Primary Myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis, which include severe fatigue, weight loss, and hepatosplenomegaly. Laboratory findings include anemia (and other cytopenias), and bone marrow biopsy reveals extensive fibrosis. Management is with hematopoietic stem cell transplantation and symptom-directed interventions.

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Overview

Definition

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by proliferation of myeloid cells, with nonclonal fibroblast proliferation and hyperactivity, resulting in an obliterative marrow fibrosis. Other names include chronic idiopathic myelofibrosis and agnogenic myeloid metaplasia.

Epidemiology

  • 0.5–1.5 cases per 100,000 individuals in the United States
  • Prevalence: 4–6 per 100,000 population
  • Increased prevalence in Ashkenazi Jews
  • Male > females
  • Generally occurs at > 50 years of age, with a median age of 65 years

Etiology

  • Generally unknown
  • Linked to the following risk factors/exposures:
    • Thorium dioxide (thorium-based radiographic contrast material)
    • Petroleum-manufacturing plants (toluene and benzene)
    • Ionizing radiation
    • Atomic bomb at Hiroshima
  • About 90% of cases have mutations involving JAK2, CALR, or MPL.
    • Janus kinase 2 (JAK2) mutation: 60%–65% of patients
    • MPL mutation: 5% of patients
    • CALR mutation: 20%–25% of patients
  • No JAK2, CALR, or MPL mutation (triple-negative): 8%–10% of patients

Pathophysiology

Hematopoiesis

Hematopoiesis starts with the hematopoietic stem cell, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors)

  • Lymphoid stem cell: gives rise to lymphocytes
  • Myeloid stem cell: eventually differentiates into platelets, erythrocytes, granulocytes (neutrophils, basophils, eosinophils) and monocytes:
    • IL-3 stimulates the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells
    • Granulocyte macrophage colony-stimulating factor (GM-CSF) → differentiation from myeloid progenitors to granulocytes (neutrophils) and monocytes 
    • IL-5 → differentiation to eosinophils
    • Thrombopoietin (TPO) → differentiation to thrombocytes (platelets)
    • Erythropoietin (EPO) → differentiation to erythrocytes (RBCs)
Bone marrow hematopoiesis

Bone-marrow hematopoiesis: proliferation and differentiation of the formed elements of blood.
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer
TPO: thrombopoietin

Image by Lecturio. License: CC BY-NC-SA 4.0

Mutations

Mutations in genes associated with hematopoiesis are noted in a significant proportion of cases of PMF.

  • Mutation of Janus kinase 2 (JAK2) gene:
    • Affects JAK2:
      • A non-receptor tyrosine kinase (encoded by JAK2 gene) in the cytoplasm involved in signal transduction (JAK–signal transducer of activators of transcription (STAT) pathway) 
      • Mediates the cellular response to growth factors and cytokines
    • Effect:
      • Rapid hematopoietic cell division and maturation, with a large number becoming megakaryocytes
      • Stimulation of megakaryocytes to secrete fibroblast growth factors
  • Mutations of the MPL gene:
    • MPL codes for the thrombopoietin receptor protein.
    • Effect: constitutive activation of thrombopoietin receptor 
  • Mutations of CALR gene:
    • CALR codes for calreticulin.
    • Calreticulin is a Ca2+-binding protein in the JAK–STAT pathway and is essential in cellular proliferation and apoptosis.
    • Effect: induces thrombopoietin receptor activation
Mutations underlying the pathophysiology of myelofibrosis

Mutations underlying the pathophysiology of myelofibrosis:
Commonly affects the JAK–STAT pathway
JAK2 (JAK2 gene involved): non-receptor tyrosine kinase facilitating extracellular signals to reach the nucleus and activate genes.
MPL or thrombopoietin receptor (MPL gene involved): activation of the thrombopoietin receptor
Calreticulin (CALR gene involved) is a regulator of STAT, and mutation causes activation of thrombopoietin receptor.

Image: “Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib” by Bryan JC, Verstovsek S. License: CC BY 4.0

Bone marrow fibrosis

  • With atypical megakaryocytic hyperplasia, there is inappropriate output of fibrogenic factors, including:
    • Transforming growth factor β (TGF-β): 
      • Major cytokine derived from megakaryocytes
      • ↑ Collagen deposition and angiogenesis
      • Interacts with thrombopoietin
    • Platelet-derived growth factor (PDGF)
    • Epidermal growth factor (EGF)
  • Bone marrow fibrosis (fibroblastic and stromal deposition) progresses, leaving no room for hematopoiesis → extramedullary hematopoiesis in the spleen and liver

Clinical Presentation

  • Approximately 15%–30% of patients are asymptomatic.
  • Anemia:
    • Fatigue (most common symptom)
    • Shortness of breath
    • Palpitations
  • Hypermetabolic state:
    • Weight loss
    • Night sweats
    • Fever
  • Extramedullary hematopoiesis: 
    • Splenomegaly:
      • LUQ abdominal tenderness
      • Abdominal fullness with early satiety
      • Left shoulder pain: due to inflammation of tissues around spleen
    • Hepatomegaly (with complications such as portal hypertension, ascites)
  • Bone and joint involvement:
    • Can cause severe bone and joint pain, especially in the lower extremities
    • Osteosclerosis:
      • Diffuse or patchy increase in bone density
      • Prominent/thick bony trabeculae
      • Mottled bone on X-ray in up to 66% of patients
    • Gout, from increased uric acid production 

Diagnosis

Initial evaluation

  • Historical details and symptoms
  • Examination:
    • Fever
    • Spleen enlargement (hallmark physical finding of PMF)
    • Hepatomegaly
    • Bone tenderness
    • Increased warmth over the tibias and knees due to increased cortical blood flow

Diagnostic tests

  • CBC:
    • Anemia (50% of patients will have hemoglobin < 10 g/dL) 
    • Platelets:
      • Early stage: either thrombocytosis or thrombocytopenia
      • Late stage: predominantly thrombocytopenia 
    • WBC count:
      • Variable: leukocytosis or leukopenia
      • Reflects variation in neutrophils
  • Biochemistry:
    • ↑ LDH: ineffective hematopoiesis
    • ↑ Uric acid: from increased cell turnover
    • ↑ Leukocyte alkaline phosphatase: liver and bone involvement
    • ↑ Vitamin B12: increased neutrophil mass
  • Peripheral blood smear:
    • Teardrop cells (dacrocytes): misshapen RBCs due to damage from marrow production
    • Leukoerythroblastosis: release of nucleated myeloid (“leuko”) and erythroid (“erythro”) cells that are immature (“blast”)
    • Anisocytosis and poikilocytosis
  • Bone marrow aspirate: dry tap (no blood cells)
  • Bone marrow biopsy:
    • Fibrosis: hallmark of PMF, seen in almost all patients
    • Megakaryocytic hyperplasia (with abnormal morphology)
    • Osteosclerosis 
  • Cytogenetic analysis:
    • JAK2 mutation (majority of cases)
    • CALR mutation
    • MPL mutation 
    • Triple-negative in up to 10%

Mnemonic

To remember PMF in summary: Bone marrow is crying (teardrop cells) because it is fibrosed and is a dry tap.

WHO diagnostic criteria

  • Major criteria (all 3 required):
    • Megakaryocytic proliferation and atypia, with reticulin and/or collagen fibrosis 
    • The following are ruled out the basis of WHO criteria:
      • Polycythemia vera (PV)
      • Essential thrombocythemia (ET)
      • CML
      • Myelodysplastic syndrome
      • Other myeloid neoplasm 
    • Demonstration of a JAK2, CALR, or MPL mutation or another clonal marker or reactive fibrosis ruled out
  • Minor criteria (confirmed in 2 consecutive measurements):
    • Anemia not attributable to a comorbid condition
    • Leukocytosis (≥ 11 × 10⁹/L)
    • Palpable splenomegaly
    • LDH above the upper limit of normal
    • Leukoerythroblastosis

Comparison with other myeloproliferative neoplasms

Myeloproliferative neoplasms can be compared with the following WHO classification:

Table: Classic types of myeloproliferative neoplasms
DiseaseMutationsKey points
CMLBCR-ABL1 (Philadelphia chromosome)Proliferation of mature and maturing granulocytes
ETJAK2, CALR, or MPLExcessive clonal platelet production
Polycythemia vera (PV)JAK2Elevated RBC mass
PMFJAK2, CALR, or MPLObliterative bone marrow fibrosis

Other types:

  • Chronic neutrophilic leukemia (CNL)
  • Chronic eosinophilic leukemia (CEL), not otherwise specified
  • Myeloproliferative neoplasm, unclassifiable

Management

Approach

Assessment of risk is important in making treatment decisions.

  • Risk stratification:
    • Reduced survival noted:
      • Old age
      • Anemia, thrombocytopenia
      • Leukocytosis, + blasts
      • Bone marrow fibrosis
      • Requires transfusion
      • Fever, weight loss, night sweats
    • Driver mutations:
      • CALR mutation: best outcome
      • Triple-negative: worst outcome
    • Other high-risk gene mutations are associated with poor prognosis (i.e., ASXL1).
  • More risk factors as listed above = higher risk of PMF
  • Transformation to acute leukemia:
    • Seen in minority of cases
    • Predictive factors:
      • Circulating blasts: ≥ 3%
      • Platelet count: < 100,000/µL

Options

  • High-risk PMF:
    • Hematopoietic stem cell transplantation if eligible
    • Clinical trial enrollment if not eligible for transplantation
    • Agents:
      • Janus-associated kinase inhibitors: ruxolitinib, fedratinib 
      • Hydroxyurea: relieve proliferative symptoms
  • Low-risk PMF: 
    • Asymptomatic patients: observation and monitoring 
    • Symptomatic patients: Janus-associated kinase inhibitors, hydroxyurea 
  • Splenectomy if symptomatic from massive splenomegaly
  • Transfusion as needed

Differential Diagnosis

Other chronic myeloproliferative neoplasms

  • Chronic myeloid leukemia (CML): malignant proliferation of the granulocytic cell line, with a fairly normal differentiation. Chronic myeloid leukemia has the Philadelphia chromosome, which contains the BCR-ABL1 fusion gene (which PMF does not have). The effect of constitutive tyrosine kinase activation leads to uncontrolled granulocytic production. Patients can have constitutional symptoms, sternal pain, and splenomegaly. Studies show elevated WBCs, increased immature cells in the peripheral blood smear, and Philadelphia chromosome demonstrated by cytogenetic techniques. Management includes tyrosine kinase inhibitors, allogeneic HCT and palliative agents.
  • Polycythemia vera (PV): condition also associated with mutation in the JAK2 gene. However, PV is from unregulated overproduction of mainly RBCs despite low levels of erythropoietin. The majority of patients present with hyperviscosity symptoms. Management includes phlebotomy, low-dose aspirin, and myelosuppressive therapies.
  • Essential thrombocythemia (ET): proliferation of megakaryocytes associated with genetic mutations (in JAK2, CALR, or MPL). The megakaryocytes are large and mature-appearing. Clinical manifestations include headaches, visual disturbances, and erythromelalgia. Excessive counts of platelets result in both thrombosis and bleeding. Management aims to reduce platelet count (with medications such as hydroxyurea) and decrease the risk of thrombosis (by systemic anticoagulation and/or antiplatelet agents). While ET and PMF share similar mutations, PMF has significant bone marrow fibrosis and leukoerythroblastosis in the peripheral blood smear. 
  • Chronic neutrophilic leukemia (CNL): rare disorder with proliferation of mature granulocytes in the blood and marrow. Organ infiltration can occur, leading to hepatosplenomegaly. Increased leukocyte alkaline phosphatase score is noted in this disorder. Chronic neutrophilic leukemia does not usually progress to AML. Management is less clear, but ruxolitinib is an option.
  • Chronic eosinophilic leukemia (CEL): rare clonal chronic myeloproliferative disorder characterized by excessive production of eosinophils in the bone marrow that leads to eosinophilic proliferation in the blood and organ infiltration (hepatomegaly/splenomegaly). Management is supportive and imatinib therapy.

Other disorders resembling primary myelofibrosis

  • Acute myelofibrosis: very rare form of AML in which there is rapid onset of severe bone marrow fibrosis. Other findings include teardrop RBCs, pancytopenia, and a leukoerythroblastic blood smear. Patients have fever, and the spleen is usually not palpable. Management is induction chemotherapy with or without hematopoietic stem cell transplantation.
  • Secondary myelofibrosis (post-ET or post-PV): Fibrosis of the bone marrow can develop in both PV and ET. Secondary myelofibrosis requires a previous diagnosis of either ET or PV. Clinical features and management are generally similar to those for PMF.

References

  1. Tefferi, A. (2021). Clinical manifestations and diagnosis of primary myelofibrosis, In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-primary-myelofibrosis
  2. Tefferi, A. (2021). Management of primary myelofibrosis. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/management-of-primary-myelofibrosis
  3. Tefferi, A. (2021). Pathogenic mechanisms in primary myelofibrosis. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/pathogenetic-mechanisms-in-primary-myelofibrosis?search=primary+myelofibrosis
  4. Visani, G., Finelli, C., Castelli, U., et al. (1990). Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients. Br J Haematol 75:4–9. https://pubmed.ncbi.nlm.nih.gov/2375922/
  5. DeLario, M.R., Sheehan, A.M., Ataya, R., et al. (2012). Clinical, histopathologic, and genetic features of pediatric primary myelofibrosis—an entity different from adults. Am J Hematol 87:461–464. https://pubmed.ncbi.nlm.nih.gov/22389089/
  6. Emanuel, R.M., Dueck, A.C., Geyer, H.L., et al. (2012). Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol 30:4098–4103. https://pubmed.ncbi.nlm.nih.gov/23071245/
  7. Deeg, H.J., Bredeson, C., Farnia, S., et al. (2015). Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups. Biol Blood Marrow Transplant. 21(11),1883–1887. https://pubmed.ncbi.nlm.nih.gov/26371371/
  8. Van Etten, R. (2021). Clinical manifestations and diagnosis of chronic myeloid leukemia. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-chronic-myeloid-leukemia
  9. Schiffer, C., Atallah, E. (2021). Overview of the treatment of chronic myeloid leukemia. In Larson, R. (Ed.), UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-chronic-myeloid-leukemia

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