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Myeloproliferative neoplasms

The myeloproliferative neoplasms (MPNs) or disorders are a group of chronic disorders characterized by increased proliferation of neoplastic haematopoietic stem cells of one or more of the myeloid cell lineages, the erythroid, granulocytic, and megakaryocytic lineages. Unlike in myelodysplastic syndromes, the stem cells are nondysplastic. The classic MPNs are:

• Chronic myeloid leukaemia (see topic 28)
• Polycythaemia vera
• Essential thrombocythaemia
• Primary myelofibrosis

The main difference between CML and the other classic MPNs is that the BCR-ABL1 (Philadelphia chromosome) translocation only occurs in CML.

All MPNs can progress into acute myeloid leukaemia or secondary myelofibrosis leading to bone marrow failure.

Polycythaemia vera

Introduction

Polycythaemia vera (PV) is an MPN characterised by trilinear proliferation, i.e. growth of erythroid, granulocytic, and megakaryocytic cell lines, causing elevation of all three types of blood cells in the blood. It’s caused by an acquired gain-of-function mutation in the JAK2 gene which makes myeloid cells proliferate independently of the hormone EPO.

Clinical features

Despite an increased blood cell mass, most people are asymptomatic. However, the increased viscosity can cause hyperviscosity syndrome, consisting of mucosal bleeding, neurological symptoms, and visual changes. It can also predispose to both thrombosis and haemorrhage. Thrombosis can be venous (renal vein, mesenteric vein, portal vein, etc.) or arterial (stroke, MI). Hepatosplenomegaly is typical.

Diagnosis and evaluation

Labs show:

• Elevated Hct
• Elevated RBC
• Elevated WBC
• Elevated thrombocytes
• Decreased EPO

Blood smear shows normal cell morphology. Bone marrow biopsy shows a hypercellular bone marrow with trilinear proliferation. Genetic testing for JAK2 mutation confirms the diagnosis.

Treatment

The basic treatment is therapeutic phlebotomy to reach normal Hct levels and aspirin to prevent thrombosis. If there is a history of thrombosis or the patient is >60 years, cytoreductive therapy is also indicated. This involves cytoreductive drugs like hydroxyurea or pegylated interferon.

Essential thrombocythaemia

Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterised by proliferation of the megakaryocyte lineage only.

50% of ET cases are associated with JAK2 mutation. The remaining cases are caused by CALR or MPL mutations.

Clinical features

Most are asymptomatic. Symptoms are related to thrombotic or haemorrhagic episodes.

Diagnosis and evaluation

Labs show:

• Normal Hct
• Normal RBC
• Normal WBC
• Elevated thrombocytes

Blood smear shows large hypogranular platelets. Bone marrow biopsy shows megakaryocytic proliferation. Genetic testing for driver mutations confirms the diagnosis.

Treatment

The basic treatment is aspirin to prevent thrombosis. If there is a history of thrombosis or the patient is >60 years, cytoreductive therapy is also indicated. This involves cytoreductive drugs like hydroxyurea, anagrelide, or pegylated interferon.

Primary myelofibrosis

Introduction

Primary myelofibrosis (PMF), previously known as osteomyelofibrosis, is a myeloproliferative neoplasm characterised by proliferation of granulocyte and megakaryocyte lineages, as well as eventual deposition of fibrous connective tissue in the bone marrow.

PMF has two phases. In the prefibrotic phase, the bone marrow is hypercellular, while in the fibrotic phase, the bone marrow undergoes fibrosis.

50% of PMF cases are associated with JAK2 mutation. The remaining cases are caused by CALR or MPL mutations.

Clinical features

Asymptomatic presentations are rare. Patients have:

• Hepatosplenomegaly (especially spleen, can grow very large)
• Anaemia
• Thrombosis
• Bleedings
• Extramedullary haematopoiesis – because of myelofibrosis

Diagnosis and evaluation

Labs show:

• Decreased Hct
• Decreased RBC
• Elevated WBC
• Elevated thrombocytes

Blood smear shows teardrop RBCs and other immature/abnormal cells. Bone marrow biopsy shows a hypercellular bone marrow with megakaryocytic proliferation in the prefibrotic stage, and fibrotic bone marrow in the fibrotic stage. Genetic testing for driver mutations confirms the diagnosis.

Treatment

There are many treatment options, depending on the patient’s symptoms and risk:

• Interferon
• JAK inhibitor (ruxolitinib)
• Erythropoiesis-stimulating agents (ESA)
• Allogeneic HSCT