Myeloproliferative neoplasm natural history, complications, and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

The natural history of myeloproliferative neoplasm begins with weight loss, fever, and night sweats. The natural history depends on the subtype of myeloproliferative neoplasm. Common complications of myeloproliferative neoplasm include splenomegaly, bleeding, thrombosis, bone marrow fibrosis, and acute leukemia. Prognosis depends on the subtype of myeloproliferative neoplasm. Each subtype has its own prognostic scoring system. In general, patients with polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia have better prognosis than patients with primary myelofibrosis. The prognosis is generally good with treatment.

Natural History

The symptoms of myeloproliferative neoplasm usually develop in the sixth decade of life and start with symptoms such as anorexia, weight loss, and fatigue. The onset of symptoms is usually insidious, and the symptoms do not frequently cause many problems initially. The disease progresses quite slowly, typically over a period of months to years. However, without treatment, patients will develop severe symptoms, such as abdominal pain, bruising, bleeding, thrombosis, fever, and infection which may eventually lead to death. The natural history of myeloproliferative neoplasm is dependent upon the subtype of myeloproliferative neoplasm and by the prognostic group. The natural history of myelodysplastic syndrome / myeloproliferative neoplasm overlap syndrome (MDS/MPN) is poor. In general, the natural history of patients above the age of 60, the presence of a JAK2 mutation, and a history of thrombosis is worse than the natural history of patients under age 60, the absence of JAK2 mutation, and no history of thrombosis. Thrombosis is an inevitable part of the natural history of many subtypes of myeloproliferative neoplasms, especially polycythemia vera and essential thrombocythemia. Approximately 41% of patients with polycythemia vera, for example, will experience thrombosis.

Complications

Myeloproliferative neoplasm may lead to the following complications:

• Thrombosis: Clot formation occurs in 15% of patients with myeloproliferative neoplasm.

• Deep venous thrombosis: Clots can develop in the deep veins of the lower extremities, such as the popliteal vein or femoral vein.
• Pulmonary embolism: Clots can develop in the segmental or subsegmental arteries of the pulmonary vasculature.
• Myocardial infarction: Clots can develop within the coronary arteries, and this is usually exacerbated by underlying cardiac risk factors.
• Stroke: Clots can develop in the anterior or posterior circulation in the brain.
• Budd-Chiari syndrome: Clots can develop in the hepatic vein.
• Splanchnic vein thrombosis: Clots can develop in mesenteric vasculature like the splenic vein, superior mesenteric vein, inferior mesenteric vein, or portal vein.

• Bleeding: Bleeding is especially common in patients with essential thrombocythemia with very high platelet counts, as this leads to a paradoxical effect known as acquired von Willebrand disease. In this condition, platelets interfere with the function of von Willebrand factor.

• Epistaxis: Bleeding can occur in the anterior or posterior circulation of the nasal cavity.
• Gingival bleeding: Bleeding gums is typically seen after brushing teeth.
• Menorrhagia: Pelvis bleeding commonly occurs in pre-menopausal females.
• Metrorrhagia: Irregular pelvic bleeding can occur in pre-menopausal females.
• Petechiae: Pinpoint hemorrhages can occur in the skin.

• Splenomegaly: Extramedullary hematopoiesis occurs when the bone marrow is unable to sustain normal cell production.
• Gout: Gout occurs most often in patients with polycythemia vera.
• Peptic ulcer

• Clonal proliferation

• Myelofibrosis: This is a condition in which the bone marrow becomes replaced by collagen and reticulin fibers. When myelofibrosis occurs in the setting of polycythemia vera, it is referred to as post-polycythemia vera (post-PV) myelofibrosis. When myelofibrosis occurs in the setting of essential thrombocythemia, it is referred to as post-essential thrombocythemia (post-ET) myelofibrosis. Myelofibrosis carries an overall poor prognosis given that collagen fibers preclude normal hematopoiesis, resulting in infections, bleeding, and fatigue.

• Acute myeloid leukemia: This is a malignancy of the hematopoietic stem cell (specifically myeloid precursors). It is characterized by clonal proliferation and resultant cytopenias and ineffective hematopoiesis. Patients typically die as a result of infections and/or bleeding.

• End-organ damage: Deposition of myeloid cells in organs can result in permanent organ damage. This is especially true to chronic eosinophilic leukemia, in which eosinophils can deposit in the lungs, heart, or other tissues and impair the function of these organs.

• Microvascular symptoms

• Hearing impairment
• Visual impairment
• Paresthesia
• Headache

Prognosis

The prognosis of myeloproliferative neoplasm depends upon the subtype. Each subtype of myeloproliferative neoplasm has a different prognostication system. Overall, the prognosis for patients with polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia is good, and prognosis of primary myelofibrosis is worse. For example, the median survival of patients with polycythemia vera is 33 years. The median survival of patients with essential thrombocythemia is 24 years.

Polycythemia vera

In polycythemia vera, patients are prognosticated based on two risk groups as follows:

Prognostic Group	Defining Features
Low risk	No history of thrombosis, and Age < 60
High risk	History of thrombosis, or Age > 60

Essential thrombocythemia

In essential thrombocythemia, patients are prognosticated based on four risk groups as follows:

Prognostic Group	Defining Features
Very low risk	No history of thrombosis Age < 60 JAK2 or MPL wild-type
Low risk	No history of thrombosis Age < 60 JAK2 or MPL mutation present
Intermediate risk	No history of thrombosis Age > 60 JAK2 or MPL wild-type
High risk	History of thrombosis, or Age > 60 with JAK2 or MPL mutation present

Primary myelofibrosis

In primary myelofibrosis, patients are prognosticated into four risk groups, based on the Dynamic International Prognostic Scoring System (DIPSS). The adverse prognostic features are age > 65 years, white blood cell count > 25,000/microliter, hemoglobin < 10 g/dl, peripheral blood blast count > 1%, and presence of constitutional symptoms. Each adverse prognostic feature is assigned 1 point (except 2 points for hemoglobin < 10g/dl).

Prognostic Group	Points
Low risk	0
Intermediate-1 (INT-1) risk	1 or 2
Intermediate-2 (INT-2) risk	3 or 4
High risk	5 or 6

Recently, the DIPSS scoring system was revised to 3 additional adverse features. These adverse features include platelet count < 100,000 per microliter, transfusion dependence, and unfavorable karyotype (monosomy 5, monosomy 7, trisomy 8, isochromosome 17, chromosome 11q23 rearrangement (MLL gene rearrangement). This new system is known as DIPSS-Plus and is used when karyotype information is available.

Prognostic Group	Points
Low risk	0
Intermediate-1 (INT-1) risk	1
Intermediate-2 (INT-2) risk	2 or 3
High risk	4 to 6

Chronic myeloid leukemia

In chronic myeloid leukemia, the prognostication is based on the Sokal score, which includes age, spleen size, platelet count, and blast count.

Prognostic Group	Sokal Score	Median Survival
Low risk	< 0.8	5 years
Intermediate risk	0.8-1.2	2-2.5 years
High risk	>1.2	2.5 years

Without treatment, Myeloproliferative neoplasm may result in death. The 5- and 10-year survival rates for myeloproliferative neoplasm are 74% to 93% and 61% to 84%, respectively. Gene expression profiling may eventually have an important role in the prognostication of myeloproliferative neoplasm.