MCCN Guidelines on Adult Myeloproliferative Disorders Polycythaemia Vera (PV) Diagnostic Criteria1 JAK2-positive PV A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)* A2 Mutation in JAK2 Diagnosis requires both criteria to be present JAK2-negative PV A1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women. A2 Absence of mutation in JAK2 A3 No cause of secondary erythrocytosis A4 Palpable splenomegaly A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells B1 Thrombocytosis (platelet count >450 × 109/l) B2 Neutrophil leucocytosis (neutrophil count > 10 × 109/l in non-smokers; >12.5 × 109/l in smokers) B3 Radiological evidence of splenomegaly B4 Endogenous erythroid colonies or low serum erythropoietin Diagnosis requires A1 + A2 + A3 + either another A or two B criteria -------------------------------------------------------------------------------- *Dual pathology (co-existent secondary erythrocytosis or relative erythrocytosis) may rarely be present in patients with a JAK2-positive myeloproliferative disorder. In this situation, it would be prudent to reduce the haematocrit to the same target as for polycythaemia vera.

*anagrelide would require an Individual Funding Application to PCT. MCCN Guidelines on Adult Myeloproliferative Disorders Polycythaemia Vera (PV) Management2 There are currently no clinical trials open for patients with PV. It is anticipated that clinical trials will open in due course and appropriate recruitment of eligible patients should be encouraged. In the meantime, the following management recommendations can be made. conventional risk factors for atherosclerosis (hypertension, hyperlipidaemia, diabetes, smoking) should be managed aggressively. Venesection to maintain the Hct to <0·45. Aspirin 75 mg/d unless contraindicated. Cytoreduction should be considered if: poor tolerance of venesection symptomatic or progressive splenomegaly other evidence of disease progression, e.g. weight loss, night sweats; thrombocytosis. Choice of cytoreductive therapy, if indicated: <40 years old: first line interferon; second line hydroxycarbamide; third line anagrelide* 40–75 years old: first line hydroxycarbamide; second line interferon; third line anagrelide* >75 years old: first line hydroxycarbamide; second line 32P or intermittent low dose busulphan. *anagrelide would require an Individual Funding Application to PCT. Special considerations Thrombosis :These event are relatively common in PV and should be managed by standard guidelines. Risk factors for thrombosis should be meticulously controlled. Bleeding: These complications are relatively uncommon compared with thrombosis. Antiplatelet therapy, or anticoagulants, should be discontinued. The role of epsilon amino caproic acid, tranexamic acid and recombinant VIIa is unclear. Paradoxically, platelet transfusions may be clinically justified. Pregnancy: The local Trust Obstetric lead should be notifed. It is recommended that these patients be notifed to the MPD registry. Management should follow current BCSH guidelines.

MCCN Guidelines on Adult Myeloproliferative Disorders Essential Thrombocythaemia (ET) Diagnostic Criteria3 A1 Sustained platelet count >450 × 109/l A2 Presence of an acquired pathogenetic mutation (e.g. in the JAK2 or MPL genes) A3 No other myeloid malignancy, especially PV*, PMF†, CML‡ or MDS§ A4 No reactive cause for thrombocytosis and normal iron stores A5 Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm. Reticulin is generally not increased (grades 0–2/4 or grade 0/3) Diagnosis requires : A1–A3 OR A1 + A3–A5 -------------------------------------------------------------------------------- *Excluded by a normal haematocrit in an iron-replete patient; PV,polycythaemia vera. †Indicated by presence of significant marrow bone marrow fibrosis (greater or equal to 2/3 or 3/4 reticulin) AND palpable splenomegaly, blood film abnormalities (circulating progenitors and tear-drop cells) or unexplained anaemia; PMF, primary myelofibrosis. ‡Excluded by absence of BCR-ABL1 fusion from bone marrow or peripheral blood; CML, chronic myeloid leukaemia. §Excluded by absence of dysplasia on examination of blood film and bone marrow aspirate; MDS, myelodysplastic syndrome.

MCCN Guidelines on Adult Myeloproliferative Disorders Essential Thrombocythaemia (ET) Risk Stratification3 Patients should be stratified according to their risk of thrombotic complications. The most widely accepted risk stratification is as follows: High risk :Patients who are either >60 years of age OR have had an ET-related thrombotic or haemorrhagic event OR who have a platelet count of >1500 × 109/l. Intermediate risk : Patients aged 40–60 years with no high risk features Low risk: Patients <40 years of age with no high risk features, and Management3 There are currently no clinical trials open for patients with high risk ET. It is anticipated that clinical trials will open in due course and appropriate recruitment of eligible patients should be encouraged. In the meantime, the following management recommendations can be made. All patient should be offered Aggressive management of conventional risk factors for atherosclerosis (hypertension, hyperlipidaemia, diabetes, smoking). Aspirin 75 mg/d unless contraindicated High Risk: Cytoreductive therapy – aim to bring platelet count <400x109/l 1st line therapy : <40 years old - interferon >40 years old - hydroxycarbamide 2nd line therapy (in those who are refractory or intolerant to 1st line therapy) relax platelet count target to 400-600 x109/l Consider alternative cytoreductive agents (including anagrelide, interferon alpha, P32, busulphan, pipobroman) as either monotherapy or in combination. Non potentially leukaemogenic agents should be used preferentially, if possible. Intermediate Risk/Low risk : Patients should be encouraged to enter the current UK PT1 trial. Otherwise, they should only be offered cytoreductive therapy if symptomatic with thrombotic (micro- or macrovascular complications) or bleeding complications.

MCCN Guidelines on Adult Myeloproliferative Disorders Primary Myelofibrosis (PMF) Diagnostic Criteria4 JAK2 positive PMF A1 Reticulin ≥grade 3 (on a 0-4 scale) A2 Mutation of JAK2V617F B1 Palpable splenomegaly B2 Otherwise unexplained anaemia (Hb <11.5g/l for men; <10g/l for women) B3 Tear drop red cells on PB film B4 Leucoerythroblastic blood film (presence of at least 2 nucleated red cells or immature myeloid cells in the peripheral blood film) B5 Systemic symptoms (drenching night sweats, weight loss >10% over 6months OR diffuse bone pain) B6 Histological evidence of extramedullary haematopoiesis Diagnosis requires A1 + A2 and any two B criteria JAK2 negative PMF A2 Absence of mutation of JAK2V617F A3 Absence of BCR-ABL fusion gene

CO (<45 years if clinically unfit) MCCN Guidelines on Adult Myeloproliferative Disorders Primary Myelofibrosis (PMF) Prognosis5 There are many prognostic scoring systems for myelofibrosis. The BSBMT use the Lille prognostic scoring system5 to stratify patients with PMF when considering the appropriateness for transplant. Factors Hb <10g/dl WCC <4x109/l or >30x109/l Score 1 point for each individual prognostic factor present. Allocate a total score for the patient. Score 0 – Low risk - median survival 96 months Score 1 – Intermediate risk 1 - median survival 26 months Score 2 – High risk - median survival 13 months Management5 It is important to identify those patients with poorer outcome who may benefit from stem cell transplant. The BSMB indications are as follows: GNR,generally not recommended. CO, clinical option. S, standard of care. Risk Group Sibling MUD RIC Allo/MUD Autograft Low GNR Intermediate CO (<45 years) CO (>45 years) CO High S (<45 years) CO (<45 years if clinically unfit)

MCCN Guidelines on Adult Myeloproliferative Disorders Primary Myelofibrosis (PMF) Management In those patients not suitable for transplant, it is hoped that clinical trials in PMF will open nationally. Until such triathe aim is to treat constitutional symptoms and reduce transfusion requirement. The following options should be considered. Supportive therapy – blood product support. Cytoreductive agents – especially in those with constitutional symptoms / progressive splenomegaly / leucocytosis or thrombocytosis / bone pain: 1st line – Hydroxycarbamide; alternatives include busulphan, melphalan, purine analogues. Erythropoietin: as per local protocol. Androgens: e.g danazol. Dose is weight dependent – <80kg 300mg bd, >80kg 400mg bd. Minimum treatment period 6 months. Those responding (Hb >1.5g/dl with transfusion independence) should continue danazol at dose 200mg bd for further 6 months, followed by stepwise dose reductions until minimum dose maintaining response is achieved. Stop danazol if failing to respond. Thalidomide - low dose (50mg daily) and prednisolone (0.5mg-1mg/kg – tapered over 12 weeks) . Median time to response 7.5 weeks (2 - 15 weeks). Response rate 77%. Splenomegaly : Splenectomy - indications - symptomatic splenomegaly refractory to treatment - severe constitutional symptoms - uncontrollable haemolysis - transfusion dependent anaemia unresponsive to treatment - portal hypertension - marked thrombocytopenia Splenic irradiation for those deemed unfit for surgery.

MCCN Guidelines on Adult Myeloproliferative Disorders References Amendment to the diagnosis and investigation of polycythaemia/erythrocytosis. British Journal of Haematology 2007; 138 (6): 821-2 Guidelines for the Diagnosis, Investigation and Management of Polycythaemia/Erythrocytosis. British Journal of Haematology 2005; 130(2): 174-95 Guideline for investigation and management of adults and children presenting with a thrombocytosis. British Journal of Haematology 2010; 149 (3) 352-375 Proposed criteria for PMF in upcoming COSMYD trials (Collaborative Study in Myeloproliferative Disorders). Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996 Aug 1;88(3):1013-8. Prepared by Dr N M Butt On behalf of the MCCN Haematology Cancer Network Group. 16th July 2010.