Primary Myelofibrosis

Primary myelofibrosis (PMF) is a rare form of bone marrow blood cancer classified by the World Health Organisation (WHO) as a type of myeloproliferative neoplasm. This group of cancers is characterised by the activation and growth of mutated cells in the bone marrow, often associated with somatic mutations in the JAK2, CALR, or MPL genes. In PMF, the bone marrow undergoes remodelling through osteosclerosis and fibrosis, leading to compromised bone marrow function and decreased production of essential blood cells such as erythrocytes, granulocytes, and megakaryocytes.

Signs and Symptoms

The primary feature of PMF is bone marrow fibrosis, often accompanied by:

• Abdominal fullness and splenomegaly due to extramedullary haematopoiesis.
• Bone pain and easy bruising or bleeding due to low platelet numbers.
• Increased risk of thrombosis, cachexia, fatigue, fever, chills, and weight loss.
• Gout and high uric acid levels, increased susceptibility to infections like pneumonia.
• Pallor and shortness of breath due to anaemia.
• Unique blood smear findings such as tear-drop-shaped RBCs, nucleated RBCs, and immature granulocytes.
• In rare cases, cutaneous myelofibrosis, characterised by dermal and subcutaneous nodules.

Causes

PMF is almost always related to acquired mutations in the JAK2, CALR, or MPL genes in haematopoietic stem/progenitor cells in the bone marrow. Approximately 90% of PMF patients have one of these mutations. The most common mutation is in the JAK2 gene, resulting in a variant protein (V617F) that leads to the constitutive activation of pathways controlling blood cell production. MPL gene mutations result in a constitutively active thrombopoietin receptor, enhancing platelet production and stimulating fibroblasts to secrete excess collagen.

Mechanism

PMF is a clonal neoplastic disorder of haematopoiesis. Abnormal haematopoietic cells, particularly megakaryocytes, produce cytokines like fibroblast growth factor, leading to collagen fibrosis and the replacement of normal bone marrow tissue. This fibrosis impairs blood cell production, causing pancytopenia. The resulting extramedullary haematopoiesis, primarily in the spleen and liver, causes organ enlargement and further contributes to pancytopenia.

Diagnosis

PMF typically develops slowly and is observed in individuals over 50 years old. Diagnosis is based on bone marrow biopsy, revealing fibrosis of grade 2 or 3 for overt PMF and grade 0 or 1 for prefibrotic PMF. Physical exams may reveal splenomegaly and hepatomegaly.

Treatment

The only curative treatment for PMF is allogeneic stem cell transplantation, which carries significant risks. Other treatments are mainly supportive and include folic acid, allopurinol, blood transfusions, and medications like dexamethasone, alpha-interferon, and hydroxyurea. Lenalidomide and thalidomide may be used, though they have side effects like peripheral neuropathy.

Splenectomy may be considered for patients with massive splenomegaly contributing to anaemia due to hypersplenism. However, this procedure carries a high mortality risk.

Several drugs have received FDA approval for PMF treatment:

• Ruxolitinib (Jakafi): An inhibitor of JAK 1 and 2, shown to reduce spleen volume and improve survival rates.
• Fedratinib (Inrebic): Approved for intermediate-2 or high-risk PMF.
• Pacritinib (Vonjo): Approved for PMF patients with low platelet levels.
• Momelotinib (Ojjaara): Approved for intermediate or high-risk PMF with anaemia.

History

PMF was first described in 1879 by Gustav Heuck and further characterised by Herbert Assmann in 1907 and William Dameshek in 1951. It was previously known by various names, including myelofibrosis with myeloid metaplasia and chronic idiopathic myelofibrosis. In 2008, the WHO adopted the name primary myelofibrosis, and in 2016, they classified prefibrotic primary myelofibrosis as a distinct clinical entity.

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Self-assessment MCQs (single best answer)

What type of cancer is Primary Myelofibrosis (PMF) classified as by the World Health Organisation (WHO)?

Which gene mutation is most commonly associated with Primary Myelofibrosis?

What is the primary feature of Primary Myelofibrosis?

Which of the following is NOT a common symptom of Primary Myelofibrosis?

What is the main curative treatment for Primary Myelofibrosis?

Which of the following drugs is an inhibitor of JAK 1 and 2 and is approved for the treatment of Primary Myelofibrosis?

What is the mechanism by which abnormal haematopoietic cells in PMF lead to fibrosis?

What is a significant finding on a blood smear in patients with Primary Myelofibrosis?

What age group is most commonly affected by Primary Myelofibrosis?

Who first described Primary Myelofibrosis in 1879?