Skip to content

Myeloproliferative Neoplasms (MPNs)

Christina Snider

Background

  • MPNs: chronic myeloid disorders caused by abnormal proliferation of mature bone marrow cell lineages (granulocytes, erythrocytes, or megakaryocytes)
  • MPNs differ from myelodysplastic syndrome (MDS); cells in MPNs are normally developed (i.e. not dysplastic)
  • Four “classic” MPNs: polycythemia vera, essential thrombocythemia, primary myelofibrosis and chronic myeloid leukemia (CML)

Polycythemia Vera

Background

  • Polycythemia is a general term: Men = Hb/Hct > 16.5/49%; Women = Hb/Hct > 16/48%
  • Relative polycythemia: concentrated H/H due to decreased plasma volume
    • Diuretic use, vomiting, diarrhea; H/H should normalize with fluid resuscitation
  • Absolute polycythemia: increased RBC mass
    • Primary polycythemia: inherited/acquired mutation in RBC progenitor
    • Secondary polycythemia: increase in RBC mass due to elevated serum EPO
      • Hypoxia/cardiopulmonary associated (chronic pulmonary disease, R-to-L cardiac shunts, sleep apnea, obesity hypoventilation syndrome, chronic carbon monoxide poisoning, including heavy smoking)
      • Kidney associated causes (following renal transplant, renal artery stenosis, hydronephrosis)
      • Autonomous EPO production from an EPO-producing tumors (rare)
      • Steroid Use
  • Epidemiology: Median age of diagnosis is 60 years; 25% cases present at age <50 years.
  • >95% PV pts have JAK2 V617F mutation, but JAK2 V617F mutation is not specific to PV and can be seen in other MPNs

Presentation

  • Incidentally elevated H/H
  • Splenomegaly, generalized pruritus (post-warm bath/shower), unusual thrombosis
  • Erythromelalgia: intermittent occurrence of red, hot, painful extremities

Evaluation

  • CBC w/ diff and peripheral smear
  • EPO level
  • Rule out secondary causes: sleep study, carboxyhemoglobin, steroids
  • Peripheral blood screen for JAK2 V617F mutation

Management

  • PV treatment aims to prevent thrombosis and bleeding events.
  • Phlebotomy: maintain Hct <45% (one unit 500 mL decreases Hct by 3%)
  • ASA 81 mg for thrombosis prevention and symptom control
  • Hydroxyurea: indicated for high-risk pts (>60 years old or with history of thrombosis)
  • Interferon-alfa, busulfan, or ruxolitinib: indicated in select high-risk pts

Essential Thrombocythemia (ET)

Background

  • Clonal stem cell disorder with increased platelet counts (>450k/uL)
  • Risks of thrombosis and hemorrhage
  • Median age of diagnosis: 60 years. Twice as common in females.

Presentation

  • Incidental thrombocytosis on CBC
  • Splenomegaly, unusual thrombosis, and erythromelalgia

Evaluation

  • Screen for conditions that cause reactive thrombocytosis: chronic inflammatory diseases, infections, bleeding/hemolysis, iron deficiency, post splenectomy
  • CBC with smear (platelet anisocytosis) ranging from very small to giant platelets
  • CMP, LDH, uric acid, iron studies
  • BCR ABL1 testing should be sent to exclude CML
  • Bone marrow bx with staining, cytogenetics, and molecular testing for JAK2, CALR, MPL mutations

Management

  • Avoid ASA 81 in pts with platelet counts >1 million complicated by acquired von Willebrand syndrome due to increased risk of bleeding
Treatment of ET
Risk Score (IPSET-thrombosis) Features Treatment
High Hx of thrombosis and/or >age 60 with JAK2 V617F mutation cytoreduction (target plt 100-400k) with hydroxyurea, systemic anticoagulation ±antiplatelet agent
Intermediate Age >60, no JAK2 V617F mutation, no history of thrombosis
Low Age =<60 w/ JAK2 V617F mutation and no history of thrombosis observation vs. daily ASA 81
Very low Age=<60, no JAK2 V617F mutation, no history of thrombosis

Primary Myelofibrosis (PMF)

Background

  • Clonal proliferation of myeloid cells with variable morphologic maturity resulting in reactive marrow fibrosis and extramedullary hematopoiesis
  • Least favorable prognosis out of MPN

Presentation

  • Fatigue, weight loss, low grade fever, bone pain, and night sweats
  • Marked splenomegaly ±hepatomegaly (due to extramedullary hematopoiesis)

Evaluation

  • Smear: teardrop shaped RBCs (dacrocytes)
  • Bone marrow biopsy: “dry tap” due to extensive reticulin and/or collagen fibrosis mutually exclusive mutations in JAK2, MPL, or CALR

Management

  • Low risk pts: observe if asymptomatic
  • Cure by allogenic HCT transplantation in young, high-risk pts
  • Treatment of anemias include transfusion support
  • Surgical splenectomy if abdominal pain or transfusion dependent anemia (used very infrequently)

Chronic Myeloid Leukemia (CML)

Background

  • Definition: MPN characterized by the overproduction of myeloid stem cells that can differentiate
  • Chronic phase:
    • Fatigue, weight loss, bleeding
    • Abdominal fullness and early satiety due to splenomegaly
    • WBC typically >100k. Smear shows neutrophilic cells in all stages of maturation with <2% blasts
  • Accelerated phase: Refractory leukocytosis, 10-19% blasts in peripheral blood or bone marrow, worsening peripheral basophilia, thrombocytopenia
  • Blast phase = acute leukemia: >20% blasts in peripheral blood or bone marrow, extramedullary proliferation of blasts

Evaluation

  • Typical findings in blood and bone marrow and confirmation of Philadelphia chromosome (BCR-ABL1 fusion gene) via conventional cytogenetics, FISH, or rt-PCR

Management

  • Hydroxyurea can be used to reduce WBC while awaiting confirmation
  • Oral tyrosine kinase inhibitors (TKI): Imatinib, dasatinib, nilotinib, and ponatinib
  • Allogenic hematopoietic cell transplantation: curative option for pts in accelerated and blast phase, as well as young pts with chronic phase CML who do not respond to TKI therapy