Fast Facts: Myelofibrosis: Reviewed by Professor Ruben A. Mesa

By D. McLornan and C.N. Harrison

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

• Language: English
• Publisher: S. Karger
• Release date: May 31, 2022
• ISBN: 9783318071092

Book preview

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.

1Presentation, 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 recommended that symptoms should be assessed using a specific score such as the MPN-symptom assessment form (MPN-SAF) or MPN10 (see Chapter 5).

Thrombosis and hemorrhage are also prevalent in patients with PMF and prefibrotic/early MF, in common with MPNs in general. Approximately one-third of patients present with anemia and most will develop it over the course of their disease. It most commonly develops at advanced stages and often coincides with thrombocytopenia. Leukemic transformation occurs in 10–20% of patients and is characterized by the persistent presence of at least 20% blasts in the blood or bone marrow.

Classification

The WHO classification system defines major and minor criteria to aid accurate diagnosis (see Table 3.1).⁴ MF is characterized by variable degrees of bone marrow fibrosis accompanied by megakaryocytic atypia and hyperplasia. In the early stages of MF, there is often increased