06-MDS.qxd 10.12.2003 04.14 PM Page 222 Comparison of FAB and WHO classifications FAB WHO RA RA (unilineage) 5q \200\223 syndrome RCMD RARS RARS (unilineage) RCMD-RS RAEB-1 RAEB-2 RAEB RAEB-t AML CMML MDS/MPD \200\223 MDS-U 222 1 Bennett, J.M. et al. (1982) Proposals for the classification of the myelodysplastic syndr omes. Br J Haematol, 51, 189 \200\223199. 06-MDS.qxd 10.12.2003 04.14 PM Page 223 Myelodysplasia 223 06-MDS.qxd 10.12.2003 04.14 PM Page 224 Clinical features of MDS 2 Presentation ranges from mild anemia to profound pancytopenia. 2 May be asymptomatic with mild anemia identified on routine FBC. 2 Macrocytic or normochromic anemia usual (60 \200 \22380%) neutropenia (50 \200\22360%) thrombocytopenia (40 \200\22360%). 2 Isolated thrombocytopenia would be a most unusual presentation for MDS. 2 Symptoms of underlying cytopenias and cellular dysfunction may develop: \200\223 Anemia: fatigue, shortness of breath, exacerbation of cardiac symptoms. \200\223 Neutropenia and dysfunctional granulocytes: recurrent infection. \200\223 Thromb ocytopenia and dysfunctional platelets: spontaneous 224 bruising, purpura, bleeding gums. 2 Constitutional symptoms including anorexia, weight loss, fevers and sweats usually feature of the more \200\230advanced \200\231 subgroups; may be due to cyto kine release. 2 Splenomegaly commonly occurs in CMML and may cause abdominal pain and easy satiety. Investigation and diagnosis 2 History: prior exposure to chemotherapy/radiation; FH of MDS/ AML; recurrent infection or bleeding/bruising. 2 Examination: pallor; infection; bruising; splenomegaly. 2 FBC: macrocytic/normochromic an emia neutropenia thrombocy- topenia neutrophilia monocytosis thrombocytosis. 2 Blood movie: may demonstrate dimorphic red cells Pappenheimer bodies in RARS; basophilic stippling in RBCs; dysplastic granulocytes: pseudo-Pelger forms, hypersegmented neutrophils, hypogranular neu- trophils, dysmorphic monocytes blasts; pl atelets may be large or hypogranular. 2 U&E, LFTs, ECG and CXR: to assess co-morbidity. 2 Serum ferritin, vitamin B12 and RBC fol ate: usually normal levels; fer- ritin may be elevated in RARS. 2 Serum Epo level: indicates probability of therapeutic response to Epo. 2 BM aspirate: dem onstrates >10% dysplastic cells in \211 2 lineages (for FAB system): megaloblastoid erythropoiesis, nuclear-cytoplasmic asyn- chrony in myeloid or erythroid precursors, dysmorphic megakary- ocytes or micro-megakaryocytes; normal or increa sed storage iron; \211 15% ringed sideroblasts in RARS; increased monocytes in CMML. 2 BM trephine biopsy: allows assessment of cellularity \200\224usually 4 or normal; may demonstrate abnormal localization of immature myeloid precursors centrally in t he intertrabecular interstitium (ALIPs), megakaryocyte dysplasia, fibrosis or hypocellular MDS variant. 2 BM cytogenetic analysis: may demonstrate clonal chromosome abnor- mality(s) confirming diagnosis and with prognostic value. 2 Definitive diagnosis of early MDS (e.g. isolated cytopenia) may be diffi- cult; regular r eview with repeat blood count and movie assessment rec- ommended; in all cases a measure of the pace of the disease over a 2 \200\2236 week period is of prognostic value. 06-MDS.qxd 10.12.2003 04.14 PM Page 225 Myelodysplasia 225 Blood movie in MDS showing bilobed pseudo-Pelger neutrophil. Cytogenetic analysis 2 Abnormalities found in BM cytogenetic analysis of 40 \200\22370% of patients with de novo MDS and 80 \200\22390% of patients with secondary MDS. 2 Single or complex abnormalities at diagnosis may evolve during course of disease. 2 More complex abnormalities associated with more aggressive subtypes and higher % blasts and with secondary MDS. 2 Most frequent abnormalities involve chromosomes 5, 7, 8, 11, 12 and 20; most typical are 8+, 7 \200\223 or 7q \200\223, 5 \200\223 or 5q \200\223. 2 Isolated 5q \200\223, 20q \200\223 and normal karyotype favorable; complex kary- otypes ( \211 3 abnormalities), 7 \200\223 or 7q \200\223 unfavorable. Differential diagnosis Exclude: 2 Other causes of anemia (haematinic deficiency, haemolysis , blood loss, renal failure). 2 Other causes of neutropenia (drugs, viral infection). 2 Other causes of thrombocytopenia (drugs, ITP). 2 Other causes of bi-/pancytopenia (drugs, infection, aplastic anemia). 2 Oth er causes of monocytosis (infection, AML) or neutrophilia (infec- tion, CML). 2 Reactive causes of BM dysplasia: megaloblastic anemia, HIV infection, alcoholism, recent cytotoxic therapy, severe intercurrent illness. 2 Other causes of marrow hypoplasia in hypoplastic MDS: aplastic anemia, PNH. 06-MDS.qxd 10.12.2003 04.14 PM Page 226 Prognostic factors in MDS FAB classification RA RARS RAEB RAEB-t CMML Proportion of patients Median survival (months) 43 Transformation to AML 15% 5% Transformed at 1 year 10% Transformed at 2 years 25% 15% 73 5% 0 0 12% 12 40% 25% 35% 15% 5 50% 55% 65% 10% 20 35% np np np \200\223 data not provided CMML median survival <5% blasts 53 months; 5 \200\22320% blasts 16 months. 226 Greenberg P.L. (2000) In: Hoffman R et al. eds Hematology: Basic Principles & Practice. 3rd ed. New York, NY: Churchill Livingstone 2000:1106 \200\2231129. International Prognostic Scoring System (IPSS) 2 Uses BM blast %, BM cytogenetics and numbe r of cytopenias to compute a risk score and stratify patients into 4 distinct groups. 2 Improved prognostic power for both survival and evolution into AML compared with earlier systems. 2 Analysis excluded CMML with a WBC >12 109/L as this was consid- ered myeloproliferative rather than MDS. 2 IPSS score should be calculated during a stable clinical state not, for example, during florid infective initial presentation. 2 May be used to assist management decisions. Score value 1.0 0.5 Prognostic variable 0 1.5 2.0 BM blast % Karyotype Cytopenias <5 Good 0/1 5 \200\22310 \200\223 Intermediate 2/3 11 \200\22320 Poor 21 \200\22330 Karyotype: Good: normal, \200\223Y, del(5q), del(20q); Poor: complex ( \211 3 abnormalitie s) or chromosome 7 anomalies; Intermediate: other abnormalities. Cytopenias: Hb <10g/dL; ne utrophils <1.8 109/L; platelets <100 109/L. IPSS risk group Combined score Median survival 25% AML evolution Low Intermediate \200\2231 Intermediate \200\2232 High 0 0.5 \200\2231.0 1.5 \200\2232.0 >2.5 5.7 yrs 3.5 yrs 1.2 yrs 0.4 yrs 9.4 yrs 3.3 yrs 1.1 yrs 0.2 yrs Greenberg, P. et al. (1997) International scoring system for evaluating prognosis in myelod ysplastic syndromes. Blood, 89, 2079 \200\2232088. 06-MDS.qxd 10.12.2003 04.14 PM Page 227 Myelodysplasia 227 06-MDS.qxd 10.12.2003 04.14 PM Page 228 Clinical variants of MDS CMML: classified as MDS/MPD in the WHO classification; clinical outcome relates to BM blast % rather than PB monocyte count ((cid:9)p234). 5q \200\223 syndrome: clinically distinct form of MDS in WHO classification; characterized by more indolent clinical course, lower rate of evolution to AML, macrocytic anemia, thromb ocytosis and dysplastic megakaryocytes Pure sideroblastic anemia (PSA): defined as sideroblastic anemia with dysplasia confined to erythropoietic cells (RARS in WHO classification); survival better (77% OS at 3yrs) than w here dysplastic features are also present in myeloid or megakaryocytic lineages (RCMD-RS in WHO classification; 56% OS at 3yrs) and very low risk of AML, even in the long term. 228 Secondary MDS: incidence increasing due to successful chemotherapy and increased pollution; multiple chromosomal abnormalities in almost all patients; poorer prognosis than de novo M DS. Hypoplastic MDS: <15% of cases of MDS have hypocellular BM on biopsy (<30% cellularity age <60; <20% aged \211 60); dysplastic megakaryocytes myeloid cells or excess blasts shoul d be present; may be difficult to distinguish from aplastic anemia in which pancytopenia us ually more severe: cytogenetic findings typical of MDS may be necessary; no particular age range, FAB type and no difference in prognosis; may respond to immunosuppressive therapy. Fibrotic MDS: up to 50% of cases have increased BM fibrosis but <15% have marked fibrosis; all FAB types; more common in secondary MDS; BM hypercellular with myelofibrosis; PB shows pancytopenia and dysplastic features and sometimes leucoerythroblastic picture; organomegal y unusual; rapid deterioration usual. Bone marrow in RARS stained for iron: note iron granules round the nucleus of the erythrobl ast. 06-MDS.qxd 10.12.2003 04.14 PM Page 229 Myelodysplasia 229 06-MDS.qxd 10.12.2003 04.14 PM Page 230 Management of MDS For patients with low risk indolent MDS, a watch and wait approach may be adopted prior to the introduction of therapy. Supportive care Supportive care is administered to most patients with MDS with the aim of r educing morbidity and maintaining quality of life. For many if not most patients this will be the mainstay of management. Red cell transfusion should be administered for symptomatic anemia; individual symptomatolo gy rather than \200\230trigger \200\231 level should initiate red cell support. Iron chelation therapy should be considered once a patient has received 25 units of RBCs if long term transfusion is likely e.g. pure sideroblastic anemia or 5q \200\223 syndrome; De sferrioxamine 20 \200\22340mg/kg by 12h SC infusion 5 \200\2237 nights/week reduced to 25mg /kg when ferritin <2000mg/L; vitamin C 100 \200\223200mg/day PO may be added after 1 month; audiometric and ophthalmological assessments prior to therapy and annually; aim for serum ferritin <1000mg/L. 230 Platelet for patients with should be administered haemorrhagic problems and those with seve re thrombocytopenia with the aim of maintaining a platelet count >10 109/L. transfusion Anti-infective therapy i.e. empirical broad spectrum antibiotics and/or antifungals should be administered promptly for neutropenic sepsis; no evidence to support routine use of prop hylactic anti-infectives in neutropenic patients; prophylactic anti-infective agents may be useful in neutropenic patients with recurrent infection. Low intensity therapy Erythropoietin G-CSF treatment of symptomatic anemia in MDS: maintenance of stable augme nted Hb may provide better quality of life than the cyclical fluctuations of transfusion pr ograms; responses in 20 \200\22330% to Epo alone, 40 \200\22360% to Epo+G-CSF; synergistic effect most evident in RARS or patients with serum Epo levels <500U/L; check iron stores an d replete if necessary. 2 For patients with RA/RAEB with symptomatic anemia, transfusion re quirement <2 units/month and a basal Epo level of <200U/L con- sider trial of Epo (10,000 u nits daily for 6 weeks); in non-responders consider adding daily G-CSF (1mg/kg/day) SC or d ouble dose Epo or both for further 6 weeks; no response after 2 \200\2233 months = treatmen t failure; in responders, reduce G-CSF to 3 weekly and Epo in steps to lowest dose retai ning response. 2 For patients with RARS with symptomatic anemia, transfusion requirement < 2 units/month and basal Epo levels <500 U/L combined therapy should be used f rom outset; consider Epo dose escalation if no response after 6 weeks; no response after 2 \200\2233 months = treatment failure; in responders titrate doses and frequency as tolerate d. 06-MDS.qxd 10.12.2003 04.14 PM Page 231 Myelodysplasia G-CSF treatment of neutropenia: for patients with neutropenia and recurrent or antibiotic r esistant infections but not recommended for chronic prophylaxis. Immunosuppression: may be effective notably for patients with hypoplastic MDS but also for other patients with low risk MDS (IPSS \211 intermediate-1). 2 ATG in clinical trials at a dose of 40mg/kg/d 4d achieved transfusion independence in 33% patients (median respons e >2 years); sustained neutrophil and platelet responses in up to 50%; response associated with significant survival benefit. 231 2 Cyclosporin A has achieved transfusion independence in a high pro- portion of patients with RA in small clinical trials; improved neutrophil and platelet coun ts also. 2 Younger age, shorter duration of transfusion dependence, HLA-DRB1* 15, hypoplastic BM and presence of a PNH clone associated with response to immunosuppression. Non-intensive chemotherapy: may be tolerated by elderly patients with transformed or \200 \230transforming \200\231 MDS; but transient reductions in blast counts may be at the price of increased cytopenia and transfusion dependence. 2 Hydroxyurea is used to control monocy tosis in CMML; titrate dose to achieve optimum control of myeloproliferation with minimum a ddi- tional cytopenia; it is preferable to oral etoposide. 2 Low dose melphalan (2mg/d) is under examination after small trials show a response rate of 40% in patients with RAEB or RAEB-t without severe side effects and prolonged survival in responders; best responses in hypoplastic MDS. 2 5-azacytidine: shows promise with 60% responses, decreased risk of AML transformation, improved QoL and improved survival in phase III trials. High intensity therapy Chemotherapy 2 AML-type chemotherapy should be considered in patient s <60 years with relatively high risk disease and good performance status (high risk IPSS/RAEB or RAEB- t); responses lower (40 \200\22350%) and treatment related morbidity and mortality higher t han de novo AML; age >50 and karyotypic abnormalities associated with poor response. 2 5-aza-2-deoxycytidine achieved 64% responses in patients with high risk IPSS scores; myel osuppressive; requires hospitalization; phase III trials under way. High dose therapy 2 Sibling allogeneic SCT offers the best prospect of prolonged survival a nd possible cure (35 \200\22340% 3 year DFS); few eligible but treatment of choice for pati ents aged <50 with \211 IPSS intermediate-1 and sibling donor; high treatment related mort ality (>40%); relapse rate up to 06-MDS.qxd 10.12.2003 04.14 PM Page 232 40%; relapse risk relates to IPSS score \200\224low risk <5%, high risk >25% as does DFS \200\224IPSS low/intermediate-1 60%, intermediate-2 36% and high risk 28% at 5 years; favor able outcome associated with younger age, shorter disease duration, compatible graft, prima ry MDS, <10% blasts, good risk cytogenetics; lower intensity non-myeloablative regi- mens u nder trial for toxicity and response rate and may increase age range to 65 years. 2 MUD allogeneic SCT associated with lower DFS (<30% at 2 years), higher treatment related mortality (>50%) but lower relapse rates (<15%); high mortality associated with patient age ; this treatment should be discussed with patients \211 40 with \211 IPSS intermediate-1 who lack a sibling donor. 2 Autologous SCT under trial for patients in CR after AML regimens; poor harvests; low TRM; high relapse rate. 232 A \200\230treatment algorithm \200\231 (BCSH Guideline: Br J Haematol (2003), 120, 187 \200\223200) 2 IPSS low: high intensity therapy inappropriate; for symptomatic anemia and R A with serum Epo <200U/L, RARS <500U/L consider trial of Epo G-CSF; otherwise supportive c are. 2 IPSS intermediate-1: offer allograft to patients <50 years with sibling donor; consider p atients aged 50 \200\22365 with good performance status and sibling donor for non-ablative conditioning and allograft within clin- ical trial; offer allograft within clinical trial ( ablative or non-ablative con- ditioning) to patients \211 40 with MUD donor; Note: pre-tra nsplant cyto- reductive chemotherapy not recommended for IPSS intermediate-1; patients \211 65 or <65 without donors should be offered supportive care or Epo G-CSF. 2 IPSS intermediate-2/high: consider patients <65 for AML-type cytoreduc- tive chemotherapy ; those achieving CR or good PR after induction and consolidation chemotherapy should recei ve sibling or MUD allograft as detailed for IPSS intermediate-1 patients; those in CR or go od PR without any donor but with good performance status and adequate harvest should receiv e autologous SCT within clinical trial. 06-MDS.qxd 10.12.2003 04.14 PM Page 233 Myelodysplasia 233 06-MDS.qxd 10.12.2003 04.14 PM Page 234 Myelodysplastic/myeloproliferative diseases (MDS/MPD) This category was created in the World Health Organization (WHO) clas- sification of myeloi d neoplasms for a group of disorders that have both dysplastic and proliferative features a t diagnosis and are difficult to assign to either myelodysplastic or myeloproliferative gro ups. WHO classification MDS/MPD diseases 2 Chronic myelomonocytic leukemia. 2 Atypical chronic m yeloid leukemia. 2 Juvenile myelomonocytic leukemia. 2 MDS/MPD unclassifiable. 234 Chronic myelomonocytic leukemia (CMML) Myeloproliferative element in CMML formerly recogniz ed by subclassifica- tion into MDS-like or MPD-like on the basis of the WBC at presentation ; MPD-like CMML associated with WBC >12 109/L, splenomegaly and con- stitutional symptom s; not a distinct condition as many patients who present with low WBC count and minimal spl enomegaly ultimately progress to meet \200\230proliferative \200\231 criteria. Clinical features 2 Predominantly presents in >60 age group. 2 Often asymptomatic and found on routine FBC. 2 Weight loss, fatigue, night sweats may occur. 2 Skin and gum infiltratio n may occur. 2 Splenomegaly (50%) and hepatomegaly (up to 20%) usually only in cases with leucocytosis and symptoms. 2 Serous effusions (pericardial, pleural, ascitic and synovial) associated with high PB monocytosis. Investigation and diagnosis 2 Investigation as for MDS. 2 Variable leucocytosis; marked in 50%; neutrophilia in some patients. 2 Monocyte count >1.0 109/L is diagnostic minimum. 2 Variable anemia; platelets usually normal or decreased. 2 Marrow typically hypercellular; blasts and promyelocytes <20%. 2 Karyotypic abnormalities associated with MDS found in most patients but no specific cytogenetic features apart from rarity of 5q \200\223. 2 Lysozyme raised in serum and urine. 2 Hypokalaemia may be present. 2 Reactive causes of m onocytosis must be excluded ((cid:9)p144). WHO diagnostic criteria for CMML 1. Persistent peripheral blood monocytosis >1.0 109/L. 2. No Philadelphia chromosome or BCR-ABL fusion gene. 3. <20% myeloblasts, monoblasts and p romyelocytes in PB or BM. 4. Dysplasia in \211 1 myeloid lineages or if myelodysplasia abs ent but above criteria present, CMML may be diagnosed if: \200\223 An acquired clonal cytogenetic abnorm ality present in BM cells or \200\223 Monocytosis persistent for \211 3 months and all other causes excluded. 06-MDS.qxd 10.12.2003 04.14 PM Page 235 Myelodysplasia Diagnose CMML-1 if <5% PB blasts and <10% BM blasts. Diagnose CMML-2 = 5 \200\22319% PB blasts or 10 \200\22319% BM blasts or Auer rods present with <20% BM blasts. Diagnose CMML-1 or CMML-2 with eosinophilia with above criteria + PB eosinophil count >1.5 109/L. Prognostic factors BM blasts: median survival for CMML with <5% BM blasts 53 months versus 16 months for those with 5 \200\22320%. 235 Management 2 Asymptomatic cases with near normal hematology apart from a monocytosis of >1.0 109/L require no intervention and should simply be monitored. Therap y otherwise supportive. 2 Patients with symptoms, organomegaly and/or 44 WBC may respond to oral chemotherapy e.g. hydroxyurea (preferred) or etoposide. 2 Rare young patients may be treated with myeloablati ve therapy and allogeneic SCT which offers only curative option. Natural history Prognosis for asymptomatic patients is favorable (several years). For those requiring therapy median survival is 6 \200\22312 months. Acute myelomonocytic leukemia (A MML) develops in 20%; poorly responsive to intensive chemotherapy. Atypical chronic myeloid leukemia (ACML) 2 Heterogeneous group of patients with Philadelphi a chromosome and BCR-ABL fusion gene negative CML. 2 Other cytogenetic abnormalities frequent. 2 Dysplastic myeloid series and often multiline age dysplasia; monocytosis frequent; no basophilia (cf. CML). 2 Short median survival (11 \200\22318 months). Juvenile myelomonocytic leukemia (JML) 2 Clonal disorder arising in pluripotent stem cell c ausing selective hyper- sensitivity to GM-CSF due to dysregulated signal transduction throu gh Ras pathway. 2 Affects infants and young children usually \211 5 years of age. 2 Marked hepatosplenomeg aly, neutrophilia and monocytosis, anemia and thrombocytopenia. 2 4 hemoglobin F. 2 No Philadelphia chromosome or BCR-ABL fusion gene. 2 Normal karyotype i n >80%. 2 No consistently effective therapy including allogeneic SCT (relapse rates up to 55%). 5 year survival after allograft 25 \200\22340%. Myelodysplastic/myeloproliferative disease, unclassifiable Category for patients with featu res of both MDS and MPD who do not meet the criteria for the three conditions above. 06-MDS.qxd 10.12.2003 04.14 PM Page 236 This page intentionally left blank 236 07-MPD.qxd 10.12.2003 04.16 PM Page 237 Myeloproliferative disorders 7 WHO classification of chronic myeloproliferative diseases 238 Polycythae mia vera (PV) 240 Secondary erythr ocytosis 246 Relative erythrocytos is (RE) 248 Idiopathic erythrocytosis (IE) 249 Essential (1 ) thrombocythae mia (ET) 250 Reactive thrombocytosis 254 Idiopathic myelofibrosis (IMF) 256 Mast cell disease (mastocytosis) 260 07-MPD.qxd 10.12.2003 04.16 PM Page 238 WHO classification of chronic myeloproliferative diseases 2 Chronic myeloid leukemia (Ph chromosome, t(9;22)(q34;q11), BCR-ABL-positive). 2 Chronic neutrophilic leukemia. 2 Chronic eosinophilic leukemia (and hypereosinophilic syn drome). 2 Polycythaemia vera. 2 Chronic idiopathic myelofibrosis (with extramedullary haema topoiesis). 2 Essential thrombocythaemia. 2 Chronic myeloproliferative disease, unclassifia ble. Chronic myeloid leukemia (cid:9)p164. Chronic neutrophilic leukemia (CNL) 2 Very rare; <150 cases reported. 2 Exclude underlying infection or neoplasia e.g. myeloma, before consid- 238 ering diagnosis of CNL. 2 Neutrophilia without left shift, eosinophilia or basophilia. 2 Modest splenomegaly common hepatomegaly. 2 NAP usually 44. 2 Marrow hypercellular. 2 BM cytogenetics usually norma l. 2 Most patients asymptomatic. 2 Treatment often unnecessary. Chronic eosinophilic leukemia (CEL) and hypereosinophilic syndrome (HES) 2 Must exclude inf ectious, inflammatory and neoplastic causes of eosinophilia including CML, AML with inv(16), other chronic myelo- proliferative disorders, lymphoma (esp. Hodgkin \200\231s). 2 Evidence of clonality = CEL; no evidence of clonality = HES. 2 CEL is uncommon; marked in crease in mature and immature eosinophils in PB and BM. Often >5% blasts in BM. Associated with tissue infiltration by im mature eosinophils, anemia and thrombocy- topenia. No dysplastic features. No Philadelphia chromosome or BCR-ABL fusion gene. Short history of malaise, sweats, weight loss, skin rash and increased susceptibility to infection. Splenomegaly common. End-organ damage as per HE S may occur. Proliferative element may be controlled by hydroxyurea. In symptomatic younger patients consider sibling allogeneic SCT. 2 HES is characterized by PB eosinophilia >1.5 109/L for >6 months and by end-organ dama ge, commonly endomyocardial fibrosis, skin lesions (angioedema, urticaria), thromboembolic disease , pulmonary lesions and CNS dysfunction. Associated with polyclonal increased in im munoglobulins including IgE. Splenomegaly 40%. Anemia 50%; neu- trophilia with left shift f requent; platelets may be normal, decreased or increased. BM hypercellular with 25 \200\223 75% eosinophils with left shift. Eosinophilia may be controlled by prednisolone, hydroxyure a or IFN-a. Allogeneic SCT may be curative in younger patients. 07-MPD.qxd 10.12.2003 04.16 PM Page 239 Myeloproliferative disorders 239 07-MPD.qxd 10.12.2003 04.16 PM Page 240 Polycythaemia vera (PV) Erythrocytosis is defined as increase in total red cell mass (RCM). It is sus- pected by fi nding a raised haematocrit (Hct) (packed cell volume, PCV). The term \200\230polycythaemia \200\231 is widely used synonymously but lacks precision and can lead to confusion. Polycy thaemia vera (PV) is a neoplastic clonal disorder of the BM stem cell causing excessive pro liferation of the ery- throid, myeloid and megakaryocyte lineages and carrying a risk of th rom- botic complications. Persistent elevation of Hct >0.48 in adult female and >0.51 in ad ult male is abnormal (Note: Hct can be raised with a normal RCM if plasma volume is reduced ). Classification of polycythaemia See table opposite. Clinical evaluation of a patient with suspected erythrocytosis May be asymptomatic or may p resent with thrombosis or vague symp- toms of headache, dizziness, tinnitus or visual upset . Take detailed history with attention to smoking habits, alcohol consumption and diuretic therapy. History of pruritus (especially after bathing) suggests PV (occurs in 50%). Burnin g sensation in fingers and toes (erythromelalgia) typical of PV. Physical examination may i dentify plethoric facies or abnormalities associated with a cause of secondary erythrocytos is such as gross obesity, hypertension, evidence of obstructive airways disease or cyanotic cardiac conditions. The presence of hepatomegaly or splenomegaly should be sought. An elev ated Hct in the absence of identifiable factors in clinical assessment requires referral fo r specialist evaluation. 240 Investigation and diagnosis 2 FBC: 44 RCC and 5 or 6 MCV and MCH (may be evidence of iron deficiency). 2 Neutrophils and platelets 4 in PV (rare in other causes of erythrocytosis). 2 NAP score: 4 score usually present in PV (but not diagnostic in isolation). 2 Red cell mass and plasma volume: patient red cells labeled with 51Cr and re-injected; simultanous plasma volume mea surement using 131I- labeled albumin. RCM 4 >25% above mean predicted value is diag- nostic of absolute erythrocytosis. Plasma volume also 4 if marked splenomegaly present. PV 4 N or 4 SE 4 N RE 4 within NR or N 5 within NR or 5 Red cell mass Plasma volume PV, polycythaemia vera; SE, secondary erythrocytosis; RE, relative erythrocytosis 2 Arterial oxygen saturation: pulse oximetry most convenient to detect chronic hypoxia. SaO 2 <92% suggests causal relationship with absolute erythrocytosis. Sleep studies may be indi cated by a history of snoring, waking unrefreshed and somnolence. 2 Haematinic assays: serum ferritin: 5 or 6 (esp. PV) and occasionally overt iron deficienc y. Serum vitamin B12: levels commonly 4 in PV due to 4 transcobalamin reflecting associated granulocytosis. Folate defi- ciency may occur. 07-MPD.qxd 10.12.2003 04.16 PM Page 241 Myeloproliferative disorders Classification of erythrocytosis Congenital Primary erythrocytosis Truncation of erythropoietin receptor Acquired Polycythaemia vera (PV) (syn. polycythaemia rubra vera (PRV); primary proliferative polycyt haemia (PPP)). Congenital Secondary erythrocytosis (SE) due to 4 endogenous Epo production High oxygen-affinity hemoglobin Congenital low 2,3-DPG Autonomous high Epo production 241 Acquired Hypoxaemia COAD Cyanotic congenital heart disease with right7left shunt Living at high altitude Chronic alveolar hypoventilation e.g. gross obesity Sleep apnoea syndromes Other causes of Smoking (4 COHb) impaired tissue O2 delivery Renal disease Polycystic kidneys Renal tumors Renal artery stenosis Post-renal transplantation Cerebellar haemangioblastoma Uterine leiomyoma Hepatoma Bronchial carcinoma Adrenal tumors Cirrhosis Hepatitis Drugs Androgens Tumors Liver disease Persistent 4 RCM, no cause found but no evidence of myeloproliferative disease or clear cau se of secondary erythrocytosis. Idiopathic erythrocytosis (IE) Normal RCM and 5 plasma volume Diuretic therapy or dehydration Gaisbock \200\231s syndrome (see p248) Smoking, alcohol, hypertension, obesity. Relative erythrocytosis (RE) Syn. apparent polycythaemia, spurious erythrocytosis, pseudopo lycythaemia 07-MPD.qxd 10.12.2003 04.16 PM Page 242 Investigation and diagnosis, cont. 2 Serum U&E: to screen for renal impairment. 2 Uric acid : often 4 in MPD. 2 Urinalysis: haematuria or proteinuria should prompt further renal investigations. 2 LFTs: to screen for liver disease. 2 Abdominal USS: for hepatosplenomegaly, renal or pelv ic abnormalities. 2 CXR: to screen for pulmonary disease (plus pulmonary function tests if indicated) and congenital cardiac abnormalities. 2 Serum erythropoietin: assays not yet part of routine laboratory investi- gation in UK: se rum Epo 5 in PV and 4 in SE; may also be low in RE and idiopathic erythrocytosis. 2 BM examination: trephine may be diagnostic in PV. Typical features include hypercellulari ty and trilineage hyperplasia with abnormal megakaryocytes (clustering with giant forms and increased ploidy). Increased fibrosis may be present. Normal BM histology does not exclude PV but is more usual in SE. 242 2 Cytogenetics: not routine; 30% have abnormalities, typically 20q \200\223. 8+, 9+ and 13q \200\223. 2 BFU-E culture: not routine; PV progenitors show increased sensitivity to growth factors and develop \200\230endogenous erythroid colonies \200\231 without added Epo. Proposed diagnostic criteria for PV A1 Raised RCM (>25% above mean normal predicted value) or Hct \211 0.60 in 9 or 0.56 in 3 A2 A3 A4 Absence of cause of secondary erythrocytosis Palpable splenomegaly Clonality marker, i.e. a cquired abnormal BM karyotype Thrombocytosis (platelet count >400 109/L) Neutrophil leucocytosis (neutrophils >10 1 09/L; >12.5 109/L B1 B2 in smokers) B3 B4 Splenomegaly demonstrated on isotope or ultrasound scan Characteristic BFU-E growth or redu ced serum erythropoietin A1 + A2 + A3 or A4 establishes PV A1 + A2 + two of B establishes PV Pearson, T.C. & Messinezy, M. (1996) The diagnostic criteria of polycythaemia rubra vera. L euk Lymphoma, 22 Suppl 1, 87 \200\22393. Natural history of PV Untreated PV carries a significant risk of thrombotic complications a nd a further long term risk of transformation into myelofibrosis or less com- monly AML. Th ere is also an 4 risk of bleeding notably from peptic ulcers. The aim of treatment is to re duce the risk of thrombotic complications and to prevent progression to myelofibrosis or le ukemia. Current treat- ments improve the untreated median survival of 18 months to >15 year s though some myelosuppressive treatments (notably chlorambucil and 32P) have been associat ed with an increased risk of AML. Thrombotic compli- cations notably MI, stroke and venous thromboembolism are the most 07-MPD.qxd 10.12.2003 04.16 PM Page 243 Myeloproliferative disorders common causes of death. Age and thrombotic history are the most important risk factors. PV characteristically presents during the proliferative phase when control of erythrocytosi s and prevention of thrombotic complications is often an urgent priority. This is often fol lowed by a stable phase of variable (but often short) duration where near normal counts are maintained without therapy due to decreasing proliferative capacity due to early myelofibr osis. This is followed by an advanced or \200\230spent phase \200\231 which is due to exte nsive myelofibrosis and associated with progressive hepatosplenomegaly and pancytopenia. In cidence 10 \200\22315% after 10 years rising to >30% at 20 years; median survival <18 month s. The incidence of AML is estimated at 2% in the absence of therapy but is over 14% after myelosuppressive therapy. 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.