Search

This document is an update of the British Society for Haematology guideline on the management of myelofibrosis. It provides healthcare professionals with clear guidance on the stratified management of primary myelofibrosis, as well as post-polycythemia myelofibrosis and post-essential thrombocythemia myelofibrosis. The guidelines discuss various treatment options, including medications like ruxolitinib, fedratinib, momelotinib, and pacritinib, as well as other therapies such as hydroxycarbamide, pegylated interferons, and anti-platelet agents. The document also covers the management of MF-associated anemia, the use of erythropoiesis-stimulating agents, danazol, immunomodulating drugs, and iron chelation therapy. It provides recommendations for special situations and emphasizes the importance of individualized treatment approaches and patient support. Additionally, the document provides recommendations for pretransplant workup, donor choice, conditioning choice, and post allo-HSCT monitoring for patients considering allogeneic stem cell transplantation. [Extracted from the article]

This document is an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF), providing healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of different types of MF. It emphasizes the importance of bone marrow biopsy and molecular testing for diagnosis, as well as the use of various prognostic models to inform clinical decisions and guide therapy. The document also discusses risk stratification and prognostication for MF patients, including the use of validated risk scores. Additionally, it provides information on the diagnosis and prognostication of prefibrotic MF, highlighting the importance of diagnostic criteria and mutational profiles. [Extracted from the article]

Background: Myelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods: Longitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data. Results: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post‐baseline visit in SIMPLIFY‐1. In SIMPLIFY‐2, the improvement in TSS observed in momelotinib‐treated patients was consistent with that observed in SIMPLIFY‐1, whereas progressive TSS deterioration was observed with control. Item‐level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib‐treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY‐1 and SIMPLIFY‐2, respectively. Odds ratios for between‐group comparison ranged from 0.75 to 1.21 in SIMPLIFY‐1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY‐2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. Conclusions: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor‐naïve and JAK inhibitor‐exposed settings. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasm (MPN)‐unclassifiable (MPN‐U) or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. Disease incidence is difficult to define but likely represents close to 5% of all MPNs when strict World Health Organisation (WHO) criteria are applied. Dynamic review over time is required to assess if the disease can be re‐classified into another MPN entity. A diagnosis of MPN‐U leads to many challenges for both the patient and physician alike including lack of agreed monitoring and therapeutic guidelines, validated prognostic markers and licenced therapies coupled with exclusion from clinical trials. MPN‐U has an inherent risk of an aggressive clinical course and transformation in some but who, and when to treat in the chronic phase, including identifying who may require more aggressive therapy at an earlier stage, remains elusive. Moreover, despite the significant thrombotic risk, there is no agreement on systematic primary thromboprophylaxis. We hereby provide a contemporary overview of MPN‐U in addition to four illustrative cases providing our collective suggested approaches to clinical challenges. Short Summary: Myeloproliferative neoplasm (MPN)‐unclassifiable or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. In this review we provide a practical and clinically‐orientated approach to challenging situations and suggest how these patients should best be managed through expert opinion and review of the literature. [ABSTRACT FROM AUTHOR]

Evidence of robust memory T-cell responses in patients with chronic myeloproliferative neoplasms following infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Keywords: COVID-19; immunity; T cell; myeloproliferative neoplasm; CML EN COVID-19 immunity T cell myeloproliferative neoplasm CML 692 696 5 05/17/21 20210515 NES 210515 Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus, has led to very significant global healthcare challenges. Patients with chronic MPN without detectable antibodies had a T-cell response that was broadly equivalent in many areas to that seen in those with detectable anti-SARS-CoV-2 antibodies. For the first time, we have demonstrated that patients with chronic MPN can mount functional memory T-cell responses following natural SARS-CoV-2 exposure. [Extracted from the article]

Summary: The common 'Philadelphia chromosome'‐negative myeloproliferative neoplasms (MPN) comprise essential thrombocythaemia, polycythaemia vera and myelofibrosis. These are clinically diverse disorders and present many challenges during their course, ranging from the management of very indolent, chronic‐phase disease through to very aggressive stages frequently associated with poor quality of life, heavy symptom burdens and potentially life expectancies of <18 months. Their management also requires expertise in thrombosis and haemostasis in addition to marrow failure, debilitating symptom control and balancing the 'pros and cons' of intensive therapy such as allogeneic stem cell transplant versus novel and established therapies. In the past 15 years this field has seen rapid advances following an understanding of the pivotal importance of constitutive Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling, the interplay of the wider genomic landscape and the development of updated diagnostic criteria, prognostic scores and targeted therapies. In this article, we review the successes and failures of novel agents and approaches to MPN management. [ABSTRACT FROM AUTHOR]

Myelofibrosis is a heterogeneous disorder with regard to both molecular pathogenesis and clinical phenotype, ranging from an initial fairly indolent condition in some through to an aggressive and debilitating scenario with profound constitutional symptoms, cytopenia frequently requiring transfusional support, and massive splenomegaly. Many advances have been made within the therapeutic arena, and an increasing array of novel agents are now available for disease management. Within this review, we focus on the current and predicted role of the JAK inhibitor momelotinib (Sierra Oncology) in myelofibrosis, with an emphasis on clinical trial evaluation, drug efficacyand safety, and discuss the suggested place in the therapeutic paradigm of myelofibrosis in 2020 and beyond. [ABSTRACT FROM AUTHOR]

Summary: Myeloproliferative Neoplasm (MPN), unclassifiable (MPN‐U) is a heterogeneous disease with regards to both clinical phenotype and disease course. Patients may initially be asymptomatic or present with leucocytosis or thrombocytosis, anaemia, progressive splenomegaly, constitutional symptom, thromboses or accelerated/blastic phase disease. Treatment strategies are variable and there are no widely accepted consensus management guidelines for MNU‐U. Allogeneic Haematopoietic Cell Transplantation (allo‐HCT) remains the only curative strategy yet outcomes, to date, are not well defined. We hereby report on the largest retrospective study of patients with MPN‐U undergoing allo‐HCT, highlighting the potentially curative role and providing clinicians with robust engraftment, GvHD and outcome data to facilitate patient discussion. [ABSTRACT FROM AUTHOR]

Fedratinib (INREBIC® [fedratinib] capsules, Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation), is a potent JAK2 inhibitor that has been approved for use in myelofibrosis, both as a first-line agent and also in second line following ruxolitinib (Novartis Pharmaceuticals, Basel, Switzerland) failure or intolerance. Within this article, we will review relevant preclinical and early/late clinical trial data concerning the use of fedratinib to treat myeloproliferative neoplasms. Moreover, we will review in detail the assumed safety issues that led to temporary cessation of all programs with the agent in 2013 which subsequently re-entered the clinical arena in 2017. We will discuss how physicians may safely transition a patient across from ruxolitinib to fedratinib following intolerance or lack of efficacy. At last, we will discuss potential future applications of this agent within the field. [ABSTRACT FROM AUTHOR]

Outcomes of patients receiving direct oral anticoagulants for myeloproliferative neoplasm-associated venous thromboembolism in a large tertiary centre in the UK Keywords: myeloproliferative disorder; thrombosis (venous); direct oral anticoagulant therapy EN myeloproliferative disorder thrombosis (venous) direct oral anticoagulant therapy e79 e81 3 04/30/20 20200501 NES 200501 Myeloproliferative neoplasms (MPN) are associated with an increased rate of venous thromboembolism (VTE), which is a major cause of morbidity and mortality, especially in the more indolent diseases of polycythaemia rubra vera (PV) and essential thrombocythaemia (ET) (Pearson, [7]; Tefferi & Barbui, [9]). Six patients presented with two thrombotic events B . b The median follow-up period was 2-1 years (range, 0-1-7-8) with 18 patients initiated on DOACs (13 rivaroxaban 20 mg daily and 5 apixaban - 5 mg bd in four patients and 10 mg bd in one patient) and 14 patients changed from VKA or low molecular weight heparin (4 rivaroxaban, 9 apixaban and 1 edoxaban). [Extracted from the article]

Summary: Allogeneic Haematopoietic Stem Cell Transplant (allo‐HSCT) remains the only curative approach for Myelofibrosis (MF). Scarce information exists in the literature on the outcome and, indeed, management of those MF patients who relapse following transplant. We hereby report on the management and outcome of 202 patients who relapsed post allo‐HSCT for MF. [ABSTRACT FROM AUTHOR]

Myelofibrosis ( MF) is a rare haematopoietic disorder, commonly diagnosed in the 6th decade: less than 20% are diagnosed before the age of 50 years. In this retrospective study we included all patients given a diagnosis of World Health Organization-defined primary or secondary MF when aged ≤50 years. Forty-three patients with a median age of 43 years were included. Median follow up was 44 months. Twenty-two (51%) harboured the JAK2 V617F mutation, 18/43 (42%) CALR, 0/43 (0%) MPL mutations and 3/43 (7%) were 'Triple Negative' ( TN). At the time of diagnosis, no significant differences existed in haematological and clinical phenotypes between JAK2, CALR and TN patients. The frequency of splenomegaly was greater ( P = 0·047) in the JAK2-mutated group compared to CALR-mutated patients. In the whole cohort, the 5-year probability of developing anaemia, thrombocytopenia and marked leucocytosis was 24%, 10% and 13% respectively. Finally, the cumulative incidence of thrombotic events and progression to acute myeloid leukaemia was 1% and 0·5% patient-year respectively. No death was reported during the follow-up. These findings suggest that MF in younger patients may have a more indolent course when compared to older patients. [ABSTRACT FROM AUTHOR]

Over the last decade, we have witnessed a massive increase in available clinical agents, both in the clinical trial setting and following commercial use approval, directed to reduced life expectancy as well as the considerable symptom, splenic and anaemia burden associated with myelofibrosis. Given the median age of onset of the disease, coupled with an ageing population globally, we will be caring for an increasingly aged myelofibrosis cohort in future years. We will need to adapt our approach, emphasizing the holistic management of the older individual with myelofibrosis accordingly. Out with the pharmacological management of the disease, consideration needs to be given to interventions based on concurrent illness, comprehensive geriatric assessments, frailty, polypharmacy and drug-drug interactions, nutritional issues, psychological concerns (depression, anxiety or distress), cognitive decline and social/economic aspects. Within this review, we summarise available data addressing these issues, outline knowledge gaps and suggest a summative and holistic approach to the older individual with myelofibrosis. [ABSTRACT FROM AUTHOR]

The article provides information on a study which examined the potential of thiamine deficiency in patients with myeloproliferative neoplasms (MPN), through blood thiamine tests in patients with myelofibrosis (MF) and other MPN. Topics discussed include treatments received such as a combination of panobinostat and ruxolitinib, median thiamine levels, and median spleen size based on imaging.

In November 2011, the United States Food and Drug Administration (FDA) approved the use of a novel Janus Kinase (JAK) 1/JAK2 inhibitor, INCB 018424 (ruxolitinib), for use in both intermediate and high risk myelofibrosis. Approvals of this agent in both Canada and Europe have followed most recently. The European Medicines Agency (EMA) concluded that ruxolitinib was indicated for disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera (PV) myelofibrosis, and post-essential thrombocythaemia (ET) myelofibrosis. In this review we will consider the rationale for targeting of the JAK-pathway, discuss the pharmacological profile of ruxolitinib and review the currently available clinical trial data. We will also postulate on the current and potential future roles of ruxolitinib within the MPN field. [ABSTRACT FROM AUTHOR]

Myelofibrosis ( MF) is a heterogeneous disease for which long-term, effective medical therapeutic options are currently limited. The role of allogeneic haematopoietic stem cell transplant ( AHSCT) in this population, many of whom are elderly, often provides a challenge with regard to the identification of suitable candidates, timing of transplantation in the disease course and choice of conditioning regimen. This review summarizes key findings from published data concerning AHSCT in MF and attempts to provide a state of the art approach to MF- AHSCT in 2012. In addition, we postulate on how the era of JAK inhibition might impact on transplantation for MF. [ABSTRACT FROM AUTHOR]

Heterogeneous practices exist across transplant centres regarding assessment prior to allogeneic haematopoietic cell transplantation (allo-HCT) for myelofibrosis, post-transplant monitoring and management of relapse. The 'Practice Harmonisation and Guidelines' and Myeloproliferative Neoplasms subcommittees of the Chronic Malignancies Working Party (CMWP) of the EBMT generated an electronic survey proposal to investigate approaches to the above aspects of myelofibrosis allo-HCT practice. This survey was sent to a total of 65 centres experienced in allo-HCT for myelofibrosis across Europe in February 2020. By time of survey closure, a total of 36 centres (55 %) had completed the survey. Responses were aggregated and reported in a comparative fashion. Marked variations in assessment prior to allo-HCT, JAK inhibitor management peri-transplant, molecular, histopathological and cytogenetic monitoring and approaches to the definition and management of relapse were apparent across surveyed centres. On the basis of these findings, future CMWP efforts will focus on defining guidelines for relapse definition in MF allo-HCT and also suggested optimal monitoring practices for the transplant community. [ABSTRACT FROM AUTHOR]

Myelofibrosis is classified as a 'Philadelphia-chromosome negative' clonal myeloproliferative disorder. The heterogeneity of this condition and patient population and array of often challenging clinical manifestations can frequently make therapeutic decisions challenging. Despite many advances in therapy with targeted and combination approaches, following an enhanced understanding of underlying disease pathogenesis, cure only remains achievable with allogeneic stem cell transplant. This option is often limited to a small group of younger transplant-eligible patients with more advanced disease who have both a suitable donor and no or few co-morbidities. In this article, we will discuss up-to-date disease prognostication, common clinical challenges associated with myelofibrosis and both standard and novel therapeutic approaches. Increasingly complex prognostic modelling utilises patient-specific, haematological and genomic parameters to improve the accuracy of risk assessment and predict disease progression. We will also focus on difficult clinical scenarios such as disease-associated anaemia, thrombocytopenia and extremes of age. Future and evolving therapies within this field are highly anticipated and novel JAK inhibitor and non-JAK inhibitor-based therapy will also be discussed, including the new challenge of how to switch from one JAK inhibitor therapy to another. [ABSTRACT FROM AUTHOR]

Highlights • We performed a retrospective review of 56 myelofibrosis patients transplanted from mismatched family donors. • Neutrophil engraftment at a median of 20days was observed in 82%. • Low rates of acute GVHD grades II to IV were observed in 28% (16% to 40%) and grades III to IV in 9% (2% to 16%). • Chronic GVHD at 1 year was found in 45% (32% to 58%). • Overall survival at 2years was 56% (41% to 70%). Abstract This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8 × 106/kg (range, 1.7 to 22.9; n = 43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion. [ABSTRACT FROM AUTHOR]