Myelofibrosis

OVERVIEW

MYELOFIBROSIS IS CHARACTERIZED BY BONE MARROW FIBROSIS, SYMPTOM BURDEN, SPLENOMEGALY, AND CYTOPENIAS

Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN)1 characterized by bone marrow fibrosis, symptom burden, splenomegaly, and cytopenias.2 Myelofibrosis is a disease with significant heterogeneity in natural history and symptom burden. Patients with myelofibrosis fall along a spectrum that ranges from those who are essentially asymptomatic to those who have severe symptoms that affect daily functioning and quality of life.3-5 Myelofibrosis can be a primary disease or it can be secondary to other conditions, including malignancies and other hematologic diseases.6

Although the precise etiology of myelofibrosis remains unknown, overactive Janus-associated kinase (JAK) pathway signaling is present in all patients with the disease.7,8 Multiple mechanisms, including genetic mutations,9-11 excessive production of cytokines,12 increased JAK1 signaling,13 and damaged intracellular signaling14 may play a role in overactive JAK pathway signaling.

Because myelofibrosis has a heterogeneous presentation, determining a patient’s prognosis can be difficult.15 However, progress in understanding the clinical variables associated with myelofibrosis has led to the development of prognostic scoring systems, including the International Prognostic Scoring System (IPSS). The IPSS estimates prognosis based on risk factors present at diagnosis.16

PREVALENCE/DEMOGRAPHICS

Myelofibrosis is a rare disease, with a prevalence of 16,000 to 18,500 patients in the United States.17 Although myelofibrosis can occur at any age, the median age at diagnosis ranges from 60 to 67 years.2,3 The disease affects both men and women.18

International Prognostic Scoring System (IPSS) for Myelofibrosis

The IPSS estimates myelofibrosis prognosis based on risk factors present at diagnosis.1,16 Learn more.

Pathophysiology

MYELOFIBROSIS IS CHARACTERIZED BY BONE MARROW AND BLOOD CELL ABNORMALITIES

Myelofibrosis is a progressive hematopoietic stem cell disorder19,20 characterized by bone marrow1,17,21 and blood cell abnormalities.17

Bone marrow abnormalities in myelofibrosis include excess fibrous tissue and an increase in megakaryocytes.2

Both marrow fibrosis and loss of hematopoietic cells drive extramedullary hematopoiesis, particularly in the spleen.23 Blood cell abnormalities in myelofibrosis include a reduction in the number of red blood cells and a variable or increased white blood cell count.17

Overactive JAK signaling is the primary driver of myelofibrosis progression.

Myelofibrosis is a complex disease characterized by multiple genetic, epigenetic, and cellular alterations. The primary driver of myelofibrosis, however, is overactive JAK signaling, including overactivation of both normal (wild-type) and mutated JAK1 and JAK2 expression.24

NO SINGLE HALLMARK MUTATION HAS BEEN IDENTIFIED FOR MYELOFIBROSIS

Although numerous JAK pathway mutations have been identified in patients with myelofibrosis, no single hallmark mutation has been identified for the disease.26-28 Approximately 50% of patients with myelofibrosis have the JAK2V617F mutation.28 As shown in the table to the left, several other JAK pathway-related mutations have been observed in patients with myelofibrosis, but the prevalence of any individual JAK pathway-related mutation other than JAK2V617F is 10% or less.28

Patients with myelofibrosis also have high levels of circulating inflammatory cytokines, such as interleukin-6, which likely contribute to a hypermetabolic state and cytokine-mediated systemic symptoms.7

SIGNS AND SYMPTOMS

CLINICAL PRESENTATION OF MYELOFIBROSIS

Myelofibrosis is a disease with significant heterogeneity in natural history and symptom burden. Patients with myelofibrosis fall along a spectrum from those who are essentially asymptomatic to those who have severe symptoms that affect daily functioning and quality of life.3-5

Disease-associated symptoms and clinical findings of myelofibrosis are listed below.2,35

These symptoms—such as the onset and impact of weight loss, and the degree and onset of anemia, fatigue, and bone pain—fall into clusters that vary among affected patients. In a study that included data from 329 patients with self-reported symptoms, myelofibrosis symptoms could be grouped into 4 clusters. The largest cluster was characterized by fatigue-dominant complaints. The cluster with the highest proportion of patients with primary myelofibrosis had the highest prevalence of prior thrombosis, prior hemorrhage, transfusions, and presence of laboratory abnormalities such as anemia, thrombocytopenia, and leukopenia.5

MOST PATIENTS WITH MYELOFIBROSIS PRESENT WITH SPLENOMEGALY AT DIAGNOSIS

At least 85% of patients with myelofibrosis present with splenomegaly at the time of diagnosis.35 Symptoms related to splenomegaly include abdominal fullness, early satiety, and pain under the left ribs that may be indicative of spontaneous splenic infarction.2

DIAGNOSIS

MYELOFIBROSIS IS DIAGNOSED BY EXCLUSION

Myelofibrosis is an uncommon MPN that may not initially be suspected because its signs and symptoms overlap with other malignant and hematologic disorders.35 An enlarged spleen may be detected on physical examination, or blood testing may yield abnormal results; anemia is a common finding.35

Myelofibrosis is diagnosed through a process of exclusion.36 A differential diagnosis should distinguish myelofibrosis from other MPNs and rule out other causes of bone marrow fibrosis (eg, infection, lymphoma, metastatic cancer, myelodysplastic syndromes, and hairy cell leukemia).36

WHO DIAGNOSTIC CRITERIA FACILITATE DIAGNOSIS OF PRIMARY MYELOFIBROSIS

Diagnostic criteria for primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) were established in 2008 by the World Health Organization (WHO).37

A diagnosis of PMF requires 3 major criteria and at least 2 minor criteria.37

Symptoms commonly present include fever, weight loss, night sweats, early satiety, and abdominal discomfort.38,39

IWG-MRT DIAGNOSTIC CRITERIA FACILITATE DIAGNOSIS OF POST-PV AND POST-ET MYELOFIBROSIS

PV and ET can progress to myelofibrosis, resulting in post-PV MF and post-ET MF, respectively.7,39,40 The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) has established a set of diagnostic criteria specific to post-PV MF and post-ET MF. As shown in the table to the right, the diagnoses require documentation of previous PV or ET by WHO criteria, presence of moderate to severe bone marrow fibrosis, and meeting 2 or more additional criteria.39,41

RISK, PROGNOSIS, AND SURVIVAL

PROGNOSIS

Because myelofibrosis has a heterogeneous presentation, determining a patient’s prognosis can be difficult.15 However, progress in understanding the clinical variables associated with myelofibrosis has led to the development of several prognostic scoring systems.1,15,16,42,43

PROGNOSIS BASED ON RISK FACTORS AT DIAGNOSIS

Early prognostic models, such as the International Prognostic Scoring System (IPSS) developed by the IWG-MRT,1,16 estimate prognosis based on risk factors present at diagnosis.15,38 The IPSS and similar models are therefore appropriate for newly diagnosed cases.38 The 5 adverse prognostic factors, 4 risk categories, and the estimated survival for patients in each category at diagnosis are shown in the table to the right.16

PROGNOSIS BASED ON DISEASE PROGRESSION

The Dynamic International Prognostic Scoring System (DIPSS), also developed by the IWG-MRT, takes into account progression of disease over time and can be used to evaluate prognosis as a patient’s condition evolves.15

DIPSS uses the same adverse prognostic factors as IPSS but weights them differently. In determining the risk categories, hemoglobin below 10 g/dL is given a score of 2, while the other risk factors are counted as 1.15 Survival by DIPSS risk category is shown in the table to the right.

MYELOFIBROSIS IS A PROGRESSIVE DISEASE

Myelofibrosis is associated with progressive constitutional symptoms, increasing splenomegaly, and worsening cytopenias. PV or ET may progress to a myelofibrotic stage41 and myelofibrosis itself can transform to secondary acute myelogenous leukemia.22 Leukemic transformation occurs in 8% to 23% of patients with myelofibrosis during the first decade after diagnosis.22

SURVIVAL

Median survival in myelofibrosis varies widely, with published estimates ranging from 1.5 to 14.2 years.16 One study of 1,054 patients with PMF examined the causes of mortality in patients with myelofibrosis. The results are shown in the following graph on the right. The most common cause of death was transformation to acute leukemia.16

CLINICAL CONSIDERATIONS

PATIENT SYMPTOM BURDEN

In clinical decision-making for patients with myelofibrosis, the risks of thrombosis and comorbid conditions (eg, metabolic syndrome, hypercholesterolemia, and diabetes) should be evaluated.38

Symptom burden is also an important consideration. In a survey that included 456 patients with myelofibrosis, patients reported symptoms that significantly compromised their3,4:

  • Social functioning
  • Physical activity
  • Independence with daily tasks
  • Global quality of life

From this work, investigators created and validated the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) Total Symptom Score (TSS), a 10-item instrument designed to monitor the most debilitating symptoms among patients with MPNs. The tool records the patient’s assessment of the incidence and severity of the following symptoms4:

  • Fatigue
  • Early satiety
  • Abdominal discomfort
  • Inactivity
  • Concentration problems
  • Night sweats
  • Itching
  • Bone pain
  • Fever
  • Weight loss

The tool can be used to provide a fast, accurate assessment of myelofibrosis symptom burden, track symptom burden over time, and guide subsequent myelofibrosis management decisions.4

FAQS

Q: What is the hallmark genetic mutation in patients with myelofibrosis?

A: In contrast to some other malignancies (eg, chronic myelogenous leukemia), no single hallmark mutation has been identified in patients with myelofibrosis.7,11 Notably, 50% of affected patients have the JAK2V617F mutation, but several other mutations have been reported in patients with myelofibrosis as well.13,28

Q: What percentage of patients with myelofibrosis have genetic mutations other than JAK2V617F?

A: The MPLW515L/K (TpoR) mutation and casitas B-lineage (CBL) lymphoma mutations are found in 5% to 10% of patients with myelofibrosis.31-33 The SH2B3 (LNK) mutation is found in 3% to 6% of patients.34 The JAK2 exon 12 mutation is seen rarely in patients with myelofibrosis.30

Q: How common is splenomegaly in myelofibrosis, and how does it affect patients?

A: Eighty-five percent or more of patients with myelofibrosis present with splenomegaly at the time of diagnosis.35 Symptoms related to splenomegaly include abdominal fullness, early satiety, and pain under the left ribs that may be indicative of spontaneous splenic infarction.2 Splenomegaly in myelofibrosis is a major independent cause of morbidity and can adversely affect quality of life.45

Q: What is the risk for progression to acute myelogenous leukemia for patients with myelofibrosis?

A: Leukemic transformation occurs in 8% to 23% of patients with myelofibrosis during the first decade after diagnosis.22

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