haemorrhage and malignant disease. Such conditions may coexist with ET, making the diagnosis difficult. Investigations include full blood count/film, haematinics, renal and liver profile, C-reactive protein (CRP), antinuclear antibody (ANA) and rheumatoid factor (RF), screening for JAK2 V617F and MPL W515 L/K mutations, chest X-ray, abdominal ultrasound scan and bone marrow examination.
Essential thrombocythaemia Clinical features ET is characterized by a persistent thrombocytosis and recent WHO criteria suggest patients with platelets persistently over 450 109/litre merit investigation. Clinical features are similar to those of PV. Microvascular events predominate, including erythromelalgia (asymmetric erythema, congestion and burning pain in the hands and feet), which may progress to ischaemia and gangrene, migrainous-like headaches and transient ischaemic attacks. The long-term risk of myelofibrosis and leukaemia is lower than that with PV.
MEDICINE 41:5
Management and prognosis Thrombosis is the major cause of morbidity and mortality. Haemorrhage occurs less commonly and is associated particularly with platelet counts of more than 1500 109/litre and acquired von Willebrand’s disease. Most patients have a near normal life expectancy. Cytoreductive agents should be used for
266
Ó 2013 Elsevier Ltd. All rights reserved.
MARROW DISORDERS
JAK-STAT pathway
Causes of an erythrocytosis
Extracellular domain Wild-type JAK2 without erythropoietin
Wild-type JAK2 with erythropoietin
P
P
P
P
JAK STAT Intracellular domain P P
P
JAK V617F
Causes of absolute erythrocytosis Primary (abnormality within red blood cells (RBCs)) Congenital C Truncated erythropoietin receptor Acquired C Polycythaemia vera Secondary (abnormality outside RBCs) Congenital C Inherited high serum erythropoietin C Abnormal haemoglobin with increased oxygen affinity C Reduced 2,3-diphosphoglycerate C Mutation in von HippeleLindau gene C Mutations in proline dehydroxylase genes Acquired (increased erythropoietin) C Conditions causing low oxygen concentration e high altitude, chronic lung disease, some congenital heart diseases C Renal disease e tumours (hypernephroma), cysts (usually, benign), hydronephrosis, following kidney transplantation C Liver disease e hepatoma, cirrhosis, hepatitis C Tumours e bronchial cancer, uterine fibroids, cerebellar haemangiomata C Endocrine abnormalities e Cushing’s syndrome, phaeochromocytoma Idiopathic (undefined primary or secondary) C May resolve or pathology may be masked initially Causes of apparent erythrocytosis C Normal variant C Early absolute erythrocytosis C Obesity, fluid loss, diuretics, smoking, hypertension, alcohol, renal disease, psychological stress
JAK2 with V617F mutation without erythropoietin
P
P
P
P
P
P13K
STAT dimer
RAS-MAPK
RAS-MAPK P P P13K STAT dimer
Nucleus Enhanced DNA transcription
Cytokines bind to their respective transmembrane peptide receptors which lack intrinsic catalytic activity. These receptors are associated with intracellular cytoplasmic tyrosine kinases of the JAK family. Cytokine binding initiates homodimerization or heterodimerization of the receptor subunits or induces a conformational change in a preformed receptor dimer. These changes enhance the proximity of the receptor-associated JAK molecules enabling the transphosphorylation of tyrosine residues and activation of JAK molecules. In cells with the JAK2 V617F mutation signalling is constitutively increased regardless of the presence of cytokine.
Table 1
therapy than anagrelide þ aspirin, which was associated with a higher rate of arterial thrombosis, haemorrhage and myelofibrotic transformation. The role of platelet-lowering agents for patients aged under 40 years with none of these risk factors (low risk) is not confirmed; aspirin alone is sufficient. For patients aged between 40 and 60 years, again lacking any of the risk factors above (intermediate risk), best practice would be to randomize such patients into ongoing clinical trials. The development of post-ET myelofibrosis or AML indicates a poor prognosis.
Figure 2
patients with a high risk of thrombosis (any patient of age >60 years, platelet count >1500 109/litre, prior disease-related thrombosis or haemorrhage, treated diabetes or hypertension).7 The total leucocyte count and allele burden of JAK2 V617F are potentially useful future risk factors for thrombosis. For all patients, reversible factors for cardiovascular disease should be managed aggressively and low-dose aspirin given unless contraindicated. HC is the gold standard cytoreductive drug. Alternatives include 32P and busulfan, although these agents are more leukaemogenic. IFN and anagrelide have the advantage that they are probably non-leukaemogenic and do not affect fertility. Both control the platelet count in most patients but are poorly tolerated, with up to 30% being unable to continue treatment in the long-term. The MRC-PT1 study made a direct comparison between hydroxycarbamide and anagrelide in patients with ET at high risk of thrombosis.4 The results suggested that hydroxycarbamide þ aspirin is a more effective first-line
MEDICINE 41:5
Myelofibrosis MF may present de novo or progress from an antecedent ET or PV. Fibrosis is thought to arise from an interaction between diseased megakaryocytes, leucocytes, and bone marrow stroma, which release mitogens such as platelet-derived growth factor and transforming growth factor b. The proliferating fibroblasts are polyclonal. Clinical features and diagnosis Median age at presentation is 50e60 years. Symptoms relate to bone marrow failure (anaemia, infection, bleeding) or progressive splenomegaly (pain and early satiety). Constitutional
267
Ó 2013 Elsevier Ltd. All rights reserved.
MARROW DISORDERS
symptoms including fevers, night sweats, pruritus and bone pain can be prominent features of the disease and impact significantly on quality of life. Progression to AML occurs in up to 25% of patients. Other MPNs (PV, ET, CML) and disorders in which marrow fibrosis can develop as a secondary feature (e.g. metastatic carcinoma, lymphoma, irradiation, tuberculosis, leishmaniasis) should be excluded. The following features are generally necessary to confirm the diagnosis of PMF: splenomegaly increased bone marrow fibrosis (coarse reticulin fibres arranged in parallel in trephine biopsy); in later stages, new bone formation (osteomyelofibrosis) leucoerythroblastic blood film (nucleated red blood cells (NRBCs) and myeloid precursors with teardrop-shaped RBCs) absence of other MPNs exclusion of secondary causes of myelofibrosis. A positive screen for JAK2 V617F or MPL W515 L/K mutations is helpful in confirming the diagnosis.
Patients with three or more of the above have a median survival time of less than 2 years. For patients without these features median survival time is 6e10 years; some survive more than 20 years. A
REFERENCES 1 Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006; 355: 2452e66. 2 Kaushansky K. The chronic myeloproliferative disorders and mutation in the JAK2: Dameshek’s 54 year old speculation comes of age. Best Pract Res Clin Haematol 2007; 20: 5e12. 3 Vannucchi AM, Guglielmelli P. Molecular pathophysiology of, Philadelphia-negative myeloproliferative disorders: beyond JAK2 and, MPL mutations. Haematologica 2008; 93: 972e6. 4 Harrison CN, Campbell PJ, Buck G, et al. United Kingdom Medical, Research Council primary thrombocythemia 1 study. Hydroxyurea, compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 85e6. 5 Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366: 787e98. 6 Landolfi R, Marchioli R. European collaboration on low-dose aspirin in polycythemia vera (ECLAP): a randomized trial. Semin Thromb Hemost 1997; 23: 473e8. 7 Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 322: 1132e6. 8 Reilly JT. Idiopathic myelofibrosis: pathogenesis, natural history and, management. Blood Rev 1997; 11: 233e42.
Management and prognosis Supportive therapy with red cell transfusions and treatment of infection is a mainstay, with androgens or erythropoietin therapy for some.8 Hydroxycarbamide, may be useful initially to reduce splenomegaly and proliferative blood counts; this may not affect prognosis. Low-dose thalidomide in conjunction with corticosteroids is beneficial for some. In rare cases, splenectomy or splenic irradiation may be useful. JAK inhibitors have been evaluated in phase III clinical trials and one such agent, ruxolitinib, is now approved for use in intermediate and high-risk MF in the USA. Ruxolitinib has proved to be effective at relieving symptoms and reducing splenomegaly with 30% of patients, achieving a 50% or greater reduction in palpable spleen size compared to best available therapy. Whether JAK inhibitors prolong survival remains to be seen. Stem cell transplantation, particularly with reduced intensity conditioning, may cure a small number of patients. Patients with the following features may have a markedly worse prognosis: anaemia (Hb <10 g/dl) advanced age (>65 years) abnormal karyotype circulating blasts 1% white blood cell count >25 109/litre constitutional symptoms.
MEDICINE 41:5
Practice points C
C C
C C
268
Myeloproliferative neoplasms (MPNs) are rare and include essential thrombocythaemia, polycythaemia vera, chronic myeloid leukaemia and primary myelofibrosis Common manifestations include thrombosis and haemorrhage Consider an underlying MPD when thrombosis occurs in an unusual site MPDs can evolve into acute leukaemia or myelofibrosis Thrombocytosis (platelets 450 109/litre) or elevated packed cell volume (>0.51 in men, >0.48 in, women) merits further investigation
Ó 2013 Elsevier Ltd. All rights reserved.
Myeloproliferative neoplasms
(JAK2 V617F) gene occurs in most patients with PV and almost half of those with ET or PMF, and less prevalent mutations have been described in exon 12 of JAK2 and the transmembrane domain of the thrombopoietin receptor cMPL, as well as others.2,3 The JAK2 V617F mutation disrupts the secondary structure of the pseudokinase domain and then enables constitutive, cytokine-independent activation of signal transduction pathways, enhancing cell proliferation (Figures 1 and 2). This has revolutionized the investigation and diagnosis of these conditions. Four large clinical trials, ECLAP, PT1 and the COMFORT studies, have developed evidence-based management further, while current clinical trials focus upon such novel agents used alone and in combination.4e6
Claire N Harrison Clodagh Keohane
Abstract The Philadelphia-negative myeloproliferative neoplasms, polycythaemia vera, essential thrombocythaemia and myelofibrosis, are uncommon clonal haematological malignancies that are generally diagnosed from late middle age onwards, although they may occur in children and young adults. Each of these disorders has unique features but their clinical courses have similarities, including thrombosis, haemorrhage, a tendency for progressive myelofibrosis and the development of acute myeloid leukaemia. Myelofibrosis is associated with a much poorer prognosis than the other conditions, and death, usually due to progressive bone marrow failure or leukaemia. Recently, a mutation at position 617 in exon 14 of the JAK2 gene (JAK2 V617F) has been identified in the majority of patients with polycythaemia vera and half of those with essential thrombocythaemia or myelofibrosis. This has improved diagnostic pathways, but challenges their current classification as separate entities. Current treatment for these patients involves aggressive management of thrombotic risk factors, aspirin for most patients unless contraindicated, and cytoreductive agents such as hydroxycarbamide for patients at high risk of thrombosis. A new class of drugs, JAK inhibitors, has proven to be effective for symptomatic myelofibrosis and the first of these agents has recently been licensed.
Polycythaemia vera Clinical features PV is characterized by raised red cell number (erythrocytosis) and with thrombocytosis and/or neutrophilia; pruritus, gout and splenomegaly are classical clinical features. Median age at presentation is 55e60 years. Clinical events include arterial and to a lesser extent venous thromboses often at atypical sites (e.g. abdominal venous thrombosis) or rarely bleeding. Over 10e15 years, myelofibrosis occurs in 10e15% and acute myeloid leukaemia (AML) in 5e10%. Investigations A packed cell volume (PCV or haematocrit) persistently greater than 0.51 in a male, or 0.48 in a female, merits investigation (Table 1). Assessment includes a thorough history and examination, full blood count/film, haematinics, renal/liver profile, serum urate, JAK2 V617F screen, urinalysis and chest X-ray (especially for smokers). In the absence of an obvious secondary cause and no detectable JAK2 V617F mutation, a red cell mass may be required to identify an absolute erythrocytosis (i.e. a truly raised red cell count). Additional tests include serum erythropoietin (suppressed in PV), bone marrow biopsy, screening for mutations in exon 12 of JAK2, truncated erythropoietin receptor, proline dehydroxylase abnormalities, abdominal ultrasound scan, sleep studies and screening for a highaffinity haemoglobin.
Keywords erythrocytosis; essential thrombocythaemia; JAK inhibitors; myelofibrosis; myeloproliferative; polycythaemia vera; thrombocytosis
The myeloproliferative neoplasms (MPNs) are clonal haematological diseases characterized by overproduction of mature blood cells and a chronic course.1 The World Health Organization (WHO) has recently modified the nomenclature from myeloproliferative disorder to neoplasm to reflect the malignant nature of these diseases. MPNs include polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET), and the rarer entities, chronic neutrophilic leukaemia, chronic eosinophilic leukaemia and chronic myeloproliferative neoplasm (unclassifiable), as well as mast cell diseases. Here, we consider the commoner, so-called classical Philadelphia-negative MPNs: ET, PV and PMF. Proliferation of a single cell type defines disease phenotype: erythrocytes in PV, platelets in ET and fibroblasts in PMF. An acquired point mutation in the JAK2
Management and prognosis The risk of vascular events in treated PV patients remains raised, at approximately 1.6 times normal. Transformation to either myelofibrosis or AML following PV are treated supportively, as the outlook is extremely poor; stem cell transplantation is an option in a minority of suitably fit patients who transform. Reversible factors for cardiovascular disease should be managed aggressively, and low-dose aspirin considered unless contraindicated (e.g. by active or previous peptic ulcer disease, prominent bleeding symptoms or acquired von Willebrand’s disease). Treatment includes repeated venesection or cytoreductive therapy to keep PCV below 0.45 in males and females, and the platelet count, in some patients, below 400 109/litre. Hydroxycarbamide (HC) is the cytoreductive drug of first choice. Concern that it might increase the risk of leukaemia is not proven but the use of phosphorus-32 (P32) or busulfan is restricted because of their well-defined leukaemogenic potential.
Claire N Harrison DM FRCP FRCPath is a Consultant Haematologist at Guy’s and St Thomas’ Hospital, London, UK. Competing interests: none declared. Clodagh Keohane MRCPI FRCPath is a Clinical Research Fellow in Myeloproliferative Neoplasms at Guy’s and St Thomas’ Hospital, London, UK. Competing interests: none declared.
MEDICINE 41:5
265
Ó 2013 Elsevier Ltd. All rights reserved.
MARROW DISORDERS
Myeloproliferative neoplasms – clinical and common molecular features Clinical features of PV: • Raised haemoglobin (usually also white blood cells (WBC) and platelets) • Splenomegaly (in 10%) • Pruritus • Plethora • Tendency to thrombosis, haemorrhage • Long-term risk of marrow failure and leukaemia
Clinical features of PMF: • Normocytic normochromic anaemia • Sometimes raised WBC and/or platelets • Splenomegaly • Leukoerythroblastic blood film with tear drop cells • Tendency to thrombosis, haemorrhage • Reduced life expectancy due to marrow failure and acute leukaemia
Clinical features of ET: • Raised platelets (sometimes also WBC) • Splenomegaly • Tendency to thrombosis, haemorrhage • Long-term risk of marrow failure and leukaemia
JAK2 exon 12 mutations
V617F + PV
V617F + PMF
V617F-MPL -PMF
MPL W515
V617F + ET
V617F-MPL -ET
MPL W515 Less common TET2, ASXL1, EZH2, CBL, LNK, IDH1/IDH2, SF3B1 … Figure 1
Interferon a (IFN) is a non-leukaemogenic alternative and recent data suggest that pegylated IFN may reduce JAK2 V617F levels, potentially eradicating the abnormal clone. Investigational agents include JAK inhibitors and histone deacetylase inhibitors, which are currently being assessed in clinical trial. A current trial is directly comparing IFN and HC.
Investigations Differential diagnosis includes other MPNs and reactive thrombocytosis. Causes of a reactive thrombocytosis include iron deficiency anaemia, infection, chronic inflammation (e.g. rheumatoid arthritis or inflammatory bowel disease), splenectomy, acute haemorrhage and malignant disease. Such conditions may coexist with ET, making the diagnosis difficult. Investigations include full blood count/film, haematinics, renal and liver profile, C-reactive protein (CRP), antinuclear antibody (ANA) and rheumatoid factor (RF), screening for JAK2 V617F and MPL W515 L/K mutations, chest X-ray, abdominal ultrasound scan and bone marrow examination.
Essential thrombocythaemia Clinical features ET is characterized by a persistent thrombocytosis and recent WHO criteria suggest patients with platelets persistently over 450 109/litre merit investigation. Clinical features are similar to those of PV. Microvascular events predominate, including erythromelalgia (asymmetric erythema, congestion and burning pain in the hands and feet), which may progress to ischaemia and gangrene, migrainous-like headaches and transient ischaemic attacks. The long-term risk of myelofibrosis and leukaemia is lower than that with PV.
MEDICINE 41:5
Management and prognosis Thrombosis is the major cause of morbidity and mortality. Haemorrhage occurs less commonly and is associated particularly with platelet counts of more than 1500 109/litre and acquired von Willebrand’s disease. Most patients have a near normal life expectancy. Cytoreductive agents should be used for
266
Ó 2013 Elsevier Ltd. All rights reserved.
MARROW DISORDERS
JAK-STAT pathway
Causes of an erythrocytosis
Extracellular domain Wild-type JAK2 without erythropoietin
Wild-type JAK2 with erythropoietin
P
P
P
P
JAK STAT Intracellular domain P P
P
JAK V617F
Causes of absolute erythrocytosis Primary (abnormality within red blood cells (RBCs)) Congenital C Truncated erythropoietin receptor Acquired C Polycythaemia vera Secondary (abnormality outside RBCs) Congenital C Inherited high serum erythropoietin C Abnormal haemoglobin with increased oxygen affinity C Reduced 2,3-diphosphoglycerate C Mutation in von HippeleLindau gene C Mutations in proline dehydroxylase genes Acquired (increased erythropoietin) C Conditions causing low oxygen concentration e high altitude, chronic lung disease, some congenital heart diseases C Renal disease e tumours (hypernephroma), cysts (usually, benign), hydronephrosis, following kidney transplantation C Liver disease e hepatoma, cirrhosis, hepatitis C Tumours e bronchial cancer, uterine fibroids, cerebellar haemangiomata C Endocrine abnormalities e Cushing’s syndrome, phaeochromocytoma Idiopathic (undefined primary or secondary) C May resolve or pathology may be masked initially Causes of apparent erythrocytosis C Normal variant C Early absolute erythrocytosis C Obesity, fluid loss, diuretics, smoking, hypertension, alcohol, renal disease, psychological stress
JAK2 with V617F mutation without erythropoietin
P
P
P
P
P
P13K
STAT dimer
RAS-MAPK
RAS-MAPK P P P13K STAT dimer
Nucleus Enhanced DNA transcription
Cytokines bind to their respective transmembrane peptide receptors which lack intrinsic catalytic activity. These receptors are associated with intracellular cytoplasmic tyrosine kinases of the JAK family. Cytokine binding initiates homodimerization or heterodimerization of the receptor subunits or induces a conformational change in a preformed receptor dimer. These changes enhance the proximity of the receptor-associated JAK molecules enabling the transphosphorylation of tyrosine residues and activation of JAK molecules. In cells with the JAK2 V617F mutation signalling is constitutively increased regardless of the presence of cytokine.
Table 1
therapy than anagrelide þ aspirin, which was associated with a higher rate of arterial thrombosis, haemorrhage and myelofibrotic transformation. The role of platelet-lowering agents for patients aged under 40 years with none of these risk factors (low risk) is not confirmed; aspirin alone is sufficient. For patients aged between 40 and 60 years, again lacking any of the risk factors above (intermediate risk), best practice would be to randomize such patients into ongoing clinical trials. The development of post-ET myelofibrosis or AML indicates a poor prognosis.
Figure 2
patients with a high risk of thrombosis (any patient of age >60 years, platelet count >1500 109/litre, prior disease-related thrombosis or haemorrhage, treated diabetes or hypertension).7 The total leucocyte count and allele burden of JAK2 V617F are potentially useful future risk factors for thrombosis. For all patients, reversible factors for cardiovascular disease should be managed aggressively and low-dose aspirin given unless contraindicated. HC is the gold standard cytoreductive drug. Alternatives include 32P and busulfan, although these agents are more leukaemogenic. IFN and anagrelide have the advantage that they are probably non-leukaemogenic and do not affect fertility. Both control the platelet count in most patients but are poorly tolerated, with up to 30% being unable to continue treatment in the long-term. The MRC-PT1 study made a direct comparison between hydroxycarbamide and anagrelide in patients with ET at high risk of thrombosis.4 The results suggested that hydroxycarbamide þ aspirin is a more effective first-line
MEDICINE 41:5
Myelofibrosis MF may present de novo or progress from an antecedent ET or PV. Fibrosis is thought to arise from an interaction between diseased megakaryocytes, leucocytes, and bone marrow stroma, which release mitogens such as platelet-derived growth factor and transforming growth factor b. The proliferating fibroblasts are polyclonal. Clinical features and diagnosis Median age at presentation is 50e60 years. Symptoms relate to bone marrow failure (anaemia, infection, bleeding) or progressive splenomegaly (pain and early satiety). Constitutional
267
Ó 2013 Elsevier Ltd. All rights reserved.
MARROW DISORDERS
symptoms including fevers, night sweats, pruritus and bone pain can be prominent features of the disease and impact significantly on quality of life. Progression to AML occurs in up to 25% of patients. Other MPNs (PV, ET, CML) and disorders in which marrow fibrosis can develop as a secondary feature (e.g. metastatic carcinoma, lymphoma, irradiation, tuberculosis, leishmaniasis) should be excluded. The following features are generally necessary to confirm the diagnosis of PMF: splenomegaly increased bone marrow fibrosis (coarse reticulin fibres arranged in parallel in trephine biopsy); in later stages, new bone formation (osteomyelofibrosis) leucoerythroblastic blood film (nucleated red blood cells (NRBCs) and myeloid precursors with teardrop-shaped RBCs) absence of other MPNs exclusion of secondary causes of myelofibrosis. A positive screen for JAK2 V617F or MPL W515 L/K mutations is helpful in confirming the diagnosis.
Patients with three or more of the above have a median survival time of less than 2 years. For patients without these features median survival time is 6e10 years; some survive more than 20 years. A
REFERENCES 1 Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006; 355: 2452e66. 2 Kaushansky K. The chronic myeloproliferative disorders and mutation in the JAK2: Dameshek’s 54 year old speculation comes of age. Best Pract Res Clin Haematol 2007; 20: 5e12. 3 Vannucchi AM, Guglielmelli P. Molecular pathophysiology of, Philadelphia-negative myeloproliferative disorders: beyond JAK2 and, MPL mutations. Haematologica 2008; 93: 972e6. 4 Harrison CN, Campbell PJ, Buck G, et al. United Kingdom Medical, Research Council primary thrombocythemia 1 study. Hydroxyurea, compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 85e6. 5 Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366: 787e98. 6 Landolfi R, Marchioli R. European collaboration on low-dose aspirin in polycythemia vera (ECLAP): a randomized trial. Semin Thromb Hemost 1997; 23: 473e8. 7 Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 322: 1132e6. 8 Reilly JT. Idiopathic myelofibrosis: pathogenesis, natural history and, management. Blood Rev 1997; 11: 233e42.
Management and prognosis Supportive therapy with red cell transfusions and treatment of infection is a mainstay, with androgens or erythropoietin therapy for some.8 Hydroxycarbamide, may be useful initially to reduce splenomegaly and proliferative blood counts; this may not affect prognosis. Low-dose thalidomide in conjunction with corticosteroids is beneficial for some. In rare cases, splenectomy or splenic irradiation may be useful. JAK inhibitors have been evaluated in phase III clinical trials and one such agent, ruxolitinib, is now approved for use in intermediate and high-risk MF in the USA. Ruxolitinib has proved to be effective at relieving symptoms and reducing splenomegaly with 30% of patients, achieving a 50% or greater reduction in palpable spleen size compared to best available therapy. Whether JAK inhibitors prolong survival remains to be seen. Stem cell transplantation, particularly with reduced intensity conditioning, may cure a small number of patients. Patients with the following features may have a markedly worse prognosis: anaemia (Hb <10 g/dl) advanced age (>65 years) abnormal karyotype circulating blasts 1% white blood cell count >25 109/litre constitutional symptoms.
MEDICINE 41:5
Practice points C
C C
C C
268
Myeloproliferative neoplasms (MPNs) are rare and include essential thrombocythaemia, polycythaemia vera, chronic myeloid leukaemia and primary myelofibrosis Common manifestations include thrombosis and haemorrhage Consider an underlying MPD when thrombosis occurs in an unusual site MPDs can evolve into acute leukaemia or myelofibrosis Thrombocytosis (platelets 450 109/litre) or elevated packed cell volume (>0.51 in men, >0.48 in, women) merits further investigation
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