261 PATHOGENESIS OF THE MPNS MPD unclassifi able \200\231 entity, and much less commonly in 5q \210\222 MDS (5%) and oth er myeloid neoplasms. The reason why this mutation is associated with 3 diff erent MPN clinical phenotypes remain s unclear. Additional genetic factors clearly contribute to the clinical phenotype of JAK2- V617F +ve MPN. Homozygosity for JAK2-V617F resulting from mitotic recombination and duplica tion of the mutant allele (acquired uniparental disomy (UPD)) is common in PV (30%), rare i n ET, and occurs occasionally in PMF (13%).10 Duplication may be important to pathogenesis of PV. Other diff erences are: (i) the proportion of chromosomes expressing the mutation (g ene dosage) is higher in PV and PMF than in ET; (ii) the allelic frequency of JAK2-V617F re mained stable over time in ET but i slightly in PV; and (iii) in PV the allelic frequency i s identical in neutrophils and platelets, in ET it is higher in platelets.11 It has been su ggested that JAK2-V617F +ve ET is a forme-fruste of PV and may have a diff erent clinical c ourse from JAK2-V617F \210\222ve ET.12 Evidence has been contradictory (reviewed in refere nces 1 and 8). Presence of JAK2-V617F may correlate with poorer survival in PMF.13 Clonal h aematopoiesis is found in JAK2-V617F \210\222ve MPN suggesting that other alleles cause my eloproliferation in these patients.14 Somatic mutations of codon 515 at the transmembrane \200\223juxtamembrane junction of the thrombopoietin receptor gene (MPL), MPL-W515L or MPL- W515K have been detected in 710% of patients with JAK2-V617F \210\222ve PMF and a smaller proportion of patients with JAK2-V617F \210\222ve ET.15 Expression of MPL-W515L transforms haematopoietic cells to factor-independent growth and activates STAT, MAPK, and P13K-Act s ignaling pathways in a manner similar to JAK2-V617F but in vivo results in thrombocytosis a nd myelofi brosis.1 A KIT-D816F allele has been detected in systemic mastocytosis (SM)16 an d an interstitial deletion producing a fusion protein FIP1L1-PDGFRA involving platelet-deri ved growth factor- has been detected in patients with a diagnosis of chronic eosinophilic leukemia (CEL) or SM.17 TET2 mutations occur in both JAK2-V617F positive and negative MPNs and are more frequent in MPN-U patients. References 1. Levine, R.L. et al. (2007). Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer, 7, 673 \200\22383. 2. Campbell, P.J. and Green, A.R. (2006). The myeloproliferative disorders. N Engl J Med, 3 55, 2452 \200\22366. 3. Baxter, E.J. et al. (2005). Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 365, 1054 \200\22361. 4. Scott, L.M. et al. (2007). JAK2 exon 12 mutations in polycythaemia vera and idiopathic erythrocytosis. N Engl J Med, 356. 459 \200\22368. 5. Wernig, G. et al. (2006). Expression of Jak2V617F causes a polycythemia vera \200\223lik e disease with associated myelofi brosis in a murine bone marrow transplant model. Blood, 1 07, 4274 \200\22381. 6. Landolfi , R. et al. (2007). Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood, 109, 2446 \200\22352. 262 CHAPTER 7 Myeloproliferative neoplasms 7. Carobbio, A. et al. (2007). Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation statu s. Blood, 109, 2310 \200\22313. 8. Skoda, R. (2007). The genetic basis of myeloproliferative disorders. Hematology 2007, 1 \200\22310. 9. Szpurka, H. et al. (2006). Refractory anemia with ringed sideroblasts associ ated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood, 108, 2173 \200\22381. 10. Scott, L.M. et al. (2006). Progenitors homozygous for the V617F JAK2 mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood, 108, 2435 \200\2237. 11. Moliterno, A.R. et al. (2006). Molecular mimicry in the chronic myeloproliferative diso rders: reciprocity between quantitative JAK2 V617F and Mpl expression. Blood, 108, 3913 \200\2235. 12. Campbell, P.J. et al. (2005). Defi nition of subtypes of essential thrombocy thaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. La ncet, 366,1945 \200\22353. 13. Campbell, P.J. et al. (2006). V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofi brosis. Blood, 107, 2098 \200\2232100. 14. Levine, R.L. et al. (2006). X-inactivation based clonality analysis and quantitative JA K2V617F assessment reveal an association between clonality and JAK2V617F in PV but not ET/ MMM, and identifi es a subset of JAK2V617F \200\223negative ET and MMM patients with clonal haematopoiesis. Blood, 107, 4039 \200\22341. 15. Pardanani, A.D. et al. (2006). MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 118 patients. Blood, 108, 3472 \200\2236. 16. Buttner, C. et al. (1998). Identifi cation of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: a possible explanation for divergent clinical beh avior. J Invest Dermatol, 111, 1227 \200\22331. 17. Cools, J. et al. (2003). A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 g enes as a therapeutic target of imatinib in idiopathic eosinophilic syndrome. N Engl J Med, 348, 1201 \200\22314. Further reading Patriarca, A. (2013). TET2 mutations in Ph-negative myeloproliferative neop lasms: identifi cation of three novel mutations and relationship with clinical and laborato ry fi ndings. Biomed Res Int, 2013, 929840. Teff eri, A. (2013). Polycythemia vera and esse ntial thrombocythemia: 2013 update on diagnosis, risk-stratifi cation, and management. Am J Hematol. 88(6), 507 \200\22316. 263 PATHOGENESIS OF THE MPNS 264 CHAPTER 7 Myeloproliferative neoplasms Polycythaemia vera (PV) Erythrocytosis is defi ned as an increase in total red cell mass (R CM). The term \200\230polycythaemia \200\231 is widely used synonymously but lacks precisi on and can lead to confusion. It is suspected by fi nding a raised haematocrit (Hct) or pac ked cell volume (PCV). Persistent elevation of Hct >0.48 in adult \231\200 and >0.51 in ad ult \231\202 is abnormal. An elevated Hct can occur with a normal RCM (absence of erythroc ytosis) if the plasma volume is reduced: \200\230relative \200\231 erythrocytosis (RE). 2 causes of polycythaemia must be excluded. PV is a neoplastic clonal disorder of the BM stem cell causing excessive proliferation of t he erythroid, myeloid, and megakaryocyte lineages and carries a risk of thrombotic complica tions. PV was traditionally diag- nosed using the criteria of the Polycythaemia Vera Study Group by the presence of an i red cell mass. The detection of JAK2 mutations in most patien ts with PV1 has revolutionized diagnostic procedures. Incidence PV is the most common MPN with an incidence of up to 3 per 100,000 per annum. It occurs in all races but is 10 \227 less frequent in Japan. Median age at diagnosis is 60 y ears. PV occurs at all ages but is very rare below 30 years. It occurs extremely rarely in childhood. The \231\202: \231\200 ratio is 1.2:1. Etiology As described on E p.260, mutation of the cytoplasmic tyrosine kinase JAK2 gene (JA K2-V617F and JAK2 exon 12 mutations) has a clear patho- genetic role. Incidence of PV is i in populations exposed to radiation (including Japan) and petroleum refi nery and chemical workers. Diff erential diagnosis of erythrocytosis See Table 7.1. Table 7.1 Diff erential diagnosis of erythrocytosis 1 eythrocytosis 1 familial and congenital polycythaemia (PFCP): gain-of-function mutation of EPO receptor gene l truncated receptor; 10 diff erent alleles described; autosomal dominant; high penet rance; early age of onset; i RCM, low sEPO, polyclonal haematopoiesis, n WBC and platelet c ounts. Congenital Familial clonal MPN: low penetrance, late onset, often JAK2-V617F +ve PV (previously: polycythaemia rubra vera (PRV); 1 proliferative polycythaemia (PPP)). Acquired High O2-affi nity haemoglobinopathy 2 erythrocytosis (SE) due to 1 endogenous EPO production Congenital (continued) 265 POLYCYTHAEMIA VERA (PV) Table 7.1 Diff erential diagnosis of erythrocytosis (continued ) Congenital 2,3-DPG defi ciency (2 erythrocytosis (SE) due to 1 endogenous EPO production) Autonomous high EPO production; autosomal recessive mutation of von Hippel \200\223Lindau ( VHL) gene; Chuvash polycythaemia (VHL-598C >T) resulting in i levels of hypoxia-induced tra nscription factor (HIF1) and i expression of EPO gene; other alleles described. Acquired Chronic lung disease Hypoxaemia Cyanotic congenital heart disease with rightlleft shunt Living at high altitude Chronic alveolar hypoventilation e.g. gross obesity Sleep apnoea syndromes Other causes of impaired tissue O2 delivery Renal disease (EPO mediated) Smoking (i COHb) Polycystic kidneys Renal tumors Renal artery stenosis Post-renal transplantation Hepatoma Tumors causing pathological EPO production Cerebellar haemangioblastoma Uterine leiomyoma Bronchial carcinoma Adrenal tumors Parathyroid carcinoma Cirrhosis Liver disease Hepatitis EPO abuse/doping Drugs Androgens Idiopathic erythrocytosis (IE) Persistent i RCM, no cause found but no evidence of MPN or clear cause of 2 erythrocytosi s. Normal RCM and reduced plasma volume; Diuretic therapy or dehydration; Gaisbock \200\231s s yndrome; smoking, alcohol, hypertension, obesity. Relative erythrocytosis (RE). Syn. apparent polycythaemia, spurious erythrocytosis, pseudo- polycythaemia 266 CHAPTER 7 Myeloproliferative neoplasms Clinical evaluation of a patient with suspected erythrocytosis A patient with erythrocytosi s may be asymptomatic or may present with thrombosis (up to 40% with PV), hemorrhage (up to 20% with PV), or vague symptoms (740% with PV) of headache, dizziness, weakness, excessive sweating, tinnitus, visual upset, or gout. Take a detailed history with attention to smoking habits, alcohol consump- tion, diuretic t herapy, dyspepsia, and thrombosis. A history of pruritus (especially after bathing) suggest s PV (occurs in 750%). A burning sensa- tion in fi ngers and toes with erythema, pallor, or cyanosis (erythromela- lgia) is typical of PV. Patients presenting with abdominal vein (po rtal vein) thrombosis should be screened for a possible underlying MPN. Physical examination may identify facial plethora or abnormalities associ- ated with 2 er ythrocytosis such as gross obesity, hypertension, evidence of obstructive airways disease o r cyanotic cardiac conditions. At diagnosis splenomegaly and hepatomegaly occur in 67% and 40%, respectively. Investigations \200 FBC and fi lm: ii RCC and d or n MCV and MCH (may be evidence of Fe d efi ciency) in PV; neutrophils and platelets frequently i in PV (rare in other causes of er ythrocytosis). JAK2 mutation analysis: screen for JAK2-V617F mutation; found in 95% of patients with PV; d iff erentiates PV from SE and RE but not from PMF or ET (58% and 50% JAK2-V617F +ve);1 seve ral JAK2 exon 12 mutations described in patients with JAK2-V617F \210\222ve PV and should be screened for if JAK2-V617F negative;2 False negatives due to low mutant allele burden po ssible.3 Serum erythropoietin (sEPO): included in initial work-up; usually d but can be n in PV, extremely unlikely to be i; i sEPO suggests 2 erythrocytosis; may be d in RE and idiopathic erythrocytosis. \200 BM examination: not always indicated. See dia gnostic algorithm on E p.267. Trephine may be diagnostic in PV; typically hypercellular for age due to trilineage hyperplasia (mainly erythroid and megakaryocytic); megakaryocytes conspicuous, pleomorphic (small to giant) and clustered round sinusoids or near trabeculae with deeply lobulated nuc lei; usually d Fe stores (95%); i reticulin fi brosis present in 30%; n BM histology does n ot exclude PV but is more usual in SE; late in the disease collagen fi brosis may supervene with clusters of dysmorphic megakaryocytes. Serum ferritin: d (esp. PV) or n; occasionally overt Fe defi ciency. \200 Serum chemistry : U&E (to exclude renal disease); uric acid (often i in MPNs); LFTs (to exclude liver disease). Urinalysis: haematuria or proteinuria should prompt further renal investigations. Arterial oxygen saturation: pulse oximetry most convenient to detect chronic hypoxia. SaO2 <92% suggests causal relationship with absolute erythrocytosis. ABG: arterial blood gas for pO2 assessment. \200 CXR: to exclude pulmonary disease and co ngenital cardiac abnormalities. 267 POLYCYTHAEMIA VERA (PV) Additional investigations useful in selected patients \200 BM examination: as above. \200 Abdominal USS: for hepatosplenomegaly, renal or pelvic abnormalities. BM cytogenetics: not routine; up to 30% have abnormalities, typically 20q \210\222. +8, +9, 7 \210\222, and 10 \210\222. BFU-E culture: not widely available and thus not routinely done; PV progenitors show i sens itivity to growth factors and develop \200\230endogenous erythroid colonies \200\231 (EEC) without added EPO. Haematinic assays: serum vitamin B12: levels commonly i in PV due to i transcobalamin relea se refl ecting associated granulocytosis. Folate defi ciency may occur. Sleep studies may be indicated if history of snoring, waking unrefreshed, and somnolence. Pulmonary function tests are indicated if lung disease is suspected. \200 O2 dissociation curve: in patients with erythrocytosis and suspected high-affi nity hemoglobin. EPO-R or VHL gene analysis if congenital erythrocytosis suspected. \200 RCM and plasma vo lume: former mainstay of diagnostic process; no longer routinely done; patient red cells la beled with 51Cr and re-injected; simultanous plasma volume measurement using 131I-labeled a lbumin. RCM i >25% above mean predicted value is diagnostic of absolute erythrocytosis. Pla sma volume also i (if marked splenomegaly present (see Table 7.2). Table 7.2 Red cell mass and plasma volume studies in erythrocytosis PV SE RE RCM i i i within NR or n Plasma volume N N or i d within NR or n PV, polycythaemia vera; SE, 2 erythrocytosis; RE, relative erythrocytosis. Diagnostic algorithm for suspected PV In a patient with suspected PV, the following diagnos tic algorithm based on the 2008 WHO criteria is recommended (Table 7.3).3 Screen blood for JAK2-V617F mutation and measure serum EPO. \200 V617F +ve and sEPO d: PV highly likely l BM biopsy encouraged but not essential. V617F +ve but sEPO n or i: PV likely l BM biopsy recommended for confi rmation. V617F \210\222ve but sEPO d: PV possible l BM biopsy and JAK2 exon 12 mutation screening l if results still not consistent with PV, consider congenital polycythaemia with EPO recept or mutation. V617F \210\222ve and sEPO n or i: PV unlikely l consider SE including congenital polycythaemia with VHL mutation. 268 CHAPTER 7 Myeloproliferative neoplasms Table 7.3 2008 WHO diagnostic criteria for PV3 1. Hgb >185g/L ( \231\202), > 165g/L ( \231\200) or Hgb or Hct >99th percentile of referenc e range for age, sex, or altitude of residence or Hgb >170g/L ( \231\202). >150g/L ( \231 \200) if associated with sustained increase \211 20g/L from baseline that cannot be attri buted to correction of Fe defi ciency or Elevated RCM >25% above mean n predicted value 2. Presence of JAK2-V617F or functionally similar Major criteria mutation (such as exon 12 mutation) Minor criteria 1. BM: hypercellular for age with trilineage growth (panmyeloisis) with prominent trilineage proliferation 2. Subnormal serum EPO level 3. EEC growth in vitro Diagnosis of PV requires that the patient meets both major criteria plus 1 minor criterion or the presence of the fi rst major criterion and 2 minor criteria. References 1. Baxter, E.J. et al. (2005). Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 365, 1054 \200\22361. 2. Levine, R.L. et al. (2007). Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer, 7, 673 \200\22383. 3. Teff eri, A. and Vardiman, J.W. (2008). Classifi cation and diagnosis of myeloproliferat ive neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic alg orithms. Leukemia, 22, 14 \200\22322. Further reading Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoie tic and Lymphoid Tissues, 4th ed. Lyon: IARC. Teff eri, A. (2013). Polycythemia vera and es sential thrombocythemia: 2013 update of diagnosis, risk-stratifi cation, and management. Am J Hematol, 88(6), 507 \200\22316. 269 POLYCYTHAEMIA VERA (PV) 270 CHAPTER 7 Myeloproliferative neoplasms Natural history of PV Untreated PV carries a signifi cant risk of early thrombotic complica tions and a further long-term risk of transformation into myelofi brosis or less commonly A ML. There is also an i risk of bleeding notably from peptic ulcers. The aim of treatment is to reduce the risk of thrombotic compli- cations and to prevent progression to myelofi bro sis (MF) or leukemia. Current treatments improve median survival to >15 years. Some myelo- suppressive treatments (notably chlorambucill and 32P) have been asso- ciated with an i ris k of AML and are no longer routinely used. Cardiovascular complications, notably MI, stroke, and VTE are the most common causes of dea th (41%). The rate of non-fatal thrombosis is 3.8 per 100 patients per annum. Major and fat al hemorrhage is rare (0.8 and 0.15 per 100 patients per annum).1 Age and thrombotic histor y are the most important risk factors for thrombosis. PV characteristically presents during a proliferative phase when control of erythrocytosis and prevention of thrombotic complications is often an urgent priority. This is often follo wed by a stable phase of variable duration. In some patients near n counts are maintained w ithout therapy as a result of d proliferative capacity due to early myelofi brosis. Subsequ ently an advanced phase can develop, which is due to extensive myelofi brosis and associate d with progressive hepatosplenomegaly, pan- cytopenia, and systemic symptoms (fever and wei ght loss). Incidence of this transformation is 10 \200\22315% after 10 years rising to >30% at 20 years; after transformation median survival <18 months. The incidence of AML is esti mated at 2%. Risk strati \201 cation Age and thrombotic history are predictive for vascular events in P V (and ET) and are used for risk stratifi cation to inform treatment decisions (Table 7.4). Other (possible) risk factors include: \200 Platelet count >1500 \227 109/L is a risk f actor for bleeding but not for thrombosis.2 i leucocyte count (>20 \200\22325 \227 109/L).3 \200 Quantitation of JAK2 mutant allele (JAK2-V617F/JAK2 wild type ratio >75%).4 Age >60 years. \200 Symptomatic splenomegaly.5 Table 7.4 Risk stratifi cation in PV2 Cardiovascular risk factorsa Risk category Age >60 years or history of thrombosis Low No No Intermediate No Yes High Yes Not applicable a Hypertension, hypercholesterolaemia, diabetes, smoking. 271 NATURAL HISTORY OF PV References 1. Marchioli, R. et al. (2005). Vascular and neoplastic risk in a large cohort o f patients with polycythemia vera. J Clin Oncol, 23, 2224 \200\22332. 2. Finazzi, G. and Barbui, T. (2007). How I treat patients with polycythemia vera. Blood, 1 09, 5104 \200\22311. 3. Landolfi , R. et al. (2007). Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood, 109, 2446 \200\22352. 4. Vannucchi, A.M. et al. (2007). Prospective identifi cation of high risk polycythemia ver a patients based on JAK2 allele burden. Leukemia, 21, 1952 \200\2239. 5. Passamonti, F. (2012). How I treat polycythemia vera. Blood, 120, 275 \200\22384. 272 CHAPTER 7 Myeloproliferative neoplasms Management of PV Modi \201 able factors and lifestyle In all PV patients, identify and treat any additional risk factors (e.g. hyper- tension) and encourage the patient to adopt a healthy lifestyle (e.g. stop smoking, take exercise). Patients with a low risk of thrombosis Venesection d RCM to n as rapidly as possible to pre vent complications (target Hct <0.45). No fi rm data exist to support these targets.1,2,3 R emoval of RBCs by venesection is the quickest way of reducing RCM. 450mL blood ( isovolae mic replacement with 0.9% saline) removed safely from younger adults every 2 \200\2233d (d volume to 200 \200\223300mL and frequency to twice weekly in elderly or patients with cardi ovascular disease). If Hct very high (>0.60) venesection may be technically diffi cult due to extreme viscosity. Maintenance therapy Venesection alone can be used to maintain the Hct at 0.40 \200\2230.45. Once target achieved monitor 4 \200\2238-weekly to establish the requirement for further v enesection. Individual requirements are variable (e.g. 2 proce- dures per year to monthly v enesection). Fe supplements should not be given. Early studies showed i risk of thrombosis in fi rst 3 years after treatment with venesection alone thus additional cytoreductive trea t- ment is required in patients with a higher risk of thrombosis. Aspirin 75 \200\223100mg daily is recommended in all PV patients without a history of major bleeding or gastric intolerance. The ECLAP study randomized 518 mainly asymptomatic low-ri sk PV patients to aspirin 100mg/d or placebo.2 Aspirin signifi cantly reduced the risk of t he combined endpoint of non-fatal MI, non-fatal stroke, pulmonary embolism, major venous th rombosis, or death from cardiovascular causes (RR 0.40; CI 0.18 \200\223 0.91; p=0.03). The incidence of major bleeding was not signifi cantly i (RR 1.62; CI 0.27 \200\2239.71). It h as been argued that the risks and benefi ts of aspirin should be carefully considered in ve ry low-risk patients, e.g. <55 years with no additional risk factors as benefi ts are propo rtional to vascular risk and below a certain level bleeding events due to aspirin may excee d vascular events prevented by it.4 Patients with an intermediate risk of thrombosis Treatment of these patients must be indivi dualized. Most may be managed as for low-risk patients but cytoreductive therapy may be req uired in some. Poor compliance to venesection or progressive mye- loproliferation (splenome galy, constitutional symptoms, leucocytosis, and thrombocytosis) can be an indication for c ytoreductive therapy.5 273 MANAGEMENT OF PV Additional treatment for patients with a high risk of thrombosis Hydroxycarbamide (HC) HC ( formerly hydroxyurea) an antimetabolite (ribonucleotide reductase inhibitor), is cytoreduct ive treatment of choice. Onset of myelosuppres- sion with HC is rapid, and overdosage is qu ickly corrected by temporary withdrawal. Start at 15 \200\22320mg/kg/day until Hct <0.45, t hen adjust to a maintenance dose to preserve response without WCC <3 \227 109/L. Review ev ery 2 weeks initially and in steady-state monitor FBC every 3 months. Randomized trials in ET6,7 have demonstrated the antithrombotic eff ect of HC but similar trials have not been r eported in PV. However HC has been shown to be eff ective and safe in PV and is the most wi dely used agent.5 Continuous treatment is required and some patients fi nd the need for fol low-up diffi cult. Longstanding concerns that HC may still carry a risk are not supported b y a large observational study8 and >10 years use in sickle cell disease. Nonetheless use HC cautiously in younger patients. Some patients experience GI upset, skin pigmentation, and leg ulcers. Leg ulcers occur in up to 10% and do not heal until HC is discontinued. The ant ithrombotic eff ect of HC may be due to more than myelosuppression including qualitative ch anges in leucocytes, d expression of endothelial adhesion molecules, and i NO generation.1 Interferon alfa IFN- can control erythrocytosis and d leucocytosis, thrombocytosis, and m odest splenomegaly. IFN- directly inhibits fi broblast progeni- tors and antagonizes PDGF , TGF- , and other cytokines that may be involved in myelofi brosis. Commence 3 million un its SC daily and when Hct <0.45 achieved reduce to lowest dose that maintains response.1 Mo nitor patients frequently initially. Side eff ects (fever, fl u-like symp- toms, weakness, myalgia, depression) can reduce compliance. 733% dis- continue it due to toxicity.9 Long-te rm follow-up in 55 patients (median 13 years) shows d thrombotic and haemorrhagic events an d confi rms the absence of leukaemogenesis.10 Pegylated-IFN may be better toler- ated; begi n at 0.5mcg/kg/week, double dose if response not achieved after 12 weeks then reduce to mai ntenance dose. IFN is treatment of choice in pregnant \231\200, and is preferred by some i n patients <40 years.1,11 Anagrelide Oral imidazoquinazoline with anticyclic AMP phosphodie sterase activity and profound eff ect on megakaryocyte maturation resulting in d platelet p roduction. Useful for control of thrombocytosis in PV patients who do not tolerate or fail to respond to HC or IFN. More useful in ET as no eff ect on progression of PV: erythrocytos is or splenomegaly. Commence at 500mcg bd, adjusting according to response with weekly incr ements of 500mcg/d; usual therapeutic dose 2 \200\2233mg/d. Therapeutic eff ect usually wit hin 14 \200\22321 days. No evidence of mutagenic activity. Side eff ects may reduce long-te rm tolerance: headache (50%), forceful heartbeat, fl uid retention, dizziness, arrhythmia ( <10%), CCF (2%), and diarrhea. Use cautiously in patients with known or suspected cardiac d isease. May be used in combination with HC or IFN to achieve disease control with reduced s ide eff ects. 274 CHAPTER 7 Myeloproliferative neoplasms Radioactive phosphorus (32P) and busulfan These are historical early treatments for PV. Pro duce d in RCM 6 \200\22312 weeks after administration (32P 2.3 mCi/m2 by IV injection every 12 weeks as necessary; busulfan by single oral dose 0.5 \200\2231mg/kg). Either agent may be repeated after 3 \200\2236 months if further myelosuppression is required. Both individu ally d thrombosis risk and myelofi brosis but markedly i the risk of AML. The incidence of AML after 32P alone is 2.5 \200\22315%.11 The use of 32P with either busulfan or hydroxycar bamide in an individual carries a very high risk of AML. Neither is therefore recom- mended for patients \211 75 years who should receive hydroxycarbamide. However, in patients >75 in whom compliance or regular monitoring of hydroxycarbamide dose is a problem, busulfan is likely the best choice of treatment.11,12 Supportive treatment \200 Maintain adequate fl uid intake and avoid dehydration. \200 G ive allopurinol (300mg/d) in the early phase of treatment to minimize risks of hyperuricaemia. Acute gout is managed by standard therapies. New treatments for PV JAK2 inhibitor: ruxolitinib. Oral agent approved for use in MF. 97% o f patients achieve a haematocrit <45%. 80% patients achieve >50% spleen reduction. Leucocyt osis normalization in 73%, thrombocytosis normali- zation in 69%. CR in 50%.13 Trials are o ngoing comparing ruxolitinib to best available therapy. Continued care and follow-up Patients with PV and idiopathic erythrocytosis should have lon g-term hematological follow-up. Measure Hct at least 3-monthly. For patients on cytotoxic t herapy with hydroxycarbamide the FBC should be checked every 8 \200\22312 weeks. Treatment of advanced phase PV Symptomatic management should be prioritized. Patients often require blood product support. Splenectomy is often considered due to dis- comfort, recurr ent infarction, or hypersplenism but often followed by massive hepatomegaly due to extramed ullary haematopoiesis. Complications of PV Pruritus: typically aquagenic, a troublesome complication for some pati ents. Unfortunately there is no satisfactory treatment. Sometimes abates when excess myelop roliferation controlled and Hct reduced but may persist despite adequate control. Antihista mines, H2-antagonists (cimetidine 400mg bd), IFN- (3 million units 3 \227 weekly), the s elec- tive serotonin re-uptake inhibitor (SSRI) paroxetine (20mg/d), or pho- totherapy with psoralen and UV light have been used. Erythromelalgia: due to microvascular disturbance. Aspirin (75 or 100mg/d maintenance) is u sually eff ective. Thrombosis: manage venous thromboembolic events according to current guidelines. Follow LMW H with warfarin (INR 2.0 \200\2233.0) for 3 \200\2236 275 MANAGEMENT OF PV months. Low-dose aspirin (75 \200\223100mg/d) is recommended following ischaemic stroke, TI A, peripheral arterial occlusion, MI, unstable angina, or in patients with evidence of coro nary artery disease.1 Role of clopi- dogrel unclear. Cytoreduction recommended in all patie nts with acute vascular events. Hemorrhage: major hemorrhage uncommon. Most frequent from skin, mucous membranes and GI tra ct. May be precipitated by antithrombotic therapy: avoid in patients with history of haemor rhagic events, gastric ulcers, or varices. Associated with platelet count >1500 \227 109/L . May be related to acquired vWD due to loss of large vWF multimers resulting in a function al defect. Normalization of the platelet count corrects the coagulopathy.14 Treat by withdr awal of any antithrombotic therapy and correction of thrombocytosis with HC. Consider antif i brinolytic therapy and/or vWF containing concentrates.15 Surgery in PV patients Relatively contraindicated in uncorrected PV. Defer surgery until Hc t and platelets normalized for \211 2 months due to risk of thrombotic and haemorrhagic co mplications; if emergency surgery necessary perform venesection. PV in pregnancy Rare. Assess risk of thrombosis and complications of pregnancy. Pre- plan c onception when possible with cessation of any teratogenic agents and control of Hct. Admini ster low-dose aspirin throughout pregnancy and prophylactic LMWH for up to 6 weeks post-par tum. When cytore- duction is necessary for uncontrolled Hct or progressive myeloprolifera- tion, IFN- is recommended.1,11,16 References 1. Finazzi, G. and Barbui, T. (2007). How I treat patients with polycythemia ver a. Blood, 109, 5104 \200\22311. 2. Landolfi , R. et al. (2004). Effi cacy and safety of low dose aspirin in polycythemia ve ra. N Engl J Med, 350, 114 \200\22324. 3. Budde, U. and van Genderen, P.J. (1997). Acquired von Willebrand disease in patients wit h high platelet counts. SeminThromb Hemost, 23, 425 \200\22331. 4. Berk, P.D. et al. (1986). Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol, 23(2), 132 \200\22343. 5. Landolfi , R. and Di Gennaro, L. (2008). Prevention of thrombosis in polycythemia vera a nd essential thrombocythemia. Haematologica, 93, 331 \200\2235. 6. Finazzi, G. and Barbui, T, (2005). Risk-adapted therapy in essential thrombocythemia and polycythemia vera. Blood Rev, 19, 243 \200\22352. 7. Cortelazzo, S. et al. (1995). Hydroxyurea in the treatment of patients with essential thrombocythemia at high risk of thrombosis: a prospective randomized trial. N Engl J Med, 3 32, 1132 \200\2236. 8. Harrison, C.N. et al. (2005). Hydroxyurea compared with anagrelide in high-risk essentia l thrombocythemia. N Engl J Med, 353, 33 \200\22345. 9. Finazzi, G. et al. (2005). Acute leukemia in polycythaemia vera: an analysis of 1638 pat ients enrolled in a prospective observational study. Blood, 105, 2664 \200\22370. 10. Lengfelder, E. et al. (2000). Interferon alpha in the treatment of polycythemia vera. Ann Hematol, 79, 103 \200\2239. 11. Silver, R.T. (2006). Long-term eff ects of the treatment of polycytemia vera with recombinant interferon alpha. Cancer, 107, 451 \200\2238. 276 CHAPTER 7 Myeloproliferative neoplasms 12. Landolfi , R. et al. (2006). Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: pathogenetic mechanisms and prevention. Best Pract Res Clin Hematol, 19, 6 17 \200\22333. 13. Robinson, S. et al. (2005). The management and outcome of 18 pregnancies in women with polycythemia vera. Haematologica, 90, 1477 \200\22383. 14. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and managemen t of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 15. Passamonti, F. (2012). How I treat polycythemia vera. Blood; 120, 275 \200\22384. 16. V erstovsek, S. et al. (2010). Durable responses with the JAK1/JAK2 inhibitor, INCB018424, in patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or into lerant to hydroxyurea (HU) [abstract]. Blood (ASH Annual Meeting Abstracts), 116, 313. Further reading Barosi, G. et al. (2009). Response criteria for essential thrombocythemia a nd polycythemia vera: result of a European LeukemiaNet consensus conference. Blood, 113(20) , 4829 \200\22333. 277 MANAGEMENT OF PV 278 CHAPTER 7 Myeloproliferative neoplasms Secondary erythrocytosis See causes of 2 erythrocytosis in E Table 7.1, p.264. Eff ects of the i red cell mass \200 i peripheral vascular resistance. \200 d cardiac o utput. \200 d systemic O2 transportation resulting in, e.g. d cerebral blood fl ow and O2 and glucose delivery to the brain. Thromboembolic complications also occur. Thus \200\230compensatory \200\231 erythrocytosis is a pathological rather than physiological condition. Symptoms Non-specifi c and those of the underlying cause (particularly if cardiac or pulmon ary) may predominate. Pruritus, splenomegaly, or the presence of leucocytosis or thrombocyt osis suggest the alternative diagnosis of PV. Investigations As listed under PV, notably JAK2 mutation analysis, serum EPO, arte- rial O2 saturation, renal and hepatic function, urinalysis, renal ultrasound and, if necessary, ab dominal CT. Treatment The aim of therapy must be correction of the underlying cause where pos- sible an d reduction of the RCM. Venesection is the treatment of choice and if possible should be co ntinued until a target Hct is achieved. The indications for venesection and recommended tar get Hct vary with the underlying cause:1 \200 High O2 affi nity haemoglobins: Indications \200\224dizziness, dyspnoea or angina, thrombosis, comparable family member with thrombosis; target Hct <0.60 or if thrombosis or symptoms wit h Hct <0.60, target <0.52. Hypoxic pulmonary disease: Indications \200\224symptoms of hyperviscosity or Hct >0.56; target Hct 0.50 \200\2230.52. Cyanotic congenital heart disease: Indications \200\224 chest and abdominal pain, myalgia and weakness, fatigue, headache, blurred vision, amaurosis fugax, paraesthesiae, slow mentation and i vis cosity; target individualized; isovolaemic venesection for symptoms. Avoid Fe defi ciency w hich may compromise O2 delivery. \200 Post-renal transplant erythrocytosis: Indication \200\224failure to respond to ACE inhibitor or angiotensin II receptor antagonist; target Hct <0.45. In patients with cyanotic congenital heart disease, pulmonary disease or high O2 affi nity hemoglobin, the benefi t of venesection can be determined by symptomatic response or by usi ng the serum EPO level as a measure of tissue hypoxia. Myelosuppressive therapy is not indicated in any of these disorders. Reference 1. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and management of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 279 RELATIVE ERYTHROCYTOSIS Relative erythrocytosis Elevation of Hb and Hct with n or minimally i RBC mass and n or d p lasma volume defi nes RE. Apparent polycythaemia, spurious poly- cythaemia, pseudopolycytha emia, stress erythrocytosis and Gaisbock \200\231s syndrome (RE associated with hypertensio n and nephropathy) are syn- onymous terms for this disorder. However the existence of chron ic plasma contraction is contentious. Etiology Unclear. Some cases may represent extreme ends of n ranges for red cell and plasma volumes, but in most obesity, cigarette smoking, and hypertension are present singly or in combination. Haemoconcentration from dehydration or diuretic therapy should be excluded. Investigations \200 FBC generally shows only modest i Hct. Confi rm persistence with at least 2 measurements over a 3-month period. Serum EPO usually n; may be d. \200 JAK2-V617F mutation \210\222ve. \200 RCM studies n ow rarely performed as PV excluded by sEPO and JAK2 analysis, however can be useful here. Demonstrate n RCM and d plasma volume in 733%; most h ave high n RCM and low n plasma volume. Important to exclude renal disease and arterial hypoxaemia. \200 BM biopsy not usually ne cessary but normal when carried out. Management \200 Involves dealing with reversible associated features, i.e. weight reduction, cessation of smoking, control of i BP (without thiazide diuretic), reduction of alcohol intake, and reduction in stress (where possible). Correction of these factors may r esult in spontaneous improvement. Venesection is not standard management; however, it is suggested that patients with recent thrombosis or Hct levels chronically >0.54 should be considered f or venesection.1 Monitor untreated patients to exclude further i in Hct. Natural history and treatment \200 Not clear. Retrospective analysis appears to suggest a n i incidence of vaso-occlusive episodes that may relate to associated risk factors in the lifestyle of the patients rather than the i PCV. Low-dose aspirin (75mg/d) advisable for patients with overt thrombotic risks and no GI contraindication. No role for myelosuppressive therapy. \200 Many patients improve with the simple measures specifi ed. \200 Follow-up can be done in primary care. Reference 1. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and management of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 280 CHAPTER 7 Myeloproliferative neoplasms Idiopathic erythrocytosis Heterogeneous group with absolute erythrocytosis (i RCM) but no c lear cause for 1 or 2 erythrocytosis. Some patients formerly given this diagnosis have been shown to have JAK2 exon 12 mutations. \200 May be physiological variant: extreme \200\230high-normal \200\231 values. \200 5 \200\22310% showed defi nite features of PV a fter several years of follow-up. Others develop clear evidence of SE, e.g. sleep apnoea. \200 Long-term follow-up is requi red in these patients. \200 Venesection to a Hct <0.45 has been recommended because of an incidence of fatal thromboembolic and haemorrhagic events similar to PV.1 Myelosuppressive therapy is contraindicated. Reference 1. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and management of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 281 ESSENTIAL THROMBOCYTHAEMIA Essential thrombocythaemia ET (syn. 1 or idiopathic thrombocythaemia) is characterized by persis- tent thrombocytosis that is neither reactive (i.e. 2 to another condition) nor d ue to another myeloproliferative neoplasm or a myelodysplastic disorder. It is a diagnosis of exclusion and is biologically heterogeneous. Incidence True incidence unknown but probably up to 3 per 100,000 annually;1 slight excess in \231\200; median age at diagnosis 60 years; frequently occurs <40 years; very rare <20 years.