Fast Facts: Myelofibrosis

C.N. Harrison, D. McLornan

Description

Myelofibrosis is a myeloproliferative neoplasm that has markedly heterogeneous features. The clinical phenotype can range from initial indolent presentation, which may be stable for many years, through to marked cytopenias, debilitating constitutional symptoms, massive splenomegaly and an inherent risk of leukemic transformation. Despite many advances regarding molecular classification, prognostication models and rapeutic options over the last few decades, allogeneic stem cell transplantation remains the only curative option, yet is suitable only for a minority of patients. ‘Fast Facts: Myelofibrosis’ is written for health professionals by two leading experts in the field, and provides up-to-date guidance on its accurate diagnosis, risk stratification and management. It also provides key insights into the molecular biology underpinning the disease. This concise handbook is an indispensable read for anyone wanting to get up to speed with best practice in the diagnosis and care of people with myelofibrosis. Table of Contents: • Presentation, classification and epidemiology • Molecular biology and pathogenesis • Clinical assessment and diagnosis • Prognostic models • Treatment approaches • Allogeneic stem cell transplantation • Management of blast-phase myelofibrosis • Therapies in development

Sujets

• Hermatology
• Medical
• Médecine
• Hematology

Informations

• Publié par: S. Karger AG
• Date de parution: 31 mai 2022
• Nombre de lectures: 0
• EAN13: 9783318071092
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Fast Facts: Myelofibrosis
First published 2022
Text 2022 Donal McLornan, Claire N Harrison
2022 in this edition S. Karger Publishers Ltd
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ISBN 978-3-318-07080-4
McLornan D (Donal)
Fast Facts: Myelofibrosis/
Donal McLornan, Claire N Harrison
Medical illustrations by Graeme Chambers, Belfast, UK.
Typesetting by Amnet, Chennai, India.
Printed in the UK with Xpedient Print.
An independent publication made possible with sponsorship from Sierra Oncology. Sierra Oncology had the opportunity to review the text for medical accuracy; however, the authors retained full editorial control. Provided as an educational resource to Healthcare Providers by Sierra Oncology.
Contents
List of abbreviations
Introduction
Presentation, classification and epidemiology
Molecular biology and pathogenesis
Clinical assessment and diagnosis
Prognostic models
Treatment approaches
Allogeneic stem cell transplantation
Management of blast-phase myelofibrosis
Investigational therapies
Useful resources
Index
List of abbreviations
ACVR1: activin A receptor type 1 (also known as ALK2)
allo-SCT: allogeneic stem cell transplantation
AML: acute myeloid leukemia
ATP: adenosine triphosphate
BAT: best-available therapy
BCL-2: B-cell lymphoma 2
BCR-ABL : a fusion gene located on the Philadelphia chromosome
BET: bromodomain and extraterminal (motif)
bp: base pair
BP-MF: blast-phase myelofibrosis
CALR: calreticulin
CI: confidence interval
CML: chronic myeloid leukemia
CR: complete response
DIPSS: Dynamic International Prognostic Scoring System
DLI: donor lymphocyte infusion
DNA: deoxyribonucleic acid
EBMT: European Society for Blood and Marrow Transplantation
EMA: European Medicines Agency
EMH: extramedullary hematopoiesis
EPO: erythropoietin
EPOR: erythropoietin receptor
ESA: erythropoiesis-stimulating agent
ET: essential thrombocythemia
ETS: erythroblast transformation
FDA: Food and Drug Administration
FLT3: FMS-like tyrosine kinase-3
G-CSFR: granulocyte colony-stimulating factor receptor
GIPSS: Genetically Inspired Prognostic Scoring System
Hb: hemoglobin
HMA: hypomethylating agent
HMR: high molecular risk
HSC: hematopoietic stem cell
IFN: interferon
IPSS: International Prognostic Scoring System
IWG-MRT: International Working Group for MPN Research and Treatment
JAK: Janus kinase
LCM: left costal margin
LDH: lactate dehydrogenase
LSD1: lysine-specific demethylase-1
MAC: myeloablative conditioning
MAPK: mitogen-activated protein kinase
MDM2: murine double minute 2
MF: myelofibrosis
MIPSS: Mutation-Enhanced International Prognostic Scoring Systems
MPL: myeloproliferative leukemia virus oncogene
MPN: myeloproliferative neoplasm
MPN-SAF: Myeloproliferative Neoplasm-Symptom Assessment Form
MRD: measurable residual disease
MUD: matched unrelated donor
MYSEC-PM: Myelofibrosis Secondary to PV and ET-Prognostic Model
NCCN: National Comprehensive Cancer Network
OS: overall survival
PET-MF: post essential thrombocythemia myelofibrosis
PI3K: phosphatidylinositol 3-kinase
PMF: primary myelofibrosis
PPV-MF: post polycythemia vera myelofibrosis
PV: polycythemia vera
RBC: red blood cell
RIC: reduced-intensity conditioning
RNA: ribonucleic acid
STAT: signal transducer and activator of transcription
TGF: transforming growth factor
TPOR: thrombopoietin receptor
TSS: Total Symptom Score
WHO: World Health Organization
Introduction
Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm that has markedly heterogeneous features. The clinical phenotype can range from initial indolent presentation, which may be stable for many years, through to marked cytopenias, debilitating constitutional symptoms, massive splenomegaly and an inherent risk of leukemic transformation. Many advances focused on MF regarding molecular classification, enhanced prognostication models and available therapeutic options have been made over the last few decades. Suggested management algorithms have become more complex and there are numerous novel agents in advanced clinical trials, hence updated knowledge of these therapeutics is required. Despite these advances, allogeneic stem cell transplantation (allo-SCT) remains the only curative option, yet is suitable only for a minority of patients.
Within this book we cover key points on epidemiology and clinical presentation, summarize advances in molecular characterization and prognostication, and highlight key advances within the MF therapeutic arena. We also summarize state-of-the-art knowledge on the role of allo-SCT and discuss the most promising agents in clinical trials. The target audience is wide and includes hematologists, oncologists, primary care providers and trainees, as well as pharmacists and specialist nurses in these fields.
After reading Fast Facts: Myelofibrosis you will:
understand how MF presents and progresses, and how to use various risk stratification systems to guide the approach to treatment and assessment of prognosis
appreciate the molecular biology underpinning the disease
appreciate how to comprehensively assess the impact of overall disease burden, including cytopenia, splenomegaly and other symptoms
understand current treatment approaches and the rationales behind them
understand the role of allo-SCT
understand how blast-phase MF is managed
be aware of ongoing clinical trials to assess novel therapeutics for the treatment of MF.
1 Presentation, classification and epidemiology
Presentation
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) characterized by a proliferation of abnormal megakaryocytes and granulocytes in the bone marrow, which in overt/fibrotic stages is associated with a polyclonal increase in fibroblasts that drives a secondary marrow fibrosis (reticulin-staining fibrosis collagen fibrosis), occasional osteosclerosis and extramedullary hematopoiesis (EMH). On occasion, PMF may present in an earlier prefibrotic state, which is characterized by a hypercellular bone marrow and minimal or absent reticulin fibrosis; many, but not all, of these patients progress to overt PMF. Around 50% of patients managed in clinics with myelofibrosis (MF) will have had antecedent essential thrombocythemia (ET) or polycythemia vera (PV), thus their disease is termed post ET MF (PET-MF) or post PV MF (PPV-MF), respectively. As a collective whole, we refer to the entire population of patients in these categories as having MF.
MF is a more aggressive condition than ET, PV or indeed prefibrotic/early MF. It is progressive and frequently has profound effects on the quality of life of affected patients. Analogous to the concept of chronic and accelerated phases in chronic myeloid leukemia (CML), it seems likely that PMF represents presentation in an accelerated phase of a previously undiagnosed MPN. Consistent with this concept, patients with PMF harbor more mutations, have more cytogenetic abnormalities and have increased risk of leukemic transformation. Up to one-third of patients are asymptomatic at diagnosis, and many cases are discovered after unrelated blood tests showing modest abnormalities, such as anemia and thrombocytopenia.
Using globally accepted transformation criteria, rates of myelofibrotic evolution from PV are estimated at 5-14% and cumulative risks of PET-MF are estimated at 9.3% at 15 years. 1 For ET, transformation rates are lower than for PV, with PET-MF frequently occurring later in the disease course. Historically, risk factors for transformation have been based loosely on age, disease duration, use of sequential DNA-damaging agents, cytogenetic anomalies, advancing disease burden and limited genomic profiling, which frequently reveals disparate signatures. 2 , 3
Splenomegaly is common, progressive and often massive, with the spleen being the commonest site of EMH in PMF. The liver is also usually involved and this can lead to significant hepatomegaly. Other, more unusual sites can sometimes be affected, leading to hematopoietic tumors surrounded by a capsule of connective tissue. Such sites include the lymph nodes, central nervous system, skin, pericardium, peritoneum, pleura, ovaries, kidneys, adrenal glands, gastrointestinal tract and lungs.
A hypermetabolic state presenting with fevers, anorexia, weight loss and night sweats can develop in many cases of MF, sometimes early on in the disease. Other symptoms are often present, particularly fatigue, bone pain and spleen-related symptoms such as pain and early satiety. The presence of specific symptoms - weight loss, night sweats and fever - is prognostically significant. It is generally recomme