myelofibrosis draft london cancer...

London Cancer MF Guidelines 2015-‐16 v1.0

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Myelofibrosis guidelines

Approved by Pathway Board for Haematological Malignancies

Coordinating author: Mallika Sehkar, Royal Free London NHS Trust

Date of issue: 12.03.2015

Version number:v1.0

These guidelines should be read in conjunction with the latest National Cancer Drug Fund information, and all applicable national /international guidance.

The prescribing information in these guidelines is for health professionals only. It is not intended to replace consultation with the Haematology Consultant at the patient’s specialist centre. For information on cautions, contra-‐indications and side effects refer to the up-‐to-‐date prescribing information. While great care has been taken to see that the information in this section is accurate, the user is advised to check the doses and regimens carefully and if there is any uncertainty about the guidance provided, you should discuss your queries with a Haematology Consultant or Senior Pharmacist. No set of guidelines can cover all variations required for specific patient circumstances. It is the responsibility of the health care practitioners using them to adapt them for safe use within their institutions and for the individual needs of patients.


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CONTENTS 1. DIAGNOSIS ...................................................................................................................... 3

1a. BCSH (2012) .................................................................................................................... 3

1b. WHO (2009) diagnostic criteria for PMF: ....................................................................... 4

2. MOLECULAR DIAGNOSTICS ..................................................................................... 5

3. RISK STRATIFICATION: ............................................................................................. 5

4. TREATMENT: ................................................................................................................. 7

4a. Low risk ........................................................................................................................... 7

4b. Asymptomatic Intermediate-1 ........................................................................................ 7

4c. Symptomatic Intermediate -1 ........................................................................................... 7

4d. Stem cell transplant: ......................................................................................................... 9

4e. Blast phase ..................................................................................................................... 10

4f. Pregnancy ....................................................................................................................... 10

4g. Portal vein thrombosis, portal hypertension .................................................................. 10

5. SERVICE SPECIFICATIONS: .................................................................................... 11

6. REFERENCES ............................................................................................................... 13


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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.


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1b. WHO (2009) diagnostic criteria for PMF:

Diagnosis requires all 3 major and ≥ 2 minor criteria.

1. Major criteria a. 1. Megakaryocyte proliferation with aberrant

morphology and dense clustering accompanied by either reticulin and/or collagen fibrosis, or

b. 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 .

c. d. 2.Not meeting WHO criteria for CML, PV, MDS or other

myeloid neoplasm e. f. 3.Demonstration of JAK2V617F or other clonal marker or

no evidence of reactive marrow fibrosis 2.

3. Minor criteria a. b. 1.Leukoerythroblastosis c. 2.Increased serum LDH d. 3.Anemia e. 4.Palpable splenomegaly

f. •IWGRT for post-‐PV/ET MF : Diagnosis requires all major criteria and ≥ 2 minor criteria

1. Major criteria a. 1.Documentation of a previous

diagnosis of PV or ET as defined by the WHO criteria

b. c. 2.Bone marrow fibrosis grade 2-‐3

(on 0-‐3 scale) or grade 3-‐4 (on 0-‐4 scale)

2. Minor criteria a. 1.leukoerythroblastosis b. 2.Increasing splenomegaly or the appearance of a

newly palpable splenomegaly c. 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)

d. 4.Anemia or sustained loss of requirement for phlebotomy in the absence of cytoreductive therapy (for PV)

e. 5.Anemia and a decrease of hemoglobin level ≥ 2 g/dL from baseline (for ET)

f. 6.Increased serum LDH (for ET)

3. a.


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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 CAL-‐R and MPL mutations, 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 and DIPPS-‐plus are 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.


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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: Ruxolitinib is recommended as first line therapy for symptomatic splenomegaly and myelofibrosis-‐related constitutional symptoms regardless of JAK2V617F mutation status (evidence grade 1b); and in particular we make the following recommendations: Indications:

-‐ Symptomatic splenomegaly -‐ Myelofibrosis-‐related symptoms -‐ Hepatomegaly and portal hypertension due to myelofibrosis are reduced by

ruxolitinib and it can be considered for these indications. -‐ Whilst treatment with Ruxolitinib is suggested to confer a survival advantage

treatment with this agent in asymptomatic patients or those who lack bothersome splenomegaly is not currently recommended.

Tolerance and side effects: Anaemia and thrombocytopenia are to be anticipated with this agent, anaemia usually peaking by weeks 12-‐16 and improving thereafter. In patients with pre-‐existing anaemia and thrombocytopenia (note those with platelets below 50 x 109/L are excluded from using this drug) a lower starting dose is recommended for example 5mg BD. See tables 2 and 3 below for toxic effects.

-‐ Second line: In patients unable to tolerate Ruxolitinib with symptoms or signs of hyperproliferation: -‐Hydroxycarbamide-‐ this can improve splenomegaly in 20-‐25% patients. -‐IFN-‐α2b at a dose of 0.5-‐1.5 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.


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•low counts and splenomegaly-‐ -‐Thalidomide 50mg/day + prednisolone 0.5mg/kg/day x 1 month, 0.25 mg/kg/day x 1 month, 0.125 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).


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•Anaemia -‐Blood transfusion support. Consider chelation therapy based on iron studies and MRI scans for measuring heart and liver iron. -‐If serum Epo levels < 125u/l, rEpo or biosimilar 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 600-‐800 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-‐12 monthly. Men must be screened for prostate cancer before and during therapy. •Combination of above. Splenectomy may be considered 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.


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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.


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4. 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.

From Ref 6


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From Ref 6


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5. REFERENCES

6.1 Janus kinase Inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure?, 2012. Harrison C, Verstovsek S, et al British Journal of Haematology, Volume 157, pages 426–437.

6.2 What are RBC-‐transfusion-‐dependence and -‐independence? Gale RP, Barosi G et al, Leuk Res. 2011 Jan;35(1):8-‐11.

6.3 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. 2012 Sep 2.

6.4 Induction of complete remission of acute myeloid leukaemia by pegylated interferon-‐alpha-‐2a in a patient with transformed primary myelofibrosis. Berneman, Z.N., Anguille, S, et al. 2010. British Journal of Haematology, 149, 152–155.

6.5 Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and management. Tefferi, A, American Journal of Hematology, Volume 86, pages 1017–1026, December 2011

6.6 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 Ianotto1, Jean-‐Jacques Kiladjian2, British Journal of Haematology,2009, Volume 146, Issue 2, pages 223–225. 6.7 JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis, 2012, Harrison C, Kiladjian JJ et al, N Engl J Med 2012; 366:787-‐79

6.8Allogeneic Stem Cell Transplantation for Myelofibrosis in 2012, 2012. McLornan, D, Mead A et al. British Journal of Haematology, Volume 157, pages 413–425, May 2012

6.9The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-‐SAF): international prospective validation and reliability trial in 402 patients.2011, Scherber R, Mesa RA. Blood. 2011 Jul 14;118(2):401-‐8.

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