Myeloproliferative Neoplasms

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 (PV)

  • 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: 2/2 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 with differential 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 patients (>60 years old or with history of thrombosis)
  • Interferon-alfa, busulfan, or ruxolitinib: indicated in select high-risk patients

 

Essential thrombocythemia (ET)

Background

  • Clonal stem cell disorder w/ 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 may be sent to exclude CML
  • Bone marrow biopsy with staining, cytogenetics, and molecular testing for JAK2 mutations

 

Management

  • Avoid ASA 81 in patients with platelet counts >1 million/uL microL 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) w/ 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 patients: Observe if asymptomatic
  • Cure by allogenic HCT transplantation in young, high risk patients
  • Complex treatment options, consult Hematology
  • Treatment of anemias include transfusion support
  • Surgical splenectomy if abdominal pain or transfusion dependent anemia

 

Chronic Myelogenous Leukemia (CML)

Background

  • Definition: MPN overproduction of myeloid stem cells that can differentiate
  • Chronic phase: 85% of pts
    • Fatigue, weight loss, bleeding
    • Abdominal fullness and early satiety due to splenomegaly
    • WBC on CBC is typically >100k, and 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 (TKIS): Imatinib, dasatinib, nilotinib, and ponatinib
  • Allogenic hematopoietic cell transplantation: Curative option for pts in accelerated and blast phase, as well as young pts w/chronic phase CML who do not respond to TKI therapy