chronic myeloid leukemia (CML, granulocytic leukemia)

Etiology

• acquired defect of clonal origin

Epidemiology

• most common myeloproliferative disease
• 15-20% of all leukemias
• 1-1.5 cases/100,000 population worldwide
• median age at diagnosis 5th - 6th decades

Pathology

• bone marrow shows hyperplasia
• myelofibrosis in 10-40% of patients

Disease stages/progression:

• chronic phase (CML-CP)
  • leukocytosis mainly from neutrophils in various stages of differentiation
  • blasts < 10%, usually < 2%
  • absolute basophilia invariably present
  • some have eosinophilia
  • hypercellular bone marrow
• accelerated phase
  • 10-19% myeloblasts
• blast phase
  • myeloblasts > 20%

Genetics

• Philadelphia chromosome t(9;22)(q34.1;q11.2) BCR/ABL
  • BCR-ABL fusion gene may inhibit Bcl-xL deamidation
• chromosomal translocations involving MSI2, t(7;17)(p15;q23) with HOXA9 & t(7;17)(q32-34;q23) may contribute to disease progression in chronic myeloid leukemia
• chromosomal translocation t(4;11)(q21;q23) involving SEPT11 with MLL/HRX may be a cause of chronic myeloid leukemia
• chromosomal translocation t(8;9)(p22;p24) involving JAK2 with PCM1
• CSF3R mutation (case report)
• other implicated genes: LHX1, AXL

Clinical manifestations

• may be asymptomatic
• malaise
• fatigue
• myalgia (case report)
• dyspnea
• anorexia, early satiety
• fever
• night sweats
• weight loss
• abdominal discomfort, abdominal fullness
• easy bruising, scattered ecchymoses
• bleeding
• gout
• priapism
• hypermetabolism
• leukocytosis
• splenomegaly in 85%
• phases:
  • chronic phase (years, the chronic course of the disease)
  • accelerated phase (< 1 year)
  • blast phase, AML (median survival 6-9 months)

Laboratory

• complete blood count (CBC) with peripheral blood smear
  • WBC generally > 100,000/uL
  • granulocytes in all phases of maturation
  • thrombocytosis (large & bizarre forms)
  • basophilia may be present
  • eosinophilia may be present
  • anemia if present is mild
• bone marrow biopsy
  • hypercellular bone marrow
  • marked myeloid proliferation
• buffy coat for chronic myelogenous leukemia genotyping
  • BCR-ABL1 fusion protein in blood/tissue (bcr/abl mRNA by RT-PCR)
• serum leukocyte alkaline phosphatase is low or absent
• serum vitamin B12 is increased
• false positive increase in serum acid phosphatase
• cytogenetics:
  • peripheral blood & bone marrow
  • Philadelphia chromosome t(9;22) >95%
• see ARUP consult
• flow cytometry not useful

Complications

• blast transformation
• leukostasis

Differential diagnosis

• leukemoid reaction may be difficult to distinguish from CML in an acutely ill patient

Management

• treatment with bcr-abl inhibitor all patients at the time of diagnosis even in asymptomatic patients
  • imatinib (Gleevec,formerly STI571)
    • an inhibitor of bcl-abl
    • may be best single agent
    • better than interferon alfa plus cytarabine
    • eradicates Philadelphia chromosome-positive cells; 70% cytogenetic remission during during phase
    • 89% 5 year survival
    • all tyrosine kinase inhibitors can prolong QT interval
      • periodic ECG monitoring
  • dasatinib & nilotinib
    • FDA-approved for imatinib-resistant CML
    • may be used 1st line instead of imatinib
    • patients in remission may be eligible for discontinuation of nilotinib after 3 years of therapy
  • ponatinib (Iclusig), marketing suspended Dec 2013
  • bosutinib
  • the PPAR gamma agonist pioglitazone causes fewer cancer stem cells to remain dormant, thereby rendering them more vulnerable to chemotherapy with imatinib
  • benefit of treatment is that a uniformly fatal disease has been changed into a chronic illness
  • imatinib + tigecycline may inhibit CML stem cells
    • CML stem cells insensitive to tyrosine kinase inhibitors but suppressed by inhibitor of oxidative phosphorylation
• earlier therapy had not appreciably prolonged survival
  • hydroxyurea
    • treatment of choice for:
      • high blast counts
      • leukostasis
      • patients who are candidates for bone marrow transplant
    • response rates of 85-90%
    • maintenance therapy is necessary
    • safe for use with concurrent thrombocytopenia
    • fewer side effects than busulfan
  • busulfan is inferior to hydroxyurea
  • interferon alfa 2a or interferon alfa 2b
    • suppresses the Philadelphia chromosome
    • may be superior to hydroxyurea (may prolong survival)
    • 5-10 million units 3-7 times/week
    • hematologic & cytogenetic response occurs within 3-12 months
    • addition of cytarabine may be of additional benefit
  • fludarabine for CML not responding to other agents
• allogeneic stem cell transplantation
  • reserved for patients with accelerated or blast phase or for patients resistant to bcr-abl inhibitors
  • high-dose irradiation followed by transplantation of allogeneic bone marrow from HLA-compatible sibling is the only curative regimen
  • studies using HLA-matched unrelated donors are ongoing
  • hematologic relapses occur in 10-20% of patients
  • long-term disease-free survival is 40-60%
• anagrelide for thrombocytosis
• platelet transfusions for thrombocytopenia
  • platelet count < 10,000/uL
  • bleeding
• splenectomy
  • patients with advanced disease who no longer respond to imatinib
  • painful splenomegaly
  • thrombocytopenia with high platelet transfusion requirement

Notes

• all tyrosine kinase inhibitors for treatment of CML cost ~$100,000/year
  • multidisciplinary support including social work may be necessary to assist patients in obtaining treatment

More general terms

• myeloid leukemia
• chronic leukemia
• chronic myeloproliferative disorder

More specific terms

• Philadelphia chromosome-positive chronic myeloid leukemia (CML)

Additional terms

• buffy coat
• chromosomal translocation t9q34.1:22q11 (Philadelphia chromosome; bcr/abl)
• chronic myelogenous leukemia genotyping
• chronic myeloid leukemia (CML) blast crisis
• leukocyte alkaline phosphatase (LAP)

Patient information

chronic myeloid leukemia patient information