London Cancer. Myelofibrosis guidelines. August Review August Version v1.0. Page 1 of 12

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1 London Cancer Myelofibrosis guidelines August 2013 Review August 2013 Version v1.0 Page 1 of 12

2 CONTENTS 1. DIAGNOSIS a. BCSH (2012) b. WHO (2009) diagnostic criteria for PMF: MOLECULAR DIAGNOSTICS RISK STRATIFICATION: TREATMENT: a. Low risk b. Asymptomatic Intermediate c. Symptomatic Intermediate d. Stem cell transplant: e. Blast phase f. Pregnancy g. Portal vein thrombosis, portal hypertension SERVICE SPECIFICATIONS: REFERENCES Page 2 of 12

3 DRAFT UCLP MYELOPROLIFERATIVE NEOPLASMS GROUP: MYELOFIBROSIS GUIDELINES 1. DIAGNOSIS BCSH criteria preferred to WHO criteria although either may be used. The WHO criteria consider a diagnostic category of pre-fibrotic myelofibrosis which the BCSH criteria do not. 1a. BCSH (2012) Diagnostic criteria for primary myelofibrosis: Diagnosis requires A1 + A2 and any two B criteria. A1 Bone marrow fibrosis 3 (on 0 4 scale). A2 Pathogenetic mutation (e.g. in JAK2 or MPL),or absence of both BCR-ABL1 and reactive causes of fibrosis B1 Palpable splenomegaly B2 Unexplained anaemia B3 Leuco-erthroblastosis B4 Tear-drop red cells B5 Constitutional symptoms* B6 Histological evidence of extramedullary haematopoiesis (*Drenching night sweats, weight loss >10% over 6 months, unexplained fever (>37 5 C) or diffuse bone pains.) Diagnostic criteria for post-pv and post-et MF: Diagnosis requires A1 + A2 and any two B criteria. A1 Bone marrow fibrosis 3 (on 0 4 scale) A2 Previous diagnosis of ET or PV B1 New palpable splenomegaly or increase in spleen size of 5 cm B2 Unexplained anaemia with 20 g/l decrease from baseline Hb B3 Leuco-erythroblastic blood film. B4 Tear-drop red cells B5 Constitutional symptoms B6 Histological evidence of EMH. Page 3 of 12

4 1b. WHO (2009) diagnostic criteria for PMF: Diagnosis requires all 3 major and 2 minor criteria. Major criteria 1. Megakaryocyte proliferation with aberrant morphology and dense clustering accompanied by either reticulin and/or collagen fibrosis, or in the absence of reticulin fibrosis (ie, prefibrotic PMF), the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis. Minor criteria 1.Leukoerythroblastosis 2.Increased serum LDH 3.Anemia 4.Palpable splenomegaly 2.Not meeting WHO criteria for CML, PV, MDS or other myeloid neoplasm 3.Demonstration of JAK2V617F or other clonal marker or no evidence of reactive marrow fibrosis IWGRT for post-pv/et MF : Diagnosis requires all major criteria and 2 minor criteria Major criteria 1.Documentation of a previous diagnosis of PV or ET as defined by the WHO criteria 2.Bone marrow fibrosis grade 2-3 (on 0-3 scale) or grade 3-4 (on 0-4 scale) Minor criteria 1.leukoerythroblastosis 2.Increasing splenomegaly or the appearance of a newly palpable splenomegaly 3.Development of 1 of 3 constitutional symptoms: > 10% weight loss in 6 months, night sweats, unexplained fever (> 37.5 C) (for both PV and ET) 4.Anemia or sustained loss of requirement for phlebotomy in the absence of cytoreductive therapy (for PV) 5.Anemia and a decrease of hemoglobin level 2 g/dl from baseline (for ET) 6.Increased serum LDH (for ET) Page 4 of 12

5 2. MOLECULAR DIAGNOSTICS 2a. jak2 V617F mutation screening should be carried out routinely in patients with PMF. Quantitative results are not required for clinical management. 2b. If the patient lacks jak2 mutation, screen for MPL mutation, if both negative and atypical features present, screen for bcr-abl 1. 2c. If significant eosinophila screen for PDGRFA and PDGRFB rearrangements. 2d. Routine screening for other mutations are not justified other than as research tool or in difficult diagnostic circumstances to establish clonal basis for fibrosis in the absence of other markers 3. RISK STRATIFICATION: Use one of 3 prognostic criteria IPSS/DIPPS/DIPPS plus. DIPPS-plus is validated for any time point of the disease. The criteria are applicable to primary and post ET/PV Mf although they have not been validated in post PV and post ET Mf. Risk assess at follow up visits. See table 1 below for details. Page 5 of 12

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7 4. TREATMENT: This is undergoing changes as there are new licensed drugs and new trials across UK. The network guidelines will be updated periodically to keep up with changes. 4a. Low risk: watchful observation 4b. Asymptomatic Intermediate-1: watchful observation 4c. Symptomatic Intermediate -1: First line: myelosuppressive therapy- In patients with symptoms of or signs of hyperproliferation: -Hydroxycarbamide- this can improve splenomegaly in 20-25% patients. -IFN-α2b at a dose of million units three times a week escalating to 15 million units three times a week -pegylated IFN α 2a- start at 45ug/ week increasing to 90 ug/ wk depending on tolerance and toxicity. Responses to Interferon α include reduction in platelet, WBC count, BM fibrosis and improvement in anemia (30-40 % response). low counts/splenomegaly- -Thalidomide 50mg/day + prednisolone 0.5mg/kg/day x 1 month, 0.25 mg/kg/day x 1 month, mg/kg/day x 1 month, then cease. -If response in Hb/platetlets/ spleen size continue thalidomide at same dose (20-30% response rate). DVT prophylaxis not required unless platelet count elevated. -Consider Lenalidomide if platelets >100 at a dose of 10mg/day with Prednisolone 10mg/day (20-30% response rate). -Pomalidomide presently undergoing clinical trial in UK. Page 7 of 12

8 Anaemia -Blood transfusion support. Chelation therapy not required. -If serum Epo levels < 125u/l, repo may be commenced at 10,000 u three times a week (or darbepoietin 150ug/wk), double dose after 1-2 months in absence of response. Discontinue Epo if no response in 3-4 months. -If Epo levels elevated, Danazol 200 mg/day escalating to mg/day (800 mg/day for >80kg wt) over 6-8 weeks. Minimum 6 months treatment. Responding patients should receive a further 6 months of 400mg/day and then taper dose to minimum required to maintain response. Monthly LFT, ultrasound liver 6-12monthly. Men must be screened for prostate cancer before and during therapy. Combination of above. Second line: - Ruxolitinib. This is approved as second line treatment via the CDF scheme. Dose 5-25mg bd depending on platelet count. (25-40% response, survival benefit across IPSS Int-2 and High Risk groups). Platelet count <50 is a dose limiting factor and other treatment options need to be considered. Patients with anaemia likely to require extra transfusion support. Beneficial for splenomegaly and constitutional symptoms. See tables 2 and 3 below for toxic effects. - Consider splenectomy in selected patients via laparotomy not laparoscopy high morbidity (30%), mortality(9%). Requires careful pre-op optimisation of coagulopathy, platelet count, vaccination, co-morbid factors. - Splenic radiation: <50cGy 1-2 times a week tailored to response. Likely to require platelet and red cell transfusion support. 4d. Stem cell transplant: -If median survival is expected to be less than 5 years and the patient is otherwise eligible, transplantation should be considered. Thus IPSS Intermediate -2 patients will be considered eligible for SCT. -Patients with transfusion dependency and/or with adverse cytogenetics should also be considered for SCT preferably before the patient has received > 20 units red cells. -Whether patients with IPSS Int-1 should be offered early transplant depends on several factors including disease, patient and donor related variables. Page 8 of 12

9 4e. Blast phase: -Azacytidine 75mg/m2 5-7 days every 28 days -induction chemotherapy followed by SCT - pegylated IFN α 2a at 135 ug/wk increasing to 180 ug/wk followed by SCT. 4f. Pregnancy -Treat as per ET guidelines if platelet counts elevated. 4g. Portal vein thrombosis, portal hypertension: TIPPS is indicated. Splenectomy may be of use in portal Hypertension. Role of anticoagulation is important. Page 9 of 12

10 5. SERVICE SPECIFICATIONS: 5a. All patients with Myelofibrosis must be discussed at a Haematology MDT meeting where a treatment plan must be agreed. Patients with complex diagnostic or treatment problems must be discussed at a specialist network MPN MDT. 5b. Follow- up visits depend on symptom burden and must include a risk stratification at 6 monthly intervals. Patients must have an assessment using the MF-SAF questionnaire every 6-12 months. 5c. Network wide audit of diagnosis and treatment must be audited at least annually. Page 10 of 12

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12 6. REFERENCES 6.1 Janus kinase Inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure?, Harrison C, Verstovsek S, et al British Journal of Haematology, Volume 157, pages What are RBC-transfusion-dependence and -independence? Gale RP, Barosi G et al, Leuk Res Jan;35(1): Pegylated interferon α2a induces complete remission of acute myeloid leukemia in a postessential thrombocythemia myelofibrosis permitting allogenic stem cell transplantation. Dagorne A, Douet-Guilbert N,et al. Ann Hematol Sep Induction of complete remission of acute myeloid leukaemia by pegylated interferonalpha-2a in a patient with transformed primary myelofibrosis. Berneman, Z.N., Anguille, S, et al British Journal of Haematology, 149, Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and management. Tefferi, A, American Journal of Hematology, Volume 86, pages , December PEG-IFN-α-2a therapy in patients with myelofibrosis. A study of the French Groupe d Etudes des Myelofibroses (GEM) and France Intergroupe des syndromes Myéloprolifératifs (FIM), Jean-Christophe Ianotto 1, Jean-Jacques Kiladjian 2, British Journal of Haematology,2009, Volume 146, Issue 2, pages JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis, 2012, Harrison C, Kiladjian JJ et al, N Engl J Med 2012; 366: Allogeneic Stem Cell Transplantation for Myelofibrosis in 2012, McLornan, D, Mead A et al. British Journal of Haematology, Volume 157, pages , May The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients.2011, Scherber R, Mesa RA. Blood Jul 14;118(2): Page 12 of 12