Myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are a group of disorders characterized by a proliferation of malignant hematopoietic stem cells that belong to the myeloid cell lineage. The most clinically relevant MPN include chronic myeloid leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET). An important etiological factor is the mutation of the Janus kinase-2 (JAK2) gene, which is present in almost all cases of PV and in approximately 50% of patients with ET and PMF. In contrast to the other subtypes, CML is characterized by a distinct translocation between chromosome 9 and 22 (BCR-ABL1 fusion gene). Each of these neoplasms has a typical pattern of cell proliferation: granulocytes are increased in CML, thrombocytes in ET, and all cell lines show increased proliferation in PV. PMF, on the other hand, shows an initial hyperproliferative phase, but eventually progresses to pancytopenia. All myeloproliferative neoplasms may lead to elevated uric acid levels and gout as a result of increased cellular breakdown. They are also associated with an increased risk of acute myeloid leukemia. Treatment involves hydroxyurea to reduce the cell count, polychemotherapy to halt the proliferation of malignant cells, and, in young patients, allogeneic stem cell transplantation.

According to the WHO classification, the following disorders belong to the group of myeloproliferative neoplasms:

• Chronic myeloid leukemia
• Polycythemia vera
• Primary myelofibrosis
• Essential thrombocythemia
• Chronic eosinophilic leukemia

With the exception of CML, all of these disorders show varying degrees of JAK2 mutations, which can be used as a diagnostic marker. The mutation causes the exchange of two amino acids (valine → phenylalanine), which, in turn, results in dysregulation of the tyrosine kinase JAK2.

References:^[1][2][3]

• Description: : any myeloproliferative neoplasm leading to bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly.
• Epidemiology: : peak incidence between age 60–70 years
• Etiology: unknown
• Genetics: JAK2 mutation in 50% of cases

Clinical features

• Weakness, fatigue, weight loss
• Splenomegaly: left upper quadrant abdominal pain
• Hyperproliferative phase (early phase): thrombocytosis (→ thromboembolic events) and leukocytosis
• Pancytopenic phase (late phase):
  • Erythrocytopenia → anemia
  • Thrombocytopenia → petechial bleeding
  • Leukopenia → increased susceptibility to infections

Diagnosis

• Laboratory studies: ↑ leukocyte alkaline phosphatase; , LDH, and uric acid
• Peripheral blood smear: dacrocytes (teardrop cells)
• Bone marrow aspiration: punctio sicca

Treatment

• Curative: allogeneic stem cell transplantation; (option for younger patients)
• Supportive
  • Hyperproliferative phase
    • Prevent thromboembolisms; : antiplatelet drug (aspirin 100 mg)
    • Control cell count: hydroxyurea, interferon alpha, cladribine
  • Pancytopenic phase
    • JAK2 inhibitor: ruxolitinib
    • Periodic transfusions
    • Low-dose thalidomide plus glucocorticoids

In myelofibrosis, RBCs shed tears (teardrop cells), because they have been forced out of the fibrosed bone marrow (extramedullary hematopoiesis).

References:^[4][5][6][7]

Overview

• Epidemiology
  • Median age at diagnosis: 60 years
  • ♀ > ♂ (2:1)
• Etiology
  • JAK2 mutation in 50% of cases
  • CALR mutation
  • MPL mutation

Clinical features

• Asymptomatic in 50% of cases
• Thromboembolic events
• Increased risk of fetal loss
• Vasomotor symptoms (headache, visual disturbances, acral paresthesias)
• Acute gouty arthritis
• Petechial bleeding
• Erythromelalgia

Diagnostics ^[8]

ET is a diagnosis of exclusion; all other causes of thrombocytosis must be ruled out before the diagnosis can be made.

• Thrombocytosis (> 600,000/μL)
• ↑ LDH and uric acid
• Bone marrow aspiration: hyperplasia of megakaryocytes

Differential diagnosis

• Reactive thrombocytosis: platelet proliferation as a reaction to a certain condition, and not because of an intrinsic defect
• See also “Thrombocytosis.”

Treatment

• Prevent thromboembolisms; : low dose aspirin
• Reduce thrombocyte count: hydroxyurea or interferon alpha

Complications

• Acquired von Willebrand disease (AVWD) ^[9][10]

• Description: leukemia with monoclonal proliferation of eosinophilic granulocytes, that causes peripheral eosinophilia and tissue damage
• Clinical features
  • Hepatosplenomegaly
  • Anemia; and/or coagulation disorders
• Diagnosis
  • CBC: ↑↑↑ eosinophilic granulocytes
  • Peripheral blood smear and bone marrow aspiration: monoclonal blast cells or cytogenetically abnormal eosinophils

References:^[11]

1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127 (20): p.2391-2405. doi: 10.1182/blood-2016-03-643544 . | Open in Read by QxMD
2. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018; 8 (2): p.15. doi: 10.1038/s41408-018-0054-y . | Open in Read by QxMD
3. Er T-K, Lin S-F, Chang J-G, et al. Detection of the JAK2 V617F missense mutation by high resolution melting analysis and its validation. Clin Chim Acta. 2009; 408 (1-2): p.39-44. doi: 10.1016/j.cca.2009.07.002 . | Open in Read by QxMD
4. Mantadakis E, Tsalkidis A, Chatzimichael A. Thrombocytosis in childhood.. Indian Pediatr. 2008; 45 (8): p.669-677.
5. Michiels JJ. Acquired von Willebrand Disease Due to Increasing Platelet Count Can Readily Explain the Paradox of Thrombosis and Bleeding in Thrombocythemia. Clinical and Applied Thrombosis/Hemostasis. 1999; 5 (3): p.147-151. doi: 10.1177/107602969900500301 . | Open in Read by QxMD
6. Awada H, Voso M, Guglielmelli P, Gurnari C. Essential Thrombocythemia and Acquired von Willebrand Syndrome: The Shadowlands between Thrombosis and Bleeding. Cancers. 2020; 12 (7): p.1746. doi: 10.3390/cancers12071746 . | Open in Read by QxMD
7. Chronic Myeloid Neoplasms - Myeloproliferative Neoplasms (MPN). http://www.pathologyoutlines.com/topic/myeloproliferativeCEL.html. Updated: March 14, 2018. Accessed: April 1, 2018.
8. Tefferi A. Clinical Manifestations and Diagnosis of Primary Myelofibrosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-primary-myelofibrosis.Last updated: February 13, 2017. Accessed: April 14, 2017.
9. Lal A. Primary Myelofibrosis. In: Besa EC, Primary Myelofibrosis. New York, NY: WebMD. http://emedicine.medscape.com/article/197954. Updated: January 30, 2017. Accessed: April 15, 2017.
10. Tefferi A. Management of Primary Myelofibrosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/management-of-primary-myelofibrosis.Last updated: February 13, 2017. Accessed: April 15, 2017.
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12. Herold G. Internal Medicine. Herold G ; 2014