The management of myelofibrosis: A British Society for Haematology Guideline

Abstract

This document represents an update of the British Society for Haematology guideline on Myelofibrosis first published in 2012 and updated in 2015.1 These guidelines aim to provide healthcare professionals with clear guidance on stratified management for primary myelofibrosis (PMF), as well as postpolycythaemia myelofibrosis (post-PV MF) and postessential thrombocythaemia myelofibrosis (post-ET MF). A separate BSH guideline covers the diagnosis and prognostic evaluation of myelofibrosis and is published alongside this guideline. These guidelines were compiled according to the BSH process https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the relevant myelofibrosis-related literature using Medline, PubMed/Medline and Cochrane searches beginning from 2012 up to mid-2022. Filters were applied to include only publications written in English, studies carried out in humans, clinical conferences, congresses, clinical trials, clinical studies, meta-analyses, multicentre studies and randomised controlled trials. Exclusion criteria included papers published in non-English journals and those publications without an abstract. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-oncology Task Force, the BSH Guidelines Committee and the Haemato-oncology sounding board of the BSH. We invited two global expert external reviewers to review contents—Professor Ruben Mesa and Professor Alessandro Vannucchi. This guideline has also been reviewed by patient representatives from MPN Voice. Myelofibrosis (MF) encompasses primary myelofibrosis (PMF), postessential thrombocythaemia (ET) MF and postpolycythaemia vera (PV) MF. It is characterised by clonal haemopoietic stem cell proliferation and elevated levels of pro-inflammatory cytokines, resulting in reticulin deposition and collagen fibrosis. The annual incidence is estimated at 1–2 individuals per 100 000 of the population in the United Kingdom, with an equal sex incidence.2 All patients newly diagnosed with MF should be reported to the National Cancer Registry, via the multidisciplinary meeting, and to MF-specific registries if available. This guideline focuses on the management of overt MF; PMF is usually treated similar to secondary (post-ET and post-PV) MF. Current management approaches are based upon clinical phenotype, prognostic group, patient age and performance status with consideration of comorbidities. Joint patient and clinician decision-making is of key importance. All patients should be considered for available clinical trials following discussion in a multidisciplinary meeting. Figure 1 shows a proposed overview of contemporary therapeutic approaches based on prognostic group and phenotype. Clinicians should be aware there is often discordance between spleen size, symptom burden and risk stratification group, and every patient requires an individualised assessment for optimal treatment approaches. Akin to all myeloproliferative neoplasms (MPNs), vascular risk should be assessed on a regular basis. Ruxolitinib is an oral JAK1/JAK2 inhibitor indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with PMF, post-ET MF and post-PV MF. Ruxolitinib was licensed based upon the pivotal COMFORT-I and -II studies which compared ruxolitinib with placebo and best available therapy (BAT) respectively.3, 4 Benefits of ruxolitinib demonstrated in these and other studies include spleen size reduction with symptomatic and quality of life improvements, as well as a likely modest survival benefit in responding patients (although a precise assessment of this is complicated by the crossover study design). Survival benefit has been linked to both spleen response and weight gain. Retrospective analysis of pooled COMFORT-I and COMFORT-II data from intermediate-2 and high-risk MF patients suggested that earlier initiation of ruxolitinib may improve clinical outcomes, with fewer cytopenic events, more durable spleen volume reduction and prolonged overall survival (OS).5 Although no prospective clinical trial has yet successfully evaluated ruxolitinib in low-risk MF, non-randomised studies have delineated benefits of ruxolitinib in intermediate-1 risk disease.6-8 Patients should be screened for hepatitis B and C and human immunodeficiency virus (HIV) prior to starting on therapy and risk factors for mycobacterial infection and herpes zoster reactivation should be evaluated. For patients commencing a JAK inhibitor, there may be an increased risk of herpes virus reactivation dependent on both the agent used and patient-specific factors. Although no conclusive evidence exists to support prophylactic aciclovir in this setting, clinicians should consider in each case whether this is appropriate. Aciclovir prophylaxis, in the main, has a benign side-effect profile although nephrotoxicity may rarely occur. With regard to herpes zoster, a non-live shingles vaccine (Shingrix®) is available for eligible individuals (adults aged 70–79 years in the United Kingdom) for whom receipt of the live vaccine is contraindicated, as is the case, in our opinion, for those on JAK inhibitors. Initial dosing of ruxolitinib is commonly individualised based upon platelet counts (Table 1). Of note, if the patient is anaemic prior to commencing the drug, one strategy is to start at 10 mg twice daily then up titrate as tolerated. Support with recombinant erythropoietin (EPO), danazol or other agents ± transfusions may be required. Full blood count monitoring and liver function testing should be performed every 2–4 weeks until the dose is stabilised and then as clinically indicated. The summary of product characteristics (SPCs) suggests interruption of dosing if platelets drop to <50 × 109/L or if the absolute neutrophil count is <0.5 × 109/L.9 However, for cases where there is ongoing clinical and symptomatic benefit from ruxolitinib, this requires consideration of risk versus benefit and can often be managed by close full blood count monitoring and/or appropriate dose reduction titrated against the platelet count. Common side effects (Table 2) include anaemia and/or thrombocytopenia (most common during the first 12–16 weeks but can occur at any stage), increased risk of infection and a higher incidence of non-melanoma skin cancers. Skin surveillance is suggested in particular for patients with a history of skin cancer, and patients should be educated and alerted to this. Patients should be counselled not to stop the drug abruptly, due to the risk of a systemic inflammatory response syndrome (SIRS), particularly in the setting of concurrent infection.10 Weight gain following on from improved appetite is common in responding patients. Pragmatic lipid profile monitoring is suggested as increases in serum cholesterol and triglyceride levels can occur and may require action. If spleen and/or symptom response is insufficient and platelet and neutrophil counts are adequate, doses should be increased in 5 mg twice-daily increments to a maximum of 25 mg twice daily as needed, attempting to ensure adequate dose exposure. Normally, the dose is not increased during the first 4 weeks of therapy and not more frequently than 2 weekly. Regular review of dosing is essential as adequate dose density is associated with improved response. Around 80% of patients treated with ruxolitinib experience ≥10% reduction in spleen volume; primary resistance is rare. Ruxolitinib can elicit rapid symptomatic responses, with nearly 40%–50% of patients achieving a 50% reduction in symptom burden in around 8 weeks when treated with adequate dose density. Assessment of response by objective symptom monitoring and spleen size assessment via palpation is recommended. Symptom assessment using a MPN 10 questionnaire or MF Symptom Assessment Form (MF-SAF) has been demonstrated to capture symptom burden dynamics. Response assessment by bone marrow (BM) biopsy is not routinely recommended in chronic phase and monitoring driver mutation variant allele frequency (VAF) burden is not of routine clinical benefit. Around half of patients remain on therapy at 3 years, the leading causes of discontinuation being disease progression, other adverse events and death. Loss of response can be heralded by worsening symptoms, sustained increase in spleen size despite dose optimisation, worsening cytopenia, sustained increase in circulating blasts or progressive leucocytosis. Ruxolitinib can be discontinued if there is no response or no improvement in symptoms/spleen size after 6 months despite dose optimisation. Fedratinib is an oral JAK2 inhibitor recommended in the United Kingdom for the treatment of disease-related symptoms or splenomegaly in adults with MF who are resistant to or intolerant of ruxolitinib.11 Recommended initial dosing of fedratinib is 400 mg once daily for patients with a baseline platelet count ≥50 × 109/L. Use of fedratinib includes a ‘black box’ warning concerning a potential risk of serious encephalopathy, including Wernicke's encephalopathy; however, of note, no Wernicke's encephalopathy occurred in patients receiving the recommended dose of 400 mg/day in previous studies. A thiamine (vitamin B1) level should be measured prior to starting fedratinib and monitored during treatment (monthly for the first 3 months then 3 monthly). If thiamine levels are low, fedratinib should not be commenced until replete and thiamine replacement should be given during treatment if levels indicate deficiency. Pragmatic thiamine replacement alongside fedratinib can also be recommended if concerns exist. The main toxicities associated with fedratinib include anaemia, thrombocytopenia, neutropenia, diarrhoea, renal impairment and elevations in serum liver function tests and pancreatic enzymes. Anti-diarrhoeal and anti-emetic prophylaxis and close monitoring of patients (1–2 weekly depending on comorbidities) during the initial treatment period is recommended. Fedratinib, like ruxolitinib, is not routinely recommended for patients with baseline platelet counts <50 × 109/L, but safety and efficacy of fedratinib in patients with lower platelet counts (50 to <100 × 109/L) has been examined in a small cohort of 48 patients from the JAKARTA-1 and -2 trials, and fedratinib 400 mg/day was found to be equally effective in terms of spleen and symptom responses as in patients with higher platelet count, with a low incidence of discontinuation due to thrombocytopenia.12 Patients who transition from ruxolitinib to fedratinib may experience a withdrawal reaction if ruxolitinib is suddenly discontinued. The management of transition from one drug to the other should ideally be discussed with a MPN specialist centre as often individualised approaches are suggested. Momelotinib is an oral inhibitor of JAK1/JAK2 and activin A receptor type 1 (ACVR1), targeting the triad of MF-associated symptoms, splenomegaly and anaemia.13-15 Momelotinib-mediated inhibition of ACVR1 downregulates hepcidin expression, a pivotal regulator of iron homeostasis, and facilitates erythropoiesis with resultant anaemia benefits. The starting dose of 200 mg is fixed, irrespective of baseline platelet count and ability to maintain dose is frequently very stable. Three large-scale phase III trials demonstrating the efficacy of momelotinib in MF have been reported in the JAK inhibitor-naïve setting (SIMPLIFY-1), those who have been previously treated with ruxolitinib (SIMPLIFY-2) and those who have failed/been intolerant to any commercial JAK inhibitor is potential side is for patients with MF and platelet counts <50 × 109/L. is not routinely available in the United volume reduction of than or equal to were in of patients for and improved symptom in for in an analysis of and The trial is ongoing in patients with platelet count <50 × 109/L. It should not be used in patients with and should be for prior to any is an which It can be where the primary for treatment is of blood often in earlier of the or symptomatic responses are although patients may and effective may be by very may be with The of neoplasms group published two studies on in MF, potential symptomatic and there was of survival benefit for a is considered in group patients with or in patients with MF of particular are not due to in agents treatment and in the MF The of in overt MF is and to be considered on an individualised dependent on estimated post-PV MF or post-ET MF, may be to in the of risk factors for The risk of events for is higher than in or overt contraindicated, should be used in patients. is the common clinical of MF and with adverse of anaemia are frequently including erythropoiesis and are also by and Initial management is to any and to any evidence of this is for the management of anaemia has been proposed based on baseline serum which should be prior to starting a JAK This has been as in Figure have been used to MF with 50% of patients demonstrating a responding patients levels routine that those with levels likely an trial for starting doses are frequently but 000 per of recombinant or with dose to 000 or per if after be to be in with however, anaemia benefits have been in 25 the of response despite dose optimisation, should be discontinued. a can anaemia responses in up to of A phase study of a of danazol and ruxolitinib increase or of in of responses may also be in a If a of weeks of therapy is to assess if there is a response. be given to potential side effects as liver function tests should be monitored in all and in given at mg per or mg daily with has been reported to improve anaemia in patients with has been assessed with and without as has particularly when is However, these have not been assessed in with JAK which are MF and of in the United Kingdom is in our opinion, is associated with cell transfusions may increase marrow and increased which are in and disease This the for iron in those who may for haemopoietic stem cell has been to be well and effective in MF patients in a cohort of patients with levels of also resulting in reduction in for a small A trial of oral and ruxolitinib suggested improved survival in patients who iron but this requires in is the of anaemia management when other are is usually when the is or depending on the of and for of support is a which to iron likely of if there is an estimated life of at If a chronic is the benefits and of cell and as yet in for the treatment of MF have in anaemia, including as patients receiving as of the study clinical in a and inhibitor, shows in trials in is an agent which demonstrated efficacy in a trial for MF-associated anaemia in both on and If therapeutic of these agents require in MF is associated with other high-risk higher symptom burden and A suggested for these patients is in Figure including where more JAK when may JAK both ruxolitinib and fedratinib are and effective in patients with baseline platelet counts ≥50 × The not support of therapy this although both are frequently used in with dose and close as is at MF patients with platelet counts <50 × 109/L. at insufficient data to whether momelotinib have a although the trial included patients with platelet counts to 25 × 109/L and data are for safety and efficacy in the inhibitor studies have suggested and efficacy from a of agents including and studies have also reported the of ruxolitinib with ± danazol and have reported platelet responses, but data are to evaluate these not in improvement in platelet counts in one and is not routinely receptor not to sustained platelet may be in patients with or in those for should be to BSH guidance for platelet The of JAK inhibitor therapy the for but can be considered in patients if there is symptomatic splenomegaly to drug or cell studies have demonstrated and and with survival benefit in the inhibitor risk of is and this to be managed in the of the risk of and of of not and may be of benefit in patients with splenomegaly prior to Patients for MF require prophylaxis, particularly against and should be considered prior to the and monitoring of blood counts is recommended following the for the of is of or may reduction in the risk of and to of have however, an for patients with symptomatic splenomegaly or intolerant to and not for include of which can be and dosing and are and often upon baseline The case included dose was in a of 8 patients more than one of with dose for treated patients being Of the to a reduction in spleen size for a of 6 months and a symptomatic occurred in patients Clinicians should be aware of the potential risk that as may group compared by dose patients were treated and a group receiving a dose of dose group of and group of in response was with the higher but with an increase in MF rarely in the and adult population years of the of and adults with PMF occurred in in and disease to MF in of driver mutation status similar to of events and are these patients should be management at a there are no guidelines or risk to this and optimal management and risk assessment should the as in but should include history and consideration of particularly in Assessment for and status is to of risk of and may than those for and risk of the is a higher MF is associated with higher of including and should be managed by a with experience of high-risk with and for of agents as and to may be where in to the of and low weight to improve are to the on in the BSH guideline for the management of in vera and secondary which of the relevant for consideration during the management of MF the only for with MF. patient and discussion is of be individualised for each patient based on the estimated of disease progression, and performance treatment and frequently and factors. Current guidelines from the and and due to be updated in patients with intermediate-2 or high-risk disease according to or and age years, should be considered potential for patients years of age with disease be considered for if with anaemia or blood blasts or adverse guidelines also suggested that patients in the intermediate-1 risk group who are or mutation or should be patients with low-risk disease should not the from the or high-risk and very high-risk in our opinion, patients in these should also be The is for patients potential the age years, thrombocytopenia, × 109/L, an mutation and driver mutation status were as risk factors for and splenomegaly is a and can as higher of function and adverse and are to a published on optimal management of splenomegaly prior to therapy with available JAK or in clinical trials to spleen response is prior to in those with Retrospective studies of patients who JAK that is performed at the of best response than until of A evaluation of in patients improved survival and incidence in those during response when compared to the ruxolitinib group and those who response. the risk of in JAK may be a period with an aim to stop the prior to commencing JAK or to although there are data data concerning of in those treated with or A study suggested that splenomegaly should ideally be to prior to and that this is associated with improved in this cohort was associated with but was by an increased risk of and no resultant benefit. However, analysis suggested that in those with progressive disease and a spleen was associated with and no increase in prior to is not without and should be considered with to the function given the risk of associated with MF with that eligible patients have an performed to out and may be particularly in those with liver function iron can upon the marrow and is an effective iron in MF and may be used prior to in individuals to potential risk of if there is MF are linked to with the of a associated with overall in the setting is associated with higher and improved for and analysis in the setting suggested using a compared to a or was and is to improve in the of is A previous study using neutrophil with primary at 2 The and was and A more study in patients demonstrated a and survival of and incidence of was of blood as a stem cell is cell is than although studies are study demonstrated that stem cell doses of × in associated with improved survival and platelet discussion on is the of this guideline. for patients or those with a is for a should be used as data improved disease survival A of have demonstrated commonly in the United Kingdom, these are and or should be with than A of are being based on the of on these have been in a expert and are to this for disease monitoring of driver where is with at both 3 and 6 months and with a higher risk of clinical phase increase to blasts in blood or and phase increase to blasts in blood or MF particularly in the patient and disease factors are associated with the risk of disease to both and including higher anaemia and thrombocytopenia, and of or of the risk of monitoring is required. The only to only a small of patients. from MF have been with a survival of only 6 months in those not for treatment are being in this patient population and approaches are often is by patient performance status and of therapy and whether the patient is for a potential or The of a mutation associated with a is associated with a particularly patients should be and be to an If clinical trial are these should be on disease and patients often or agent with a to blasts prior to may with approaches. is no evidence to or is with and and there is no to other as and or in this patients with were from pivotal studies of in secondary on patients with not any in as or compared to chronic phase but higher of 5 years were A analysis of patients from the suggested for patients with a performance status and in at the of the setting, the is on disease and quality of trials should be and is to is or or with ruxolitinib are used as previous has been are and disease agents as and remain have been in small but no in were a patients response to to therapeutic are required. Figure 4 a suggested to the of or in disease and with treatment or is essential that written is for the patient-specific literature from MPN or It is of that patients with MF have to a clinical specialist in to disease and treatment a in the and support of patients and and Patients should ideally be the and support by MPN a which a disease and treatment patient around the United Kingdom during the and a support to with to in similar All to guideline review and All the to the and review of these The like to Professor Ruben Mesa and Professor Alessandro for external expert review of this guideline. We also like to the of MPN who these guidelines and the BSH Haemato-oncology Task Force, the BSH sounding board and the BSH Guidelines Committee for guidance and was no associated with this All have a of to the BSH and Task which may be on All of have been with the British Society of the and in this guidance is to be and at the of to the the BSH the any for the of this