Guidelines for diagnosis and management of adult myeloproliferative neoplasms (PV, ET, PMF and HES)

Transcription

1 Guidelines for diagnosis and management of adult myeloproliferative neoplasms (PV, ET, PMF and HES) Author: Dr N Butt, Consultant Haematologist On behalf of the Haematology CNG Written: July 2010 Reviewed: September 2012, Jan 2013, April 2015 Revised: July 2015 Re-issued: September 2015 Review: No later than April 2017 MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 1 of 10

2 Polycythaemia Vera (PV) Diagnostic Criteria 1 JAK2-positive PV A1 A2 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)* Mutation in JAK2 Diagnosis requires both criteria to be present JAK2-negative PV A1 A2 A3 A4 A5 B1 B2 B3 B4 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women. Absence of mutation in JAK2 No cause of secondary erythrocytosis Palpable splenomegaly Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells Thrombocytosis (platelet count > /l) Neutrophil leucocytosis (neutrophil count > /l in non-smokers; > /l in smokers) Radiological evidence of splenomegaly 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 neoplasm. In this situation, it would be prudent to reduce the haematocrit to the same target as for polycythaemia vera. MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 2 of 10

3 Algorithm for the management of PV Advise primary care to address conventional risk factors for atherosclerosis (hypertension, hyperlipidaemia, diabetes, smoking) Aspirin 75 mg per day unless contraindicated; clopidogrel if aspirin intolerant Commence venesection to maintain the Hct to <0 45 Cytoreduction should be considered if: thrombocytosis. symptomatic splenomegaly poor tolerance of venesection significant constitutional symptoms Age <40yrs Age yrs Age >75yrs 1 st line interferon 2 nd line hydroxycarbamide or anagrelide** 3 rd line consider MAJIC trial * 1 st line hydroxycarbamide 2 nd line - consider MAJIC trial* - else interferon or anagrelide** 1 st line hydroxycarbamide 2 nd line - consider MAJIC trial*; P32 or low dose busulphan MAJIC trial* - ruxolitinib in high risk PV (or ET) intolerant or refractory to hydroxycarbamide (Open at RLUH / APH) Special Considerations: Thrombosis; Bleeding; Pregnancy Please refer to BCSH guidelines 2. **Funding may need to be sought. Check with local haematology pharmacist. MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 3 of 10

4 Essential Thrombocythaemia (ET) Diagnostic Criteria 3 A1 Sustained platelet count > /l A2 Presence of an acquired pathogenetic mutation (e.g. in the JAK2 or MPL genes) [+CALR ] A3 A4 A5 No other myeloid malignancy, especially PV*, PMF, CML or MDS No reactive cause for thrombocytosis and normal iron stores 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 A *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. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. Nangalia et al. N Engl J Med 2013; 369: Risk Stratification 3 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 ETrelated thrombotic or haemorrhagic event OR who have a platelet count of > /l. Intermediate risk : Patients aged years with no high risk features Low risk: Patients <40 years of age with no high risk features MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 4 of 10

5 Algorithm for the management of ET Determine risk group stratification Advise primary care to address conventional risk factors for atherosclerosis (hypertension, hyperlipidaemia, diabetes, smoking) Aspirin 75 mg per day unless contraindicated; clopidogrel if aspirin intolerant There are currently no clinical trials open across the MCCN for 1st line therapy in ET Management by Risk Group High risk ET Intermediate Risk / Low risk Cytoreductive therapy: - aim : bring platelet count to <400 x 10 9 / l 1 st line - <40 years old interferon >40 years old hydroxycarbamide No proven benefit in cytoreductive therapy Observe for high risk features 2 nd line failed 1 st line therapy - consider entry MAJIC trial (RLUH / APH) - otherwise consider - relax platelet target to x 10 9 / l consider alternative cytoreductive agents (including anagrelide, interferon alpha, P32, busulphan, pipobroman) as either monotherapy or in combination. MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 5 of 10

6 Primary Myelofibrosis (PMF) Diagnostic Criteria 4 A1 Bone marrow fibrosis >3 (on 0-4 scale) A2 Pathogenetic mutation (e.g. JAK2 or MPL), or absence of both BCR-ABL1 and reactive causes of bone marrow fibrosis B1 Palpable splenomegaly B2 Unexplained anaemia B3 Leuco-erythroblastosis B4 Tear-drop red cells B5 Constitutional symptoms** B6 Histological evidence of extramedullary haematopoiesis Diagnosis requires A1 + A2 and any two B criteria **Drenching night sweats, weight loss >10% over 6 months, unexplained fever (>37.5 o C) or diffuse bone pains. Prognosis There are many prognostic scoring systems for myelofibrosis the current BCSH guidelines recommend the DIPSS-Plus 5 prognostic scoring system for treatment decisions. The DIPSS-Plus score is derived from a combination of the DIPSS score with additional information derived from karyotype, platelet count and transfusion dependence. DIPSS score - variable Adverse points Age > 65 years +1 Constitutional symptoms + 1 Hb < 10 g/dl + 2 Leukocytes > /L + 1 Blood blasts 1% + 1 DIPPS: 0 points = low risk,; 1 to 2 points = intermediate-1 risk,; 3 to 4 points = intermediate-2 risk; 5 to 6 points = high risk MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 6 of 10

7 DIPSS-Plus Variables : DIPSS Score Adverse points Low risk = +0 points Intermediate-1 risk = +1 point Intermediate-2 risk = +2 points High risk = +3 points Plus: Platelets < /L Red blood cell transfusion need Unfavorable karyotype: +8, 7/7q-, 5/5q-, i17q, 12p-, 11q23 rearrangement DIPSS-Plus Score: + 1 point + 1 point + 1 point Total 0 points = low risk 1 points = Intermediate-1 risk 2 to 3 points = intermediate-2 4 to 6 points = high risk - DIPSS-Plus Risk Group: o Low risk o Intermediate-1 disease o Intermediate-2 disease o High-risk disease - median survival 185 months - median survival 78 months - median survival 35 months - median survival 16 months MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 7 of 10

8 No role Autograft Algorithm for the management of PMF PMF : Calculate DIPSS-Plus score Transplant Eligible Transplant candidate Transplant Ineligible Contact Katy Knight Research Nurse RLUH <40yrs, INT2 (must meet all criteria) Myeloablative SCT Allograft donor available >40yrs, INT2, >2 HSCT-CI (must meet all criteria) Non-myeloablative SCT Ruxolitinib CDF criteria (March 2015) 1. Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anti-cancer therapy 2. a) Intermediate / high risk primary myelofibrosis, OR b) Post polycythaemia myelofibrosis, OR c) Post essential thrombocytosis myelofibrosis 3. a) 1st line indication, OR b) 2nd line indication 4. Symptomatic splenomegaly and/or constitutional symptoms 5. Unsuitable for a stem cell transplant Failiing ruxolitinib, consider: - Persist 2 trial (RLUH ) - Imetelstat trial (RLUH ) - Supportive care No donor available Surgical management splenectomy -if failed medical management of anaemia, splenomegaly, hyperproliferation, portal hypertension Radiotherapy if unsuitable for splenectomy extramedullary haemopoiesis severe bone pain Intermediate / High risk MF Consider PERSIST 2 Trial (RLUH ) Consider ruxolitinib (as per CDF) Low risk MF or declines / ineligible for ruxolitinib or PERSIST 2 Hyperproliferative symptoms Hypercatabolism Leucocytosis /thrombocytosis Constitutional symptoms Symptomatic splenomegaly 1 st line For supportive care Medical Management without cytopenias hydroxycarbamide Anaemia Blood transfusion EPO therapy Danazol with cytopenias thalidomide* + prednisolone 2 nd *Funding may need to be line sought. Check with local Interferon haematology pharmacist. MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 8 of 10

9 Hypereosinophilic syndromes Diagnosis Hypereosinophilia PB Eosinophils >1.5 x10 9 /l Obvious secondary cause Δ Reactive hypereosinophilia - Treat underlying cause No Proceed to bone marrow aspirate, trephine and cytogenetics Eosinophilia 2y to AML (M4eo), MDS, CML, SM etc) Treat underlying cause No Request FISH on BM for FIP1L1- PDGFRA Positive Δ CEL with FIP1L1-PDGFRA Treatment Box A Negative Abnormal cytogenetics? 5q33? Δ probable CEL with PDGFRB rearrangements Treatment Box A Request TCR rearrangement studies No No 8p11? No Other? Δ probable CEL with FGFR1 rearrangements - Treatment Box B ΔCEL (not otherwise specified) - Treatment Box B Evidence of T-cell clone? Δ T-cell associated hypereosinophilia Treatment Box B Treatment Box A Treat with imatinib* Final diagnosis of exclusion - ΔIdiopathic hypereosinophilia Treatment Box B Treatment Box B Evaluate for end organ damage. Consider conventional therapies corticosteroids, hydroxycarbamide; Alternatives include cyclosporin, vincristine, etoposide; interferon; NB low dose imatinib* mg daily may be considered in idiopathic hypereosinophilia *Funding may need to be sought. Check with local haematology pharmacist. MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 9 of 10

10 References 1. McMullin MF, Reilly JT, Campbell P, Bareford D, Green AR, Harrison CN, Conneally E; National Cancer Research Institute, Myeloproliferative Disorder Subgroup, Ryan K; British Committee for Standards in Haematology (2007) Amendment to the diagnosis and investigation of polycythaemia/erythrocytosis. British Journal of Haematology, 138, McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D, Polkey MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B; General Haematology Task Force of the British Committee for Standards in Haematology (2005). Guidelines for the Diagnosis, Investigation and Management of Polycythaemia/Erythrocytosis. British Journal of Haematology, 130, Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M, Erber W, Everington T, Green AR, Hall GW, Hunt BJ, Ludlam CA, Murrin R, Nelson-Piercy C, Radia DH, Reilly JT, Van der Walt J, Wilkins B, McMullin MF; British Committee for Standards in Haematology. (2010) Guideline for investigation and management of adults and children presenting with a thrombocytosis. British Journal of Haematology, 149, Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR, Michaeel NG, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M, Wilkins B, Harrison CN; Writing group: British Committee for Standards in Haematology. (2012). Guideline for the diagnosis and management of myelofibrosis.british Journal of Haematology, 158, Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, Van Dyke D, Hanson C, Wu W, Pardanani A, Cervantes F, Passamonti F, Tefferi A. (2011) DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.. J Clin Oncol. Feb 1;29(4):392-7 Prepared by Dr N M Butt On behalf of the MCCN Haematology Clinical Network Group. Revised April MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015 Page 10 of 10