Chronic myeloid leukemia

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.

• Sex: ♂ > ♀
• Incidence: : peak incidence is 50–60 years

Epidemiological data refers to the US, unless otherwise specified.

• Idiopathic (in most cases)
• Ionizing radiation (e.g., secondary to therapeutic radiation)
• Aromatic hydrocarbons (especially benzene)

Philadelphia chromosome

• Reciprocal translocation between chromosome 9 and chromosome 22 → formation of the Philadelphia chromosome t(9;22) → fusion of the ABL1 gene (chromosome 9) with the BCR gene (chromosome 22) → formation of the BCR-ABL gene → encodes a BCR-ABL non-receptor tyrosine kinase with increased enzyme activity
• Result: inhibits physiologic apoptosis and increases mitotic rate → uncontrolled proliferation of functional granulocytes

Genetic changes and clinical course

• Additional chromosomal changes and mutations of tumor suppressor genes and oncogenes (p53, Rb1, or Ras), which emerge during the course of the disease, are responsible for the progression from chronic to accelerated phase and, ultimately, the transition to acute leukemia.

References:^[1]

Chronic phase

• Can persist for up to 10 years and is often subclinical
• When symptomatic, features include:
  • Weight loss, fever, night sweats, fatigue
  • Splenomegaly: abdominal discomfort in the left upper quadrant
  • Lymphadenopathy is not typical in CML.

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

Accelerated phase

• Erythrocytopenia: anemia
• Neutropenia: infection and fever
• Extreme pleocytosis
  • Infarctions: splenic and myocardial infarctions, retinal vessel occlusion
  • Leukemic priapism
  • Terminal phase: myelofibrosis
• Extreme splenomegaly : palpable in lower left quadrant or pelvic cavity

Blast crisis

The blast crisis is the terminal stage of CML.

• Symptoms resemble those of acute leukemia.
• Rapid progression of bone marrow failure → pancytopenia, bone pain
• Severe malaise
• Subtypes :
  • Myeloid blast crisis → AML (⅔ of cases)
  • Lymphoid blast crisis → ALL (⅓ of cases)

References:^[2]

Approach ^[3][4][5]

• Clinicians should maintain a high index of suspicion if patients present with the following:
  • Severe leukocytosis on routine laboratory testing
  • Splenomegaly
  • Constitutional symptoms (e.g., malaise, fatigue) with nonspecific signs of bone marrow suppression (e.g., anemia, thrombocytopenia)
• Initial diagnostic workup should include:
  • CBC
  • Peripheral blood smear
  • Bone marrow aspiration and biopsy
• Diagnostic confirmation: identification of the Philadelphia chromosome and/or the BCR-ABL1 fusion gene.
• Evaluate patients without the Philadelphia chromosome or the BCR-ABL1 fusion gene for other myeloproliferative disorders.

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

Initial evaluation ^[5][6][7]

• CBC and peripheral blood smear
  • Leukocytosis with midstage progenitor cells (e.g., myelocytes, metamyelocytes) and mature cells (e.g., neutrophils)
  • Thrombocytosis
  • Basophilia and eosinophilia
  • Blast cells in peripheral blood can indicate the transition to AP-CML.
  • Anemia
• Further laboratory studies
  • Leukocyte alkaline phosphatase (LAP): Low LAP is a typical finding and can help distinguish CML from other types of leukemia and leukemoid reactions ^[3][4]
  • Flow cytometry: can be used to assess the type and maturity of leukocytes in order to detect progression to advanced phases of CML ^[7][8]

• Bone marrow aspiration and biopsies
  • Indications: all patients with suspected CML
  • Supportive findings: hyperplastic myelopoiesis (predominantly granulocytosis) with elevated granulocytic precursor cells, especially myelocytes and promyelocytes

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.

• Cytogenetic testing: used to confirm the presence of the BCR-ABL1 fusion gene and/or the Philadelphia chromosome, and identify additional genetic mutations
  • Conventional karyotyping: for confirmation of the Philadelphia chromosome, which contains the BCR-ABL1 fusion gene
  • FISH analysis: for confirmation of the BCR-ABL1 fusion gene
• Molecular testing: quantitative RT-PCR ^[4]
  • Highly sensitive detection and quantification of cells with BCR-ABL1 transcripts
  • Especially useful to assess treatment response and remission status

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
  • Higher proportion of blast cells compared with AP-CML
  • Extramedullary blast proliferation
  • Often resistant to targeted therapy due to the presence of multiple genetic mutations

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]

• Pretreatment: individualized evaluation in consultation with a hematologist-oncologist
  • Baseline laboratory studies
  • Screening for infections (e.g., hepatitis B)
  • Cardiac evaluation including ECG and echocardiogram
  • Prophylaxis and management of tumor lysis syndrome (e.g., IV fluid therapy, allopurinol)
• Chronic phase
  • TKIs: first-line and second-line treatment
  • Adjunctive medical treatment or hematopoietic stem cell transplantation (HSCT) may be considered if other treatments fail.
• Accelerated phase
  • Begin treatment with TKIs.
  • Consider systemic chemotherapy or HSCT, if the patient is eligible.
• Blast phase: Treatment is similar to that of acute leukemia.
  • Aggressive systemic chemotherapy in combination with a TKI
  • HSCT, if the patient is eligible

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
  • Selective inhibition of tyrosine kinase (e.g., by blocking its ATP binding site): inhibits tyrosine phosphorylation of downstream signaling proteins (no phosphate transfer from ATP to tyrosine residues)
  • Disruption of the BCR-ABL1 pathway: inhibits proliferation and induces apoptosis in BCR-ABL1-positive cells
• 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
  • Omacetaxine may be used in addition to TKIs in TKI-resistant CML to improve treatment response.
  • Hydroxyurea or IFN-α may be used to reduce leukocyte counts and control symptoms associated with extreme leukocytosis or thrombocytosis. ^[7]
• 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)

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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