Chapter 66: Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells that manifest clinically as overproduction of cells that contribute to the myeloid lineage

Classification WHO Myeloproliferative Neoplasm (MPN) Categories

1. Classic MPN

   • Chronic myelogenous leukemia (CML); see Chapter 21

   • Polycythemia vera (PV)^✫

   • Essential thrombocythemia (ET)^✫

   • Primary myelofibrosis (PMF)^✫

2. "Nonclassic" MPNs

   • Chronic neutrophilic leukemia (CNL)

   • Mast cell disease (MCD)

   • Chronic eosinophilic leukemia not otherwise categorized (CEL-NOC)

   • "MPN unclassifiable"

Epidemiology

BCR-ABL–negative classic MPN

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)

Polycythemia vera (PV)

1. Incidence: 0.8–2.6/100,000

2. Median age at diagnosis: ≈60 years

3. Median survival: >15 years

4. 10-year risk of myelofibrosis: <4%

5. 10-year risk of AML: <2%

Note: Longer disease duration and evolution into myelofibrosis significantly increase the risk of leukemic transformation

Ania BJ et al. Am J Hematol 1994;47:89–93

Gangat N et al. Br J Haematol 2007;138:354–358

Gangat N et al. Leukemia 2007;21:270–276

Mesa RA et al. Am J Hematol 1999;61:10–15

Essential thrombocythemia (ET)

1. Incidence: 0.2–2.5/100,000

2. Median age at diagnosis: ≈60 years

3. Median survival: >15 years

4. 10-year risk of myelofibrosis: ≈10%

5. 10-year risk of AML: ≈6%

Note: Longer disease duration and evolution into myelofibrosis significantly increase the risk of leukemic transformation

Primary myelofibrosis (PMF)

1. Incidence: 0.4–1.5/100,000

2. Median age at diagnosis: ≈60 years

3. Median survival: <3 years to >10 years

4. 10-year risk of myelofibrosis: N/A

5. 10-year risk of AML: ≈20% based on the presence or absence of well-defined prognostic determinants

6. Most important indicators of adverse prognosis:

   • Age >65 years

   • Hemoglobin <10 g/dL

   • Leukocyte count >25,000/mm³

   • Circulating blasts ≥1%

   • Constitutional symptoms

   • Unfavorable karyotype included complex karyotype or single or two abnormalities including +8, −7/7q-, i(17q), −5/5q-, 12p-, inv(3), or 11q23 rearrangement

   • Thrombocytopenia <100,000/mm³

Cervantes F et al. Br J Haematol 1997;97:635–640

Dupriez B et al. Blood 1996;88:1013–1018

Gangat N et al. J Clin Oncol 2011;29:392–397

Passamonti F et al. Blood 2010;115:1703–1708

Tefferi A et al. Cancer 2007;109:2083–2088

Mutations in MPN

Chronology:

• 1951: CML, PV, ET, and PMF recognized to have significant overlap in both clinical and biological features and felt to be related diseases

• 1960: CML recognized as distinct entity after discovery of Philadelphia chromosome

• Early 1980s: Analysis of X chromosome inactivation patterns in women with CML, PV, ET, or PMF carrying a polymorphic variant of the glucose-6-phosphate dehydrogenase gene establishes all 4 diseases as clonal stem-cell disorders

• 2005: Somatic mutation involving Janus Kinase 2 (JAK2) identified in patients with PV, ET, and PMF. Mutation at codon 617, [JAK2V617F] is a G→T transversion at nucleotide 1849 in exon 14 of JAK2 gene, with substitution of valine by phenylalanine at codon 617

• 2006–2007: Additional JAK2 and MPL (thrombopoietin receptor) mutations described in these diseases; some induce PV-like (JAK2) or PMF-like (MPL) phenotype in mice

Adamson JW et al. N Engl J Med 1976;295:913–916

Dameshek W. Blood 1951;6:372–375

Fialkow PJ et al. Blood 1981;58:916–919

Mutations

1. JAK2V617F ...