243 Management of PV In younger patients (<40) who have a low risk of cerebrovascular or car- d iovascular events the use of venesection in combination with low dose aspirin and non-leuka emogenic therapy such as anagrelide or IFN- should be considered to reduce the risk of le ukemia. Venesection: to 5 blood volume to normal as rapidly as possible and prevent complic ations (target Hct <0.45). Removal of RBCs by venesection is the quickest way of reducing r ed cell mass. 450mL blood ( isovolaemic replacement with 0.9% saline) removed safely from younger adults every 2 \200\2233 days (5 volume or frequency to twice weekly in older pati ents). If Hct very high (>0.60) venesection may be technically difficult due to extreme vis cosity. Maintenance therapy: venesection alone can be used to maintain the Hct at 0.42 \200\2230.45 . Individual requirements are variable (e.g. 2 procedures per year to monthly venesection). However, early studies showed 4 risk of thrombosis in first 3 years after treatment with v enesection alone thus additional myelosuppressive treatment is required in most patients. Hydroxyurea: an antimetabolite (ribonucleotide reductase inhibitor), is most commonly used therapy. Onset of myelosuppression with hydroxyurea is rapid, but overdosage quickly correc ted by temporary withdrawal. Once Hct 5, a daily dosage of 10 \200\22320mg/kg/d normally su fficient as maintenance therapy. Lower incidence of thrombosis by ensuring better Hct (<0.4 5) and platelet counts (<400 109/L). Lower incidence of leukemia than 32P/alkylator ther apy but still concerns. Radioactive phosphorus (32P) and busulfan: long established treatme nts for PV. Produce 5 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). Ei ther agent may be repeated after 3 \200\2236 months if further myelosuppression is required . Both individually 5 thrombosis and myelofibrosis but markedly 4 the risk of AML. The use of 32P and either busulfan or hydroxyurea in an individual is associated with a very high r isk of AML. Neither is recommended for patients \211 65 years who should 07-MPD.qxd 10.12.2003 04.16 PM Page 244 receive hydroxyurea. However, in patients >65 in whom compliance or regular monitoring of h ydroxyurea dose may be a problem busulfan or 32P can be considered as both offer intermitte nt therapy rather than long term maintenance. Anagrelide: oral imidazoquinazoline with anti-cyclic AMP phosphodiesterase activity and pro found effect on megakaryocyte maturation resulting in reduced platelet production. No evide nce of mutagenic activity. Useful for control of thrombocytosis in PV but no effect on sple nomegaly or other lineages. Side effects: headache (50%), forceful heartbeat, fluid retenti on, dizziness, arrhythmia (<10%) and CCF (2%). Use with caution in patients with known or s uspected cardiac disease. Aspirin: 75mg daily as antiplatelet therapy is common practice in myeloproliferative condit ions. Higher doses are associated with hemorrhage. Large trial of low dose aspirin (40mg/d) in progress. Meantime reasonable to use 40mg/d aspirin in patients with history of MI thro mbotic CVA, erythromelalgia and other microvascular or neurological and ocular disturbances . Avoid in those with a history of hemorrhage particularly in the GI tract. 244 Interferon-a therapy at a dose of 3 \200\2235MU three times weekly can control erythrocytos is and 5 leucocytosis, thrombocytosis and splenomegaly in 60 \200\22375% of patients over 6 \200\22312 months. A useful observation is that it can diminish the severity of pruritus i n 80% of patients. Tolerance is a problem but may be reduced by the use of pegylated-interf eron. Supportive intake and avoid dehydration. Give allopurinol to minimize complications of hype ruricaemia. Acute gout is managed by standard therapies. Pruritus is a troublesome complica tion for some patients, unfortunately there is no satisfactory treatment. Sometimes abates when excess myeloproliferation controlled and Hct reduced but may persist despite adequate control of the Hct. Worth trying antihistamines, H2-antagonists or interferon-a. Surgical p rocedures relatively contraindicated in active PV: defer until Hct and platelets normalized for \211 2 months due to risk of thrombotic and haemorrhagic complications; if emergency surgery necessary perform venesection and cytapheresis. treatment: maintain adequate fluid 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 hydroxyurea the FBC should be checked every 8 \200\22312 weeks. Treatment of advanced phase PV Symptomatic management should be prioritized and the patient often requires blood product support. Splenectomy is often considered due to discomfort, r ecurrent infarction or hypersplenism but is often followed by massive hepatomegaly due to e xtramedullary haematopoiesis. 07-MPD.qxd 10.12.2003 04.16 PM Page 245 Myeloproliferative disorders 245 07-MPD.qxd 10.12.2003 04.16 PM Page 246 Secondary erythrocytosis Causes of secondary erythrocytosis are listed in the table on page 241. Effects of the increased red cell mass 2 4 peripheral vascular resistance. 2 5 cardiac outp ut. 2 5 systemic O2 transportation resulting in e.g. 5 cerebral blood flow and oxygen and glucose delivery to the brain. 2 Thromboembolic complications also occur. Thus \200\230compensatory \200\231 ery- throcytosis is a pathological rather than physiological condition. Symptoms and signs are non-specific and those of the underlying cause (particularly if card iac or pulmonary) may predominate. Pruritus, splenomegaly or the presence of leucocytosis o r thrombocytosis suggest the alternative diagnosis of PV. 246 Investigation as listed under PV, notably RCM and plasma volume, arterial oxygen saturation , renal and hepatic function, urinalysis, serum erythro- poietin, renal ultrasound and if n ecessary abdominal CT. The aim of therapy must be correction of the underlying cause where pos- sible and reductio n of the red cell mass. Venesection is the treatment of choice and if possible should be co ntinued until a target Hct of <0.45 is achieved. In patients with cyanotic congenital heart disease, pulmonary disease or high O2-affinity hemoglobin, the extent of venesection can b e determined by symptomatic response or by using the serum Epo level as a measure of tissue hypoxia. Induction of iron deficiency by chronic vene- section assists control of erythroc ytosis. Myelosuppressive therapy is not indicated. 07-MPD.qxd 10.12.2003 04.16 PM Page 247 Myeloproliferative disorders 247 07-MPD.qxd 10.12.2003 04.16 PM Page 248 Relative erythrocytosis (RE) Elevation of Hb and Hct with normal or minimally 4 RBC mass an d normal or 5 plasma volume defines RE. Apparent/spurious polycythaemia, pseudopolycythaemi a, stress erythrocytosis and Gaisbock \200\231s syndrome are synonymous terms for this diso rder. Etiology Unclear. Some cases may represent extreme ends of normal ranges for red cell and p lasma volumes, but in most obesity, cigarette smoking and hypertension are present singly o r in combination. Haemoconcentration from dehydration or diuretic therapy should be exclude d. Investigation 2 FBC generally shows only modest 4 Hct. 2 Further investigations should be u ndertaken as appropriate for persis- tent erythrocytosis but, by definition, fail to reveal any other abnor- mality. 248 2 RCM studies demonstrates normal RCM and 5 plasma volume in 33%; most have high normal RCM and low normal plasma volume. 2 Important to exclude renal disease and arterial hypoxaemia. 2 Bone marrow biopsy is not u sually necessary but is normal when carried out. Management 2 Involves dealing with reversible associated features, i.e. weight reduc- tion, cessation of smoking, control of 4 BP and reduction in stress (where possible). Correction of these factors will result in sponta- neous improvement. 2 Venesection is not standard management; however, it is suggested that patients with Hct l evels chronically >0.54 should be considered for venesection. Natural history and treatment 2 Not clear. Retrospective analysis appears to suggest an 4 i ncidence of vaso-occlusive episodes that may relate to associated risk factors in the lifestyle of the patients under observation (rather than the 4 PCV). 2 Low dose aspirin (75mg/d) advisable f or patients with overt throm- botic risks and no GI contraindication. 2 No role for myelosuppressive therapy. 2 Many pati ents improve with the simple measures specified. In 33% the Hct returns to the normal rang e. In a further 33% the Hct oscil- lates between minimal elevation and the normal range. In the remaining 33% the Hct remains elevated and these patients should receive long term fol low-up. In a minority absolute erythrocytosis may develop. 07-MPD.qxd 10.12.2003 04.16 PM Page 249 Myeloproliferative disorders Idiopathic erythrocytosis (IE) Heterogeneous group with absolute erythrocytosis (4 RCM) but no clear cause of primary or secondary erythrocytosis. 2 May be physiological variant. 2 5 \200\22310% show definite features of PV after several years follow up. 2 Others develop c lear evidence of SE, e.g. sleep apnoea. 2 Long term follow-up is required in these patients . 249 Pearson, T.C. (1991) Apparent polycythaemia. Blood Rev, 5, 205 \200\223213. 07-MPD.qxd 10.12.2003 04.16 PM Page 250 Essential (1 ) thrombocythaemia (ET) ET (syn. primary or idiopathic thrombocythaemia) is characterized by per- sistent thrombocy tosis that is neither reactive (i.e. secondary to another condition; pXXX) nor due to anoth er myeloproliferative or myelodys- plastic disorder. It is a diagnosis of exclusion and may be biologically het- erogeneous. Incidence True incidence unknown; slight excess in 3; median age at diagnosis 60 years; fre quently occurs <40 years; very rare <20 years. Pathogenesis Etiology unknown. No association with radiation, drugs, chemicals or viral inf ection. Not all cases are clonal. Clonal and non-clonal cases may have different natural hi stories: thrombosis is less common in polyclonal ET as is the risk of leukaemic transformat ion. Platelets in ET are often functionally abnormal showing impaired aggregation in vitro. High platelet counts (>1000 109/L) are associated with an acquired von Willebrand syndr ome; reduction in the platelet count corrects the abnormality and reduces haemorrhagic epis odes. 250 Clinical features 2 Diagnosis often follows routine FBC; up to 30% patients asymptomatic. 2 Presentation may be due to \200\230vasomotor \200\231, thrombotic and/or haemor- rhagic symptoms. 2 Vasomotor symptoms occur in 40%: headache, light-headedness, syncope, atypical chest pain, visual upset, paraesthesiae, livedo reticu- laris and erythro melalgia (erythema and burning discomfort in hands or feet due to digital microvascular occ lusion). 2 Haemorrhagic symptoms occur in 25% (major <5%): easy bruising, mucosal or GI bleeding or unexplained or prolonged bleeding after trauma or surgery. 2 Thrombosis occurs in 20% (major <10%): arterial > venous, e.g. MI, CVA. 2 Splenomegaly i s found in <40% (less common and less marked than in other myeloproliferative disorders). 2 Splenic atrophy may occur from repeated microvascular infarction. 2 Recurrent abortions a nd fetal growth retardation due to multiple pla- cental infarctions may occur in young women with ET. Investigation and diagnosis 2 FBC \200\223 Platelets persistently >600 109/L (may be as high as 5000 109/L). \200\223 Hb usually normal; may be 5 with 5 MCV due to chronic blood loss. \200\223 WBC usually no rmal; raised platelet distribution width (PDW). \200\223 Mean platelet volume (MPV) usuall y normal. \200\223 Automated FBC may give erroneous data in severe cases as giant platelets may be counted as RBCs. 2 Blood movie \200\223 Thrombocytosis, variable shapes and sizes (platelet anisocytosis), giant platelet s and platelet clumps; megakaryocyte fragments; basophilia may be present; variable degree of RBC abnormality: 07-MPD.qxd 10.12.2003 04.16 PM Page 251 Myeloproliferative disorders may be hypochromic and microcytic; may be changes of hypos- plenism (p44). 2 Bone marrow aspirate: not reliable for diagnosis; may show 4 platelet clumps, atypical me gakaryocytes including micromegakaryocytes and other maturation abnormalities. 2 Bone marrow trephine biopsy: cellularity usually 4; megakaryocytes 4, with clustering, nu clear pleomorphism and atypical nuclear ploidy. Other elements may show abnormal distributi on and maturation abnormalities. Reticulin normal or 4 (25%); no fibrosis. 2 Cytogenetics: abnormal in 5%; no recognized diagnostic abnormalities; occasionally 20q \200\223 or 21q \200\223. 2 Uric acid: 4 in 25%. 2 Pseudohyperkalaemia: in 25%. 2 Acute phase proteins: CRP and fibri nogen, and ESR usually normal. 2 Bleeding time: usually normal (4 in 20%) \200\224rarely n ecessary; platelet 251 aggregation studies not clinically helpful nor diagnostic. DIagnostic criteria for ET 1. Persistent elevation of the platelet count >600 109/L. 2. Absence of identifiable cause of reactive thrombocytosis. 3. Normal red cell mass or Hct <0 .40. 4. Normal BM iron stores or normal serum ferritin or normal MCV. 5. Absence of Ph chro mosome and BCR-ABL fusion gene. 6. Absence of significant BM fibrosis (<33% of biopsy in ab sence of splenomegaly and leucoerythroblastosis. 7. Absence of cytogenetic or morphological evidence of MDS. Differential diagnosis Before a diagnosis of ET is made, causes of reactive thrombocytosis (p254) must be excluded as must PV, CML, idiopathic myelofibrosis (IMF) and MDS with a pred ominant thrombocytosis which can mimic ET. Prognostic factors in ET 2 Thrombosis associated with previous thrombosis and age >60. 2 He morrhage associated with extreme thrombocytosis (>1000 109/L) and antiplatelet therapy. Risk stratification in ET Low risk 2 Age < 60 and 2 No history of thrombosis and 2 Platelet count < 1500 109/L and 2 No cardiovascular risk factors (smoking, obesity, hypertension ) Intermediate risk 2 Neither low risk nor high risk. High risk 2 Age \211 60 or 2 Previous history of thrombosis. 07-MPD.qxd 10.12.2003 04.16 PM Page 252 Natural history ET generally follows an indolent course and life expectancy is near normal. The risk of life-threatening complications or of leukaemic transformation is very low. How ever, the risk of AML is increased by cytotoxic therapy and such treatment should be used c autiously. The need for therapy must be individualized balancing risks of therapy against t hrombotic risks (e.g. cigarette smoking, family history), FBC results, co-morbidity and age . Risk of AML 5 \200\22310%; risk of evolution to myelofibrosis 5%. Management 2 Aim to 5 risks and incidence of haemorrhagic and thrombotic compli- cations by normalization of platelet count (target <400 109/L); need to balance these risks with p otential short and long term risks of therapy (e.g. aspirin) and cytotoxic therapy. 2 Patients should be advised to make lifestyle changes (smoking, exer- cise, obesity) to re duce their risk of thrombosis and atherosclerosis. 2 NSAIDs and standard dose aspirin should be avoided. 252 Low risk patients 2 Incidence of thrombosis <2/100 patient years and hemorrhage 1/100 patient years only; no added risk with pregnancy or surgery. 2 Observation aspiri n 75mg/d (if no contraindication) without cyto- toxic therapy. Intermediate risk patients 2 Cytoreductive therapy (see below) for patients with marked thr ombo- cytosis (>1500 109/L) who are at increased risk of thrombosis. 2 Others in this group ma y be treated with low dose aspirin (if no con- traindication) and observation. 2 Smokers should be encouraged to stop smoking and obese patients to lose weight to reduce their risks of thrombosis. High risk patients 2 Control of thrombocytosis with hydroxyurea reduces the risk of thrombo sis in these patients (<4% vs. 24% after 2 years in a ran- domised study). 2 Hydroxyurea: treatment of choice for patients >60 years (0.5 \200\2231.5g/d maintenance after higher initial doses to bring platelets <400 109/L); used in symptomat ic patients <60 intolerant of anagrelide and inter- feron-a; some patients may need combina tion therapy with anagrelide or interferon-a to achieve normalization of the platelet count ; side effects myelosuppression, oral ulceration, rash; contraindicated in preg- nancy and breast feeding. 2 Anagrelide (2 \200\2232.5mg/d) is preferred in younger patients <60 years (especially those of childbearing potential); interferes with megakary- ocyte differentiati on; side effects: headache, palpitations, fluid reten- tion; contraindicated in pregnancy a nd patients with CCF or known cardiac disease. 2 Interferon-a: (3 \200\2235mU 3 \200\2235 weekly) can control thrombocytosis due to ET in younger patients intolerant of anagrelide; not associated with risk of AML; rarely used due to inconvenience of administration and poor tolerance. 2 32P therapy (2.3mCi/m2 IV which may be repeated after 3 \200\2236 months) may be more app ropriate in elderly patients (>75) or those unable to 07-MPD.qxd 10.12.2003 04.16 PM Page 253 Myeloproliferative disorders comply with regular hydroxyurea therapy; side effects: myelosuppres- sion, long term risk o f AML. 2 Aspirin 75mg/d recommended for patients with thrombotic event; increases risk of hemorrhage (safest when platelets <1000 109/L); relieves erythromelalg ia quickly (2 \200\2234 days); extreme caution in patients with haemorrhagic complications or history of peptic ulceration; H2- antagonist or proton pump inhibitors may be needed; ma rkedly increased bleeding risk with higher aspirin doses. Dipyridamole is an alternative ag ent for those unable to tolerate aspirin. ET in pregnancy 2 First trimester abortion frequent in young women with ET (>40%). 2 Low do se aspirin and interferon-a are treatments of choice because of 253 the theoretically greater teratogenic risk of hydroxyurea. 2 However, successful pregnancy reported following first trimester treat- ment with hydroxyurea. Life-threatening hemorrhage in ET 2 Stop anti-platelet agents. 2 Identify site of bleeding. 2 DDAVP/Factor VIII concentrate if evidence of acquired von Willebrand disease. 2 Platelet transfusion if no evidence of acquired vWD. 2 Plateletpheresis if persistent hem orrhage. 2 Hydroxyurea 2 \200\2234g/day 3 \200\2235d (takes 3 \200\2235d for effect). Arterial thrombosis in ET 2 Commence aspirin 75mg/d (rapid response in TIA and erythrome- lalgia). 2 Hydroxyurea to normalize platelet count. 2 Plateletpheresis if life threatening. Surgery in ET 2 Surgical procedures may require specific antithrombotic strategies e.g. heparin. 2 Thrombotic risks lessened if platelet count normal. Murphy, S. et al. (1997) Experience of the Polycythemia Vera Study Group with essential thr om- bocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol, 34, 29 \200\22339. 07-MPD.qxd 10.12.2003 04.16 PM Page 254 Reactive thrombocytosis Platelet counts of >450 109/L occur as a reactive phenomenon and may be seen in: 2 Infection. 2 Following surgery, especially splenectomy. 2 Malignancy e.g. underlying carc inoma. 2 Trauma. 2 Chronic inflammatory states e.g. collagen disorders. 2 Blood loss and ir on deficiency. 2 Rebound in response to haematinics and/or chemotherapy. 2 Any severely ill patient on ITU. Raised platelet count in clonal hematological disorders occurs in CML, ET, PV, IMF and also in MDS (esp. 5q \200\223 syndrome). 254 In reactive thrombocytosis platelets are usually <1000 109/L but levels of 1500 109/L may occur. Platelet morphology usually normal but differ- entiation from ET relies on full clinical evaluation. No specific treatment is required for reactive thrombocytosis. Short term anticoagulant or antiplatelet therapy is advised for marked thrombocytosis in the imme - diate post-splenectomy period. 07-MPD.qxd 10.12.2003 04.16 PM Page 255 Myeloproliferative disorders 255 07-MPD.qxd 10.12.2003 04.16 PM Page 256 Idiopathic myelofibrosis (IMF) Idiopathic myelofibrosis (syn. agnogenic myeloid metaplasia) is a myelo- proliferative diso rder characterized by marrow fibrosis, splenomegaly, extramedullary haematopoiesis and a le ucoerythroblastic peripheral blood. Incidence Rare disorder; 5 cases per million per annum; predominantly elderly patients (me dian 65 years). Pathogenesis 2 Clonal neoplastic proliferation arising from early haematopoietic stem cell. 2 May evolve from PV ( 9% of cases evolve into MF) or ET ( 2% of cases evolve to MF); minority may follow previous chemotherapy or radiotherapy. 256 2 Haemopoietic cells clonal, fibroblasts not clonal. 2 Fibrosis is a cytokine-mediated reac tive process (TGF-b, PDGF, IL-1, EGF, calmodulin and bFGF); can develop in response to chro nic myeloproliferative disorders, myelodysplasia and secondary carcinoma. 2 Exaggeration of normal BM reticulin pattern progresses to intense col- lagen fibrosis which disrupts and f inally obliterates normal marrow architecture; ultimately osteosclerosis may develop. 2 Hig h levels of immature progenitors appear in PB. 2 Extramedullary haemopoiesis develops in sp leen and/or liver \200\223occasion- ally other sites, e.g. lymph nodes, skin and serosal surfaces. Clinical features and presentation 2 \211 20% may be asymptomatic at diagnosis: mild abnor malities identified on routine FBC or splenomegaly at clinical examination. 2 Most present with symptoms of pro gressive anemia and hepatosplenomegaly associated with hypercatabolic features of fatigue, weight loss, night s weats and low grade fever. 2 Abdominal discomfort (heavy sensation in left upper quadrant) and/or dyspepsia from press ure effects of splenic enlargement may prompt presentation. 2 Symptoms and signs of marrow failure: lethargy, infections, bleeding. 2 Splenomegaly is a lmost universal (>90%): moderate to massive (35%) enlargement; variable hepatomegaly (up to 70%); lymphadenopathy is uncommon (<10%). 2 Gout in 5%; portal hypertension, pleural effusion and ascites (due to portal hypertension or peritoneal seeding) also occur. Investigation and diagnosis 2 FBC: Hb usually 5 or normal (<10g/dL in 60%); normochromic no rmo- cytic indices; WBC 5, normal or 4 (rarely >100 109/L); platelets usually 5 or norma l; occasionally 4. 2 Blood movie: leucoerythroblastic anemia (nucleated red cells, myelo- cytes) with tear dro p poikilocytes (96%) and polychromasia; giant platelets and megakaryocyte fragments. 2 Bone marrow aspirate: usually unsuccessful ( \200\230dry tap \200\231). 07-MPD.qxd 10.12.2003 04.16 PM Page 257 Myeloproliferative disorders 2 BM trephine biopsy: essential for diagnosis; characteristically shows patchy haemopoietic cellularity (often focally hypercellular) and vari- able reticulin fibr osis (often coarse and branching); 4 numbers of large irregular megakaryocytes; distended m arrow sinusoids with intravas- cular haematopoiesis. 2 Coagulation screen: features of DIC in 15%; usually occult but causes problems at surgery (e.g. splenectomy); defective platelet aggregation common. 2 Cytogenetics: abnormalities in up to 75%: 13q \200\223, 20q \200\223 and 1q+ most frequent. 2 Serum chemistry: bilirubin 4 in 40%; alkaline phosphatase and ALT 4 in 50%; urate 4 in 60%. 257 2 MRI: readily distinguishes fibrotic BM from cellular BM. Bone marrow trephine in myelofibrosis: note streaming effect caused by intense fibrosis Differential diagnosis 2 Exclude other myeloproliferative disorders (CML, PV, ET) M7 AML (a cute myelofibrosis), myelodysplasia, lymphoproliferative disorders (particularly hairy cell leukemia), metastatic cancer (esp. breast, lung, prostate, stomach), tuberculosis, histopl asmosis and SLE. 2 IMF is \200\223ve for Ph chromosome and BCR-ABL fusion gene. 2 Metastat ic cancer in marrow, especially breast, prostate and thyroid, can give similar FBC features but without splenomegaly; metastatic car- cinoma cells are ap parent on marrow biopsy and/or aspirate. 2 Prefibrotic stage recognized: classical features may be minimal or absent and difficult to distinguish from PRV/ET; prominent neutrophil proliferation, decrea sed erythroid precursors and markedly abnormal megakaryocytes. Prognostic factors Short survival associated with: 2 Hb <10 g/dL. 2 WBC <4 109/L or >30 109/L. 2 Constitutional symptoms. 07-MPD.qxd 10.12.2003 04.16 PM Page 258 2 \211 1% blasts in PB or >10% blasts + promyelocytes + myelocytes in BM. Management 2 Myelofibrosis incurable except by allogeneic SCT; no other treatment alters disease course or prevents leukaemic transformation. 2 Treatment palliative; aiming to improve anemia, alleviate symptomatic organomegaly and hypercatabolic symptoms. 2 Asymptomatic cases with minimal FBC abnormalities and splenic enlargement should simply b e observed with regular follow-up. 2 Regular blood transfusion for anemic symptoms; transfuse on basis of symptoms not at a sp ecific Hb level; iron chelation therapy with des- ferrioxamine should be considered after 2 5 units. 2 Corticosteroids: 33% of anemic patients respond to combination therapy with an androgen (oxymethalone 50mg tds) and corticosteroid (prednisolone 1mg/kg/da y). 2 Allopurinol to treat or prevent hyperuricaemia. 2 Hydroxyurea: often effective in reducin g spleen size, leucocytosis, 258 thrombocytosis, hypercatabolic symptoms. 2 Analgesia: for acute splenic infarction; severe pain may respond to splenic irradiation. 2 Splenectomy indicated for massive or symptomatic splenomegaly, excessive blood transfusio n requirements, refractory thrombocy- topenia, hypercatabolic symptoms unresponsive to hydr oxyurea; eval- uate coagulation system pre-operatively; 10% mortality; 40% morbidity. 2 Splenic irradiation to reduce splenic size and discomfort in those unfit for splenectomy (3 \200\2236 month benefit). 2 Radiotherapy also a useful treatment of extramedullary haemopoietic infiltrates at other sites e.g. pleural and peritoneal cavities. 2 Allogeneic SCT: should be discussed with younger patients (e.g. \211 55) with \211 2 adverse risk factors (see above) and a sibling donor; median 5 year survival 50%; actuarial probability of disease recurrence at 5 years 30%. Prognosis 2 Median survival 4 \200\2235 years (range 1 \200\22330 years). 2 Hypersplenism o ften develops as the spleen enlarges. 2 Progressive cachexia occurs due to hypercatabolic s tate in advanced IMF. 2 Death in symptomatic cases usually due to infection and hemorrhage. 2 Around 5 \200\22310 % transform to AML refractory to intensive chemotherapy. 2 Asymptomatic cases usually die from unrelated causes. 07-MPD.qxd 10.12.2003 04.16 PM Page 259 Myeloproliferative disorders 259 07-MPD.qxd 10.12.2003 04.16 PM Page 260 Mast cell disease (mastocytosis) Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation o f mast cells in one or more organ systems, including skin, bone marrow, liver, spleen and l ymph nodes. Epidemiology Median age of systemic mastocytosis 50 \200\22360 years; range 5 \200\22388; m edian age of urticaria pigmentosa 2.5 months; after age 10 median age of urticaria pigmento sa 26 years. Pathogenesis Mast cells are derived from pluripotential haemopoietic dells and are the effe ctor cells of the immediate allergic reaction via high affinity receptors for IgE. Most var ients of systemic mast cell disease are clonal and a somatic mutation of c-KIT, the proto-o ncogene that encodes the receptor for stem cell factor, is usually present. These mutations lead to constitu- tive activation of KIT which causes mast cell proliferation and prevents mast cell apoptosis. In pediatric mastocytosis KIT-activating mutations are rare. Clinical symptoms are due to the release of mast cell mediators (including histamine, tryptase, hep arin, TNF-a, PGD2, cytokines and chemokines) which have both local and systemic effects, an d to organ infil- tration. 260 WHO classification of mast cell disease (mastocytosis) 2 Cutaneous mastocytosis. 2 Indolent systemic mastocytosis. 2 Systemic mastocytosis with associated clonal, hematological non-m ast cell lineage disease. 2 Aggressive systemic mastocytosis. 2 Mast cell leukemia. 2 Mast cell sarcoma. 2 Extracutan eous mastocytoma. Clinical features and presentation 2 Patients usually present with symptoms of mediator release: urticaria, flushing, dermatographism, pruritus, angioedema; paroxysmal hyper- or hypotension; abdomina l pain, dyspepsia, diarrhea and malabsorption (80% of SM), multiple peptic ulcers, hemorrha ge; wheezing, dyspnoea, rhinorrhoea; neuropsychiatric symptoms (headache, fatigue, irritabi lity, cognitive disorganization, nightmares); bone pain (25%). 2 Most cases are seen in infants and children; involvement is generally limited to the skin; commonest forms are solitary cutaneous tumors (mastocytomas) or widesp read cutaneous involvement with a few or many small lightly pigmented red-brown macules and papules (urticaria pigmentosa). Usually transient; begins in first year of life and disapp ears at puberty. 2 Adult urticaria pigmentosa is associated with small heavily pigmented macular lesions; onset in young adults; often progressive with systemic organ involvement u sually bone marrow (46%), lymph nodes ( 25% at diagnosis), spleen ( 50% at diagnosis), live r and GI tract. 2 Familial mastocytosis causes cutaneous disease in infancy, persists into adult life and may progress to systemic involvement; rare. 07-MPD.qxd 10.12.2003 04.16 PM Page 261 Myeloproliferative disorders Investigation and diagnosis 2 Diagnosis of cutaneous mastocytosis (usually in children) bas ed on typical clinical and histological skin lesions and absence of definitive signs of sys temic involvement. 2 Diagnosis of systemic mastocytosis (SM): \200\223 Bone marrow trephine biopsy: essential for diagnosis; multifocal lesions consisting of foci of spindle shaped mast cells with eosinophils and lymphocytes in a fibrotic stroma (90%); in advanced SM diffuse mast cell infiltration may occur. \200\223 Bone marrow aspirate: increased numbers of mast cells; clusters of confluent mast cells are a more specific finding (<30%); features of accompanying hematological disorder may be present, usually myelodysplastic or myeloproliferative disorder rarely lymphoprolif- erative. 261 \200\223 Biopsy of other extracutaneous tissue: notably liver or lymph node; rarely necessary. \200\223 Serum mast cell tryptase and/or histamine:elevated in SM but not in isolated urticaria pigmentosa. \200\223 24 hour urine for mediators (histamine metabolites, tryptase, PGD2 metabolites). \200\223 Bone scan/skeletal survey: bone lesions in 60%; generalized osteosclerosis, focal sclerosis or generalized osteopenia. \200\223 FBC and movie: no characteristic features; circulating mast cells rare (2%) unles s very advanced disease or mast cell leukemia; mild to moderate anemia in about 45%; eosino philia up to 25%; thrombo- cytopenia about 20%; monocytosis about 15%; pancytopenia may dev elop due to BM infiltration or hypersplenism. \200\223 GI studies: as necessary. \200\223 EEG: if necessary. Variants of SM 2 Indolent SM: commonest form of SM; associated with maculopapular skin lesi ons (90%), slow involvement of target organs and good prog- nosis. 2 Aggressive SM: characterized by impaired organ function due to infil- tration of BM, liver, spleen, GI tract or skeletal system and predisposi- tion to severe me diator release attacks with haemorrhagic complications. 2 SM with associated hematological non-mast cell disease: <50% have urticaria pigmentosa; g enerally CML or CMML; classified according to FAB/WHO criteria; poorer survival. 2 Mast cell leukemia: defined by \211 20% MC in BM aspirate and \211 10% in PB; diffuse i nfiltration on trephine biopsy; no skin lesions, severe peptic ulcer disease, hepatosplenom egaly, anemia, multiorgan failure and short survival. 2 Mast cell sarcoma: a tumor consisting of atypical MC; locally destruc- tive growth; no systemic involvement. 07-MPD.qxd 10.12.2003 04.16 PM Page 262 Differential diagnosis Diagnosis often delayed due to protean clinical features. Exclude re active mast cell hyperplasia, mast cell activation syndromes, myeloproliferative disorders with increased mast cells, carcinoid syndrome, phaeochromocy- toma, myelofibrosis, liver di sease and lymphoma. Management 2 No curative treatment; management consists of prevention of medi- ator effects and treatment of accompanying hematological disease where present. 2 Avoid factors triggering acute mediator release: extremes of tempera- ture, pressure, fri ction; aspirin, NSAIDs, opiates, alcohol, specific aller- gies. 2 Treat acute mast cell mediator release. 2 Anaphylaxis: epinephrine (adrenaline) 0.3mL of 1:1000 dilution (adult dose) every 10 \200\22315 minutes as needed. 2 Refractory hypotension and shock: fluid resuscitation and epinephrine 262 (adrenaline) IV bolus plus infusion of 1:10,000 dilution (up to 4 \200\22310mg/min); add in otropes if unresponsive. 2 Commence H1 plus H2 receptor antagonists and steroids. 2 Treat chronic mast cell mediator release: H1 plus H2 receptor antago- nists: H1 antihistamines: diphenhydramine (25 \200 \22350mg PO 4 \200\2236 hourly; 10 \200\22350mg IM/IV), hydroxyzine (25mg PO tid or qid; 25 \200\223100 mg IM/IV) or loratadine (non-sedating; 10mg PO od); H2 antihistamines: ranitid ine (150mg PO bd; 50mg IV) or cimetidine (400 \200\2231600mg/day PO in divided doses; 300mg IV). Titrate doses for individual patient require- ments; prednisolone 40 \200\22360 mg/da y PO for malabsorption tailing; bis- phosphonates and radiotherapy for bone pain; PUVA for urticaria pigmentosa; a small number of patients gain symptomatic relief from interferon- or cyclosporin-A for refractory symptoms. 2 Treat any associated hematological disorder: generally achieve short partial remission at best; splenectomy may help pancytopenic patients. SCT should be considered in appropriate patients. 2 Attempt to control organ infiltration by mast cells: daunorubicin plus cytarabine and CVP have been reported to produce partial responses. Prognosis Most patients with SM have only slowly progressive disease and many survive sever al decades. 33% evolve into a hematological malignancy, fre- quently intensive chemotherapy and has a survival of only a few months. leukemia. Mast cell leukemia is resistant to Escribano, L. et al. (2002) Mastocytosis: current concepts in diagnosis and treatment. Ann Hematol, 81, 677 \200\223690; Valent, P. et al. (2001) Diagnostic criteria and classificati on of mastocytosis: a con- sensus proposal. Leuk Res, 25, 603 \200\223625. 07-MPD.qxd 10.12.2003 04.16 PM Page 263 Myeloproliferative disorders 263 07-MPD.qxd 10.12.2003 04.16 PM Page 264 This page intentionally left blank 264 08-plasma cell.qxd 10.12.2003 04.21 PM Page 265 Paraproteinaemias 8 Paraproteinaemias 266 Monoclonal gammopathy of undetermined significance (MGUS) 268 Asymptomatic (smoldering) myeloma 270 Multiple myeloma 272 Variant forms of myeloma 281 Waldenstr m \200\231s macroglobulinaemia (WM) 284 Heavy chain disease (HCD) 288 AL (primary systemic) amy loidosis 288 08-plasma cell.qxd 10.12.2003 04.21 PM Page 266 Paraproteinaemias Heterogeneous group of disorders characterized by deranged prolifera- tion of a single clon e of plasma cells or B lymphocytes and usually associ- ated with detectable monoclonal immu noglobulin (paraprotein or M-protein) in serum and/or urine. Conditions associated with paraprotein production Stable production 2 Monoclonal gammopathy of undetermined significance (MGUS). 2 Asymptomatic (smoldering) myeloma. Progressive production 2 Multiple myeloma (MM). 2 Complete immunoglobulins: IgG, IgA, IgD, IgM, IgE. 2 Free light chains (Bence Jones protein). 2 \200\230Non-secretory \200\231. 2 P lasma cell leukemia (PCL). 2 Solitary plasmacytoma of bone (SPB). 2 Extramedullary plasmacy toma (SEP). 2 Waldenstr m \200\231s macroglobulinaemia (WM). 2 Chronic lymphocytic leukemi a. 2 Malignant lymphoma. 2 Primary amyloidosis (AL). 2 Heavy chain disease. 266 08-plasma cell.qxd 10.12.2003 04.21 PM Page 267 Paraproteinaemias 267 08-plasma cell.qxd 10.12.2003 04.21 PM Page 268 Monoclonal gammopathy of undetermined significance (MGUS) MGUS describes the presence of a stable monoclonal paraprotein in serum or less commonly in urine in the absence of clinicopathological evi- dence of multiple myeloma (MM), Waldenstr m \200\231s macroglobulinaemia (WM), amyloidosis (AL) or other lymphoproliferative disord er. Incidence Median age 66 years. Incidence rises with age. Occurs in 1% population >50 years of age, 3% >70 years, 5% >80 years. More frequent in Afro- Caribbeans than Caucasians. Pathophysiology There is intraclonal variation in the Ig gene mutation and MGUS appears to arise from a pre-germinal center cell whose progeny pass through the germinal center and un dergo mutation. Progression to MM may be due to outgrowth of a single clone. There is a con tinuing rate of progression to MM, WM, AL and other lymphoproliferative disorders. FISH dem on- strates same MM cytogenetic abnormalities in MGUS often acquired over time. Expression microarrays show MGUS much closer to MM than to normal plasma cells. No specific trigger fo r progression yet identified. 268 Natural history 2 >50% patients die of unrelated causes over a 25 year follow-up period. 2 1% progress to MM, WM, AL or other lymphoproliferative disorder per annum. 2 10% progress within 8 years; 26% after 25 years. 2 5% patients do not progress, some may show a 4 in paraprotein levels. Clinical features 2 Typically asymptomatic and often incidental finding on investigation of 4 ESR/PV or 4 globulin on routine LFTs. 2 No abnormal physical findings (end-organ damage) except unrelated. 2 Lack of progression and absence of additional evidence of progressive plasma cell or B-cell lymphoproliferative malignancy. Investigation and diagnosis 2 Perform investigations listed for MM ((cid:9)p273). 2 Serum p rotein electrophoresis with immunofixation and densitometry to detect, characterize and qua ntitate paraprotein levels: IgG 66%; IgA 20%; IgM 10%; biclonal 1%; light chain 1%; median 15g/L. 2 Urine electrophoresis: identifies only low levels of Bence Jones pro- teinuria (generally <1g/24h). 2 Stable paraprotein and other parameters on prolonged observation. 2 Immunoglobulin quanti tation: by nephelometry; only 25% have immuneparesis of uninvolved Ig classes (cf. myeloma). 2 Serum b2-microglobulin levels normal (unless renal impairment). 2 BM aspirate: <10% plasm a cells in BM; median 5%. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 269 Paraproteinaemias 2 BM cytogenetics: normal by conventional techniques but all abnormalities in MM described in MGUS by FISH; del(13), t(4;14), ras mutations, p16 and p53 inactivation less common.