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Chronic myeloid leukemia

Last updated: September 22, 2021

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Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm involving hematopoietic stem cells that results in overexpression of cells of myeloid lineage, especially granulocytes. It is caused by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome, which contains the BCR-ABL1 fusion gene. The BCR-ABL1 fusion gene encodes a hybrid tyrosine kinase with increased enzymatic activity that leads to unregulated proliferation of hematopoietic stem cells. These cells subsequently differentiate into mature myeloid cells, resulting in CML. CML has three distinct phases: the chronic phase (CP-CML), the accelerated phase (AP-CML), and the blast phase (BP-CML, also referred to as blast crisis. Patients with CP-CML may be asymptomatic or present with nonspecific symptoms (e.g., fever, weight loss, night sweats) and splenomegaly. AP-CML is characterized by complications secondary to the suppression of other hematologic cell lines (e.g., thrombocytopenia, anemia, recurrent infections), and the clinical picture of BP-CML is similar to that of acute leukemia. Important diagnostic features in BP-CML are severe leukocytosis (with leukocyte counts as high as 500,000/mm3), basophilia, and massive splenomegaly. The most effective treatment for CML is targeted therapy with tyrosine kinase inhibitors (TKIs). This class of drug has revolutionized the efficacy of treatment and greatly improved the prognosis of patients with CML.

Epidemiological data refers to the US, unless otherwise specified.

Philadelphia chromosome

Malignancy Detection of Philadelphia translocation
CML
  • > 90% of patients
ALL
  • ∼ 20% of adults
  • ∼ 5% of children
AML
  • < 2% of patients

Genetic changes and clinical course

References:[1]

Chronic phase

Unlike AML, CML is not characterized by recurrent infections during early stages, since the granulocytes are still fully functional.

Accelerated phase

Blast crisis

The blast crisis is the terminal stage of CML.

References:[2]

Approach [3][4][5]

CML can cause extreme leukocytosis (often > 100,000/mm3) and is frequently associated with basophilia. [5][6]

Initial evaluation [5][6][7]

Diagnostic confirmation [5][7][9][10]

Diagnostic confirmation relies on the detection of the Philadelphia chromosome and/or the BCR-ABL1 gene or its transcripts in the bone marrow or peripheral blood. These tests are usually repeated to assess response to treatment.

Identification of the BCR-ABL1 fusion gene is the hallmark of CML and confirms the diagnosis. [7][9]

Definitions of CML phases [9][11]

AP-CML and BP-CML have characteristic laboratory parameter values (e.g., the proportion of blast cells in peripheral blood or bone marrow). Some definitions also include further genetic mutations and responsiveness to treatment.

  • Accelerated phase
    • Significantly increased proportion of blast cells
    • Additional genetic mutations are often present.
  • Blast phase

The presence of additional mutations is associated with more advanced stages of CML (i.e., AP-CML or BP-CML) and can cause resistance to targeted therapy. [9]

BP-CML is a life-threatening condition that is clinically similar to acute leukemia. It should be recognized early and treated immediately.

Approach [4]

Targeted therapy: tyrosine kinase inhibitors [4][7][10]

  • Indication: all patients with CML, regardless of the phase
  • Agents
    • First-generation TKIs (imatinib): indicated in low-risk CP-CML, patients with comorbidities, or older patients
    • Second-generation TKIs (e.g., dasatinib, nilotinib): usually indicated in AP-CML
    • Third-generation TKIs (e.g., ponatinib): especially effective in patients with additional mutations
  • Mechanism of action
  • Special considerations
    • Second-generation and third-generation TKIs are more effective in patients with certain additional mutations than first-generation TKIs, but are also associated with more adverse events.
    • TKIs can interact with many common medications and herbal supplements.

TKIs are the primary drug class used to treat CML.

Further treatment options [4][10]

  • Adjunctive medical treatment
  • Systemic chemotherapy: indicated in BP-CML and certain cases of AP-CML
  • Allogeneic HSCT: Should be considered in patients with TKI-resistant CML and certain patients in advanced phases (AP-CML or BP-CML)
Differential diagnosis between leukemoid reaction and myeloproliferative neoplasms
Disease CBC and peripheral blood smear LAP score Genetics/cause
Polycythemia vera
  • JAK2 mutation in 95% of cases
Primary myelofibrosis
  • JAK2 mutation in up to 60% of cases
Essential thrombocythemia
  • JAK2 mutation in 50% of cases
Chronic myeloid leukemia
Leukemoid reaction [12]

The differential diagnoses listed here are not exhaustive.

  • Survival rate without treatment:
    • Chronic phase: 3.5–5 years
    • Blast phase: 3–6 months
  • In most patients, life expectancy can be markedly improved through targeted therapy with imatinib. In some cases, it even results in molecular remission.
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  12. Radich JP, Deininger M, Abboud CN, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network. 2018; 16 (9): p.1108-1135. doi: 10.6004/jnccn.2018.0071 . | Open in Read by QxMD
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