WHO Classification 1. CML – BCR-ABL 2. Chronic neutrophilic leukaemia 3. Chronic eosinophilic leukaemia 4. Chronic idiopathic myelofibrosis 5. PV 6. ET 7. Myeloproliferative disorders unclassified
Polycythaemia Classification § Raised Hb / Red cell mass § Should be measured in relation to surface area rather than ml/kg § Because of avascularity of adipose tissue in obese patients § Not raised = apparent polycythaemia § Raised = true polycythaemia § Primary polycthaemia = PV or congenital polycythaemia § Secondary polycythaemia § Eg. Increased epo § Idiopathic erythrocytosis § Exclusion criteria met but not positive criteria
Polycythaemia vera § 2-3/ 100 000 § Median age of onset is 55-60 years § M:F: 1:1
§ Expansion of total red cell mass +/- increased platelets, neutrophils
§ Pathophysiology § Red cells, platelets, neutrophils and a variable number of BB lymphocytes all from the malignant clone § Erythropoiesis independent of epo and epo levels are low § Thrombocytosis / Raised HCT and viscosity lead to thrombotic complications but platelets also clonal and often have abnormal function leading to bleeding. § 2 phases: § Initial proliferative phase § Increased red cell mass § ‘spent’ post-polycythaemic phase § Cytopenias, fibrosis, extramedullary haemopoiesis and hypersplenism
Clinical features Thrombotic complications (20-40% of deaths) § Presenting feature in 25% § Arterial (2/3) § Increased if pre-existing vascular disease / risk factors § Venous (1/3) § Mesenteric, splenic, hepatoportal thromboses are not uncommon presentations § Microvascular (eg. Erythromelalgia) § Sluggish cerebral blood flow (headaches, drowsiness, insomnia, amnesia, tinnitus, vertigo, chorea, visual disturbances)
Haemorrhagic complications (5-10% deaths)
Skin § Pruritius (25%) § Characteristically aquagenic - usually relieved by controlling PCV § Exacerbated by hyperhistaminaemia and iron deficiency § Plethora, dilated conjunctival vessels, brown discolouration of skin § Sweets syndrome (erythematous popular rash with fever – associated with a variety of haematological malignancies and rhematological conditions)
Splenomegaly (30-50%) § May be associated with increased risk of progression to MF
Hypertension
Hyperuricaemia in 5%
Myelofibrosis / Post Polycythaemic Myeloid Metaplasia (PPMM) § <5% reticulin fibrosis at diagnosis – 50% at 20 years § Extramedullary haemopoiesis – hepatosplenomegaly § Median survival 3 years § 25-50% transform to AML
Leukaemic transformation (AML) § Rare in patients treated only with venesection (1-3%) § Risk increases with radioactive phosphorus, chlorambucil, irradiation (time to progression with these treatments is 5-8 years) § Treated with standard induction but responds poorly
Investigations § HCT >0.52 males, >0.48 females for >2 months should have a red cell mass § HCT >0.6 males, >0.56 females can be assumed to have an absolute erythrocytosis
Jak-2 mutations – probably first line investigation now § V617F mutation (2005 NEJM – Swiss group) § 95% in PV § 50% in IMF and ET § 20% in atypical CML and MPDu § 2-3% in HES, CMML and SM
§ If negative: § Exon 12 mutations 3% in PV (Green et al., 2007 – NEJM - Cambridge) § Recent case series in BJH – 114 patients meeting Polycythaemia Vera Study Group Criteria § 110 had V617F mutations § 3 had exon 12 mutations § 1 case had V617F detectable in the erythroid independent colonies which had been at too low a level to be detected by allele specific PCR § However probably possible to have PV without currently identified mutations in JAK2
§ Jak kinases are composed of 4 domains 1. N-terminal FERM domain § Interacts with cytokine receptors 2. SH2 domain 3. Pseudokinase (JH2) domain § Involved in inhibition of kinase activity § Location of V617F mutation § Gain of function § Mutant Jak-2 binds to cytoplasmic domain of intracellular and cell surface epo receptor , which promotes ligand independent signalling 4. C-terminal kinase (JH1) domain
Modified diagnostic criteria § Jak 2 – positive; both criteria need to be present § HCT >0.52 men, >0.48 women or raised red cell mass (>25% predicted) § Mutation in Jak 2 § Jak 2 – negative; A1 + A2 + A3 + either 1 other A or 2 B’s § A1: HCT >0.6 men, >0.56 women or raised red cell mass § A2: Absence of Jak 2 mutation § A3: No cause of secondary erythrocytosis § A4: palpable splenomegaly § A5: acquired genetic abnormality (excluding Bcr-Abl) § B1: thrombocytosis > 450 § B2: neutrophilia >10 in non-smokers (>12.5 in smokers) § B3: radiological evidence of splenomegaly § B4: endogenous erythroid colonies or low epo
§ Stage 1 § History and examination § Including pulse oximetry § Misleading in § CO poisoning § High affinity Hb/ low 2,3-biphosphoglycerate levels § Sleep apnoea § Sa02 <92% indicates a causal relationship with an absolute erythrocytosis § FBC and film § Neutrophilia in 1/3 § In smokers should consider ULN 12.5 § Thrombocytosis in ½ § Jak 2 mutation § Ferritin and B12 § Low ferritin more common in PV than secondary causes § Elevated B12 due to trancobalamin release from increased granulocytic mass § Renal, bone and liver function
§ Stage 2 – if Jak 2 negative and no obvious secondary cause § Red cell mass § Arterial oxygen saturation § Abdominal USS § Excludes underlying renal/ hepatic pathology § Splenomegaly § Epo § Usually low in PV, even following venesection § Bone marrow § Baseline to assess disease progression § Chromosoamal abnormalility establishes clonality § Karyotype § Culture studies of erythroid burst-forming units (BFU-e) § Endogenous erythroid colonies § Not standardised and expensive
§ Stage 3 – erythrocytosis but do not fulfil criteria § Arterial oxygen dissociation curve § Sleep study § Lung function studies § Gene mutations (VHL, EPOR)
§ Morphology § Polycythaemic stage § Blood film § Packed film § Thrombocytosis (50%), neutrophilia § Basophilia § Iron deficiency § Monocytes are not increased § Hypercellular bone marrow – panmyelosis § Erythroid hyperplasia § Granulocytic and megakaryocytic (large with increased lobulation but increased micromegakaryocytes may be seen on trephine) § Increased reticulin § Hepatosplenomegaly, if present due to congestion § Post-polycythaemic / fibrotic stage § Red cell mass normalises, then decreases § Progressive fibrosis and leucoerythroblastic film § Reticulin and collagen fibrosis § Hepatosplenomagely, if present cue to extramedullary haemopoiesis § Cytogenetics § Only in10-20% § +8, +9, del(20q), del(13q) and del(1p)
Treatment Venesection § Target haematocrit <0.45 for PV § Target haematocrit <0.54 if secondary polycythaemia § Often result in iron deficiency and thrombocytosis § Polycythaemia vera study group (PVSG) have found that initial aggressive phlebotomywithout myelosuppression may be associated with increased risk of thrombosis especially in the elderly § Should consider adding hydroxyurea if over 60 or thrombotic risk factors § HCT should be controlled for 3 months before elective surgery
Aspirin § ECLAP study established benefit – 60% reduction (7.9% to 3.2% at 3 years) in thrombotic events with no increase in major bleeding § Consider clopidogrel if intolerant § CURE study showed benefit of aspirin and clopidogrel to reduce cardiovascular events but at the expense of more bleeding, therefore role unclear in MPD
Cytoreductive therapy § Recommended for § Thrombocytosis/ poor tolerance of venesection § Symptomatic splenomegaly (except anagrelide) § B symtpoms § Hydroxyurea § 1st line >40 years § Non-alkylator § Reduces haematocrit and platelets § Side effects = GI disturbance, leg ulcers, photosensitivity § Potentially leukaemogenic but not found to be in ECLAP study § Interferon alpha (SC 3-5,000,0000 U x3/week) § 1st line < 40 years § Suppresses proliferation of pluripotent and lineage committed haematopoietic progenitors § Reduces platelets and haematocrit § Formidable side effects (anorexia, nausea, flu like, depression) § Useful in young patients reluctant to take cytotoxic agents, in pregnancy and in intractable pruritis § Anagrelide § Inhibits megakaryocyte differentiation § Can be combined with hydroxyurea to allow lower doses of both § 10% completely refractory § Side effects = headaches, palpitations, fluid retention § PT1 trial in ET showed worse than aspirin and HU – increased thrombosis and progression to MF § Busulphan § Alkylating agent § Convenient as can be administered intermittently § Better than radioactive phosphorus § Should be reserved for the elderly § Probably increases risk of leukaemia § Chlorambucil § High rate of acute leukaemia - NOT recommended § Pipobroman § Used extensively in Europe – little evidence of increased AML § Radioactive phosphorus § Good disease control § Intermittent treatment and therefore less follow up § Clearly increases leukaemic transformation
Address other risk factors § Smoking, BP etc § No role for thombophilia screening
Pruritus § Antihistamines, Cimetidine § PUVA, Iron replacement § IFN alpha
Prognosis § Untreated median survival 18 months § Treated – survival 10-18 years for patients age <40
Pregnancy § High risk of complication if § Previous venous/ arterial thrombosis § Previous haemorrhage attributed to PV § Previous pregnancy complication that mey be attributable to PV § 3 or more first trimester or 1 or more 3rd trimester pregnancy losses, birthweight <5th centile for gestation § IUD or still birth (no other obvious cause and placental dysfunction and growth restricted fetus) § Ante or post partum haemorrhage requiring transfusion § Severe pre-eclampsia (requiring delivery <37 weeks) § Plt >1000
§ Treatment § Venesect to within normal range for pregnancy <36% § Aspirin is safe (CLASP study) § Consider LMWH if high risk and for all in puerperium § Previous venous thrombosis of fetal mortality § 40mg enoxaparin od, increased to bd at 16-20 weeks, reduced to od 3 days post partum for 6 weeks § Previous arterial thrombosis § 40mg bd throughout pregnancy § If evidence of recurrence, consider increasing after 14 weeks § Treat iron deficiency § IFN if cytoreduction needed (not safe for breast feeding) § Regular growth scans including Doppler for placenctal insufficiency § HU and anagrelide should be withdrawn 3-6 months before conception
Primary polycythaemia § Primary and familial congenital polycythaemia § Rare § Erythropoiesis intrinsically overactive § AD § Isolated erythropoiesis § Not associated with evolution to leukaemia or MF § Mutations in the gene encoding the epo receptor have been described § Increased sensitivity to epo
Secondary polycythaemia Hypoxia § Chronic lung disease § Associated with cor pulmonale and poor prognosis § Referred to respiratory for consideration of LTOT § Suggest venesect if symptomatic and haematocrit > 0.56, target of 0.50-0.52 § Limited evidence of beneficial effect of ACE-I or angiotensin receptor antagonists § High altitude § Some decompensate and develop chronic mountain sickness (Monge’s disease) – PCV > 0.75 § ACE-I may reduce haematocrit and proteinuria § Congenital cyanotic heart disease § PCV > 0.65 § Surgical correction if possible § Like chronic lung disease, increase in oxygen carrying capacity but also increased viscosity. Unlike lung disease patients are young and can tolerate higher PCVs § Decision to venesect should be based on symptoms
High affinity Hb § Release less oxygen for a given oxygen partial pressure § Result in tissue hypoxia § Epo-driven polycythaemia with a resultant normalization in epo § Left shift in the oxygen dissociation curve § Diagnosis by DNA or mass spectrometry § Dominantly inherited § Most due to mutations in B-globin gene § Most asymptomatic § Plethoric § Excessive muscle fatigue after exercise § No increase in cardiovascular morbidity or mortality § No adverse effect in pregnancy § Indications for venesection § Symptoms likely caused by HCT eg. Dizzy, dyspnoes § 1 or more thrombotic episodes § Asymptomatic but complications in family members § Target <0.6 § Red cell metabolic defects § Low 2,3-BPG § Low P50 § AR
Methaemoglobinaemia § Increased affinity for Hb § Left shifted oxygen dissociation § Can result from exposure to strong oxidants § Dapsone, paraquat benzocaine § Can be life threatening § Rarely sufficiently long-lived to give rise to polycythaemia § Can be inherited – secondary erythrocytosis as per high affinity Hbs
Heavy smoking § Mild polycythaemia in the absence of hypoxic lung disease § Raised carboxy-Hb § CO levels - <2% in non-smokers, 3-20% in smokers
Sleep apnoea § Epworth score >10/24 § BMI >30
Absence of hypoxia Inherited – Chuvash polycythaemia (AR) § Russian mid-Volga river region, but also some in Asia and with West European ancestry § Mutation in the von-Hippel Lindau gene (increased epo but no mutations of epo receptor)
Abnormal epo secretion § Renal tumours § PCKD/ Renal cysts / Hydronephrosis / Renal artery stenosis § Post renal transplant § 10-15% develop erythrocytosis 8-24 months after transplant § Avoid dehydration § Treat with ACE-I or angiotensin II inhibitor § Venesect to a HCT <0.45 § Hepatocellular carcinoma § Cerebellar tumours § Fibroids
Endocrine disorders § Overproduction of androgens which increase epo levels
Idiopathic erythrocytosis § Raised red cell mass, but don’t fill criteria for PV and no other cause can be found § Venesect to <0.45 if HCT >0.54 § Venesect to <0.45 if HCT <0.54 and increased risk of thrombosis § Cytoreductive therapy contraindicated
Apparent polycythaemia § Raised haematocrit but normal red cell mass § Smoking, hypertension, obesity, alcohol and diuretics § Consider venesection § Recent thrombosis or additional RFs for thrombosis § HCT >0.54 § Aim <0.45
Relative erythrocytosis § RCM in normal ranges, but plasma volume low § True pathological states of dehydration
§ Epidemiology § 1.5-2/ 100 000 § Median age is 50-55 § Second peak at 30 years, where women are more commonly affected § Clinical Features § 50% are asymptomatic § Thromobotic complications (15-20% at presentation) § Risk factors § Age > 60 years § Previous thrombosis § Plt > 1000 § Hyperlipidaemia § Hypertension § Smoking § Haemorrhagic complications § Platelet function abnormalities don’t correlate with bleeding risk § More common if plt > 1000 § May be related to acquired vWD (reduced HMW multimers) § Splenomegaly and hyposplenism § 20-50% at presentation § Progressive enlargement raises possibility of MF § Occasionally splenic atrophy due to infarcts § Transformation to PV or MF § MF (<10%) >PV (1-2%) § May represent correction of iron deficiency § Leukaemic transformation § Increased risk with cytogenetic abnormalities or alkylating agents
Investigation § Plt >600 for at least 2 months § No cause for reactive thrombocytosis with normal ESR/ CRP § No evidence of PV / CML / MF / MDS § No evidence of iron deficiency § Morphology § Platelet anisocytosis (some giant and hypogranular) § Platelet aggregates, occasionally bare megkaryocyte nuclei § Mild elevation in wcc § Occasionally signs of hyposplenism due to splenic infarction § Bone marrow § Proliferation of large to giant megakaryocytes § Loose clusters § Megas have abundant mature cytoplasm, deeply and hyperlobulated nuclei § The bizarre, highly atypical features of MF are not a feature § Fibrosis if present, suggests MF § Cytogenetics § 50% JAK 2 positive § Found only in 5-10% § +8, +9, del(13q22) Treatment § High risk § Age > 60 § Plt > 1500 § Prior history of thrombosis § Thrombotic risk factors eg. Diabetes, hypertension § Target of treatment – platelet count <400 (unless requiring high doses in which case <600 is acceptable) § Hydroxyurea and aspirin (age >40) § Starting dose 15-20 mg/kg/day § If plt count very high consider delaying aspirin if risk of acquired vWD § PT-1 trial (Harrision et al NEJM 2006) § Hydroxyurea and aspirin versus anagrelide and aspirin § Anagrelide arm was associated with more arterial events, major haemorrhage and myelofibrotic transformation, but less venous thrombosis § Interferon alpha - as for PV (possibly first line if age <40) § Anegralide § Need to check ECG / Echo prior to commencing treatment § Busulphan, radioactive phosphorus, alkylating agents § Splenectomy, results in a dramatic increase in platelets § Intermediate risk § 40-60 years and no risk factors § Not clear whether it is beneficial to lower platelet count § Most treat with aspirin alone § Low risk § < 40 years and no risk factors § Aspirin or alternative anti-platelet Prognosis § In high risk patients, HU reduces risk of thrombosis from 10.7 to 1.6 per 100 patient years
Pregnancy § Fertility is probably reduced § First trimester miscarriage in 30% § Placental microinfarcts and insufficiency § Reported increased incidence of APLa may contribute § Live birth in 60% § Most recommend aspirin § If high risk, interferon +/- LMWH prophylaxis § Platelet count may rise dramatically post partum § Can be controlled with HU or anagrelide, but this excludes breast feeding
Chronic megakaryocytic leukaemia (Idiopathic myelofibrosis) § Pathophysiology § Clonal proliferation of multiple cell lineages with progressive marrow fibrosis § Fibrosis is secondary to cytokine release from abnormal clonal cells which stimulate fibroblast proliferation and fibrosis § Epidemiology § 0.5-1.5/ 100 000 § Median age 50-60 § M=F § Clinical features § Up to 1/3 discovered incidentally § Splenomegaly § Almost all at presentation § May have splenic discomfort and splenic infarcts § Massive splenomegaly may result in portal hypertension § Extramedullary haemopoiesis § Most commonly spleen and liver § Rarely other sites, eg. CNS, lymph nodes § Systemic symptoms § B- symptoms § Associated with worse prognosis § Anaemia § Reduced erythropoiesis § Hypersplenism § Bleeding § Iron/ folate deficiency § Aquired HbH is a rare complication § Platelet abnormalities § Often raised at presentation but progressively fall § Dysmegakaryopoiesis adds to haemorrhagic risk § White cells § Leucocytosis is common followed by leucopenia § Transformation to AML in 5-10% and is rapidly fatal
Investigation § A1 + A2 + B1 + 1 other B or A1 + A2 + 4B’s (if not B1) § A1 = diffuse marrow fibrosis § A2 = No Philadelphia chromosome § B1 = splenomegaly § B2 = anisopoikilocytosis with tear drop poikilocytes § B3 = circulating immature myeloid cells § B4 = circulating erythroblasts § B5 = clustered and anomalous megakarycocytes § B6 = myeloid metaplasia
§ Bone marrow § Silver – reticulin fibres § Collagen fibres – trichrome stain § Grade I – IV § <10% - osteosclerois § Pre-fibrotic stage § 20-30% detected at this stage § Diffusely hypercellular § Diagnosis largely based on megakaryocyte abnormalities in the trephine (very variable megakaryocytes ranging from small hypolobated forms to hyperchromatic hyperlobated cells, which may be clustered) § Fibrotic stage § Becomes hypocellular replaced with connective tissue or flat § Dilated sinuses and inttrasinusoidal haemopoiesis
§ Cytogenetics § No specific defect § Occur in about 60% § Del(13q), del(20q), partial trisomy 1q, +8, +9
Treatment § Curative treatment is SCT § Most treatment is supportive § > 45 years, long-term survival 10-20% § Danazol and epo for anaemia, but most become transfusion dependant § HU may be useful for thrombocytosis, B-symptoms, organomegaly § Splenomegaly § Pain § B-symptoms § Portal hypertension § Transfusion dependant anaemia § Problems § Bleeding, infection, thrombosis § Rebound thrombocytosis § Progressive hepatomegaly § Splenic irradiation § Thalidomide § Increases thrombotic risk § Poorly tolerated at standard dose § May be used at lower dose combined with steroids § Bisphosphonates § Bone pain § JAK2 inhibitors § CEP70 tried at MD Anderson with little activity § INCYTE more promising – reduced splenomegaly, fatigue and pruritus
Prognosis § Median survival is 3-5 years § Adverse prognostic features § Elevation in the circulating CD34 count / marked granulocytic immaturity § Age >70 § Hb <10 § Plt <100 § Abnormal karyotype
Pathophysiology § C kit point mutation (D816V) = tyrosine kinase receptor for stem cell factor § Ligand independent phosphorylation of c-kit and clonal expansion of mast cells
Classification § Cutaneous mastocytosis § Urticaria pigmentosa § Mastocytoma of the skin § Systemic mastocytosis § Indolent § Aggressive § SM with associated haematological non-mast cell disorder § Mast cell leukaemia § Mast cell sarcoma
Clinical Features § Cutaneous § Urticaria pigmentosa, pruritus, flushing § Darier’s sign § Systemic (due to mast cell mediator release) § Fever, fatigue and weight loss § Angiodema, anaphylaxis § Abdo pain, diarrhoea, nausea and vomiting, gastritis and peptic ulceration, malabsorption § Osteoporosis § Cytopenia secondary to bone marrow involvement § Organ infiltration and failure in aggressive disease
Investigations § Diagnostic criteria (1 major and 1 minor or 3 minor) § Major § Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous tissues § Minor § > 25% of mast cells are atypical or spindle shaped § D816V mutation § Mast cells expressing CD25 or CD2 § Tryptase > 20ng/mL § Mast cells easier to identify with toluidine blue stain § USS abdomen § Bone densitometry § OGD (Gastric ulcers secondary to histamine induced acid release)
Treatment § Avoid factors that trigger mediator release § Eg general anaesthesia, contrast, insect stings, morphine § Treatment of acute mediator release § Epipen § Treatment of chronic mediator release § H1 and H2 blockers § Topical corticosteroids, sodium chromoglycate § PUVA § PPI § Bisphosphonates and calcium supplements § IFN-alpha +/- steroids § Reduction of mast cell burden § Novel agents/ tyrosine kinase inhibitors § Imatinib inhibits wild type kit but not theD816V mutation
Prognosis § Paediatric – 50% resolve
Clonal hypereosinophilic syndromes § Eosinophilia § 0.5-1.5 = mild § 1.5-5 = moderate § >5 = severe
Pathophysiology § Reactive § Reflects release of IL3, IL5 and GM-CSF § Infections § Parasitic – tissue invasive parasitosis § Stool, duodenal aspirates and sputum § Neoplasia § HD, NHL, ALL § Vasculitides § PAN, Churg-Strauss § Connective tissue disorders § RA, SLE § Allergic and inflammatory disorders § Asthma, ABPA (aspergillus fumigatus), eczema, IBD § Drug reaction § Hypersensitivity § Immunodeficiencies § Wiskott-aldrich
§ Idiopathic - Hypereosinophilic syndrome § Unexplained eosinophilia (>1.5)for more than 6 months with end-organ damage, but no increase in blasts and no evidence of clonality § M>>F § <50% 10 year survival
§ Clonal § Chronic eosinophilic leukaemia § Eosinophils >1.5 with evidence of clonality or increased blasts (but <20%) in blood or bone marrow § Eg. FIP1L1 PDGFR-alpha fusion generates an active TK § Responds to imatinib § M>F § Atypical CML (PDGFR-beta) § Also responds to gleevec § 8p11 myeloproliferative syndrome (FGFR1) § Eosinophilia and T-cell lymphoblastic lymphoma § May respond to PKC-412 § CML § AML Eo § ALL
Clinical Features § Tissue damage secondary to eosinophil degranulation and mediator release § Eg. Eosinophil cationic protein, major basic protein § Constitutional symptoms § Pruritius, angiodema, diarrhoea cough § Cardiac damage is main cause of mortality § Endomyocardial fibrosis, pericarditis, myocarditis, intramural thrombus formation and dilated cardiomyopathy § Troponin level correlates with presence of cardiomyopathy § Neurological § Mononeuritis multiplex, paraparesis, encephalopathy, dementia § Pulmonary damage § Infiltrates, fibrosis, pleural disease § GI damage § Diarrhoea, gastritis, colitis, hepatitis, Budd-chiari
Investigations § Diagnostic criteria § Exclude reactive eosinophilia § Exclude underlying neoplasm with reactive eosinophilia § Exclude neoplasm where eosinophils are part of the neoplastic clone § Exclude abberant T-cell population with abnormal cytokine release § If all of the above and no clonality = HES § If all of the above, and clonality or blasts <2% in PB or 5-19% in BM = CEL
§ Echocardiogram annually as major cause of morbidity
Morphology § Usually mature eosinophilia § Sparse granulation § Cytoplasmic vacuolation § Hyper, hyposegmentation § Not specific for clonal disease § Bone marrow § Charcot-leyden crystals § Fibrosis secondary to eosinophil degranulation § Cytogenetics
Cytogenetics § TCR rearrangements § FIP1L1-PDGFRa § Bcr-Abl § PDGFRb - D816V (and tryptase) § FGFR1 § +8 or i(17q) or 8p11 abnormalities
Treatment § Imatinib if PDGFRa/b rearrangements § HES § Prednisolone § 70% response rate § Relapses off therapy are usual § HU, IFN-alpha § Alemtuzumab has shown promising results § Cladrabine, Cyclosporine
Prognosis § Adverse risk factors § Lack of response to steroids § Markedly elevated eosinophil count § Normal IgE levels § Splenomegaly § Dysplastic features § Male sex § Blasts § Probably markers of clonal disease
§ Sustained neutrophilia with hypercellular bone marrow and hepatosplenomegaly § Diagnosis of exclusion § <100 cases reported § Diagnostic criteria § PB Leucocytosis >25 x109/L § Neutrophils and bands >80% § Immature granulocytes <10% § Myeloblasts <1% § Hypercellular marrow § Neutrophil granulocytes increased § Myeloblasts <5% § Maturation pattern normal § Hepatosplenomegaly § Exclude reactive neutrophilia § Including underlying neoplasm § No Ph or Bcr-Abl § Exclude other MPD § Exclude MDS § Clinical Features § Splenomegaly +/- hepatomegaly § Bleeding from mucocutaneous surfaces in 25-30% § Gout and pruritus § Morphology § Neutrophilia >25 § Immature granulocytes usually account for <5% § Myeloblasts almost never observed § Neutrophils may appear toxic, but are not dysplastic § Bone marrow § Hypercellular, M:E: 20:1 or greater § Fibrosis is uncommon § Often reported with MM, therefore need to exclude plasma cell dyscrasia § If MM present, need to confirm clonality of neutrophils before making a diagnosis of CNL § Cytogenetics § 90% normal § +8, +9, del(20q), del(11q) § Can get a variant Bcr-Abl, P230 – should be considered CML § Prognosis § 6 months – 20 years § Can get progressive marrow failure, MDS, AML
Myeloproliferative disease unclassifiable § Clinical, laboratory and morphological features of a MPD, but fail to meet the diagnostic criteria of any of the above
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