Chronic myeloid leukemia

Chronic myeloid leukemia (CML) belongs to the group of myeloproliferative neoplasms. It is a malignancy of the hematopoietic stem cells with excessive proliferation of the myeloid lineage (especially granulocytes). It is caused by a cytogenetic aberration (Philadelphia chromosome 22) that results in the formation of a BCR-ABL fusion gene. The increased activity of this gene's product – a tyrosine kinase – promotes unregulated proliferation of myeloid progenitor cells, which eventually differentiate into mature cells. CML has three distinct clinical phases. The chronic phase is characterized by nonspecific symptoms (fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years. The accelerated phase is characterized by complications secondary to the suppression of the other cell lines (thrombocytopenia, anemia, recurrent infections). The clinical picture of the terminal phase, blast crisis, resembles that of acute leukemia. Important diagnostic features are severe leukocytosis (> 500,000/μl), basophilia, and extreme splenomegaly. The most important therapeutic principle is targeted therapy with imatinib, which selectively inhibits BCR-ABL tyrosine kinase. This drug has revolutionized CML treatment and greatly improved the prognosis of CML.

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

References:^[1]

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)

References:^[2]

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][2][3]

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][4]

Peripheral blood analysis

• CBC and blood smear
  • Leukocytosis with midstage progenitor cells (e.g., myelocytes, metamyelocytes) and mature cells (e.g., neutrophils, myelocytes)
  • Basophilia and eosinophilia
  • Blasts can indicate transition to the accelerated phase.
  • Thrombocytosis

CML causes the most severe leukocytosis (> 500,000/μl) of all forms of leukemia. Increasing basophilia is a sign of acceleration.

• Cytochemistry: ↓ leukocyte alkaline phosphatase (LAP) versus a leukemoid reaction
• Cytogenetics: confirmation of BCR-ABL (Philadelphia chromosome) fusion gene

Low LAP is a distinct feature of CML that distinguishes it from all other forms of leukemia!

Bone marrow

• Hyperplastic myelopoiesis: predominantly granulocytosis
• Elevated granulocytic precursor cells (especially myelocytes and promyelocytes)

WHO classification of the CML phases

References:^[1][2][5][6]

• Targeted therapy: first-line for chronic and accelerated phase
  • Tyrosine kinase inhibitors: e.g., imatinib, dasatinib, nilotinib
    • Mechanism of action: selectively inhibit the enzyme tyrosine kinase by binding to its active ATP site → no transfer of phosphate (from ATP) to tyrosine residues on the enzyme's substrates (i.e., cell signaling proteins of the BCR-ABL1 pathway) → inhibits proliferation and induces apoptosis of malignant cells that carry the mutant tyrosine kinase
    • Adverse effects include: fluid retention, pulmonary edema, QT prolongation, nausea, vomiting, diarrhea, and pancytopenia
  • Lifelong treatment
• Allogeneic stem cell transplantation: if targeted therapy is not successful or in young patients without any major comorbidities (the only curative option)
• Cell count normalization: supportive therapy if targeted therapy fails
  • Hydroxyurea
• Blast phase: acute leukemia treatment

References:^[7][8]

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.

References:^[2][7]

1. Le T, Bhushan V, Bagga HS. First Aid for the USMLE Step 2 CK. McGraw-Hill Medical ; 2009
2. Besa EC. Chronic Myelogenous Leukemia (CML). Chronic Myelogenous Leukemia (CML). New York, NY: WebMD. http://emedicine.medscape.com/article/199425-overview. Updated: March 11, 2017. Accessed: April 14, 2017.
3. Van Etten RA. Clinical manifestations and diagnosis of chronic myeloid leukemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-chronic-myeloid-leukemia.Last updated: April 10, 2017. Accessed: April 14, 2017.
4. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
5. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The Biology of Chronic Myeloid Leukemia. N Engl J Med. 1999; 341 (3): p.164-172. doi: 10.1056/nejm199907153410306 . | Open in Read by QxMD
6. Kotiah SD. Chronic Myelogenous Leukemia Staging. Chronic Myelogenous Leukemia Staging. New York, NY: WebMD. http://emedicine.medscape.com/article/2006731-overview. Updated: December 30, 2015. Accessed: April 14, 2017.
7. Chronic Myeloid Leukaemia (CML) : An overview and advancement in the treatment . http://www.orion-group.net/journals/Journals/vol16_sept2003/99.htm. Updated: September 1, 2003. Accessed: August 30, 2017.
8. Sakka V, Tsiodras S, Giamarellos-Bourboulis EJ, Giamarellou H. An update on the etiology and diagnostic evaluation of a leukemoid reaction. Eur J Intern Med. 2006; 17 (6): p.394-398. doi: 10.1016/j.ejim.2006.04.004 . | Open in Read by QxMD
9. Seiter K. Chronic Myelogenous Leukemia (CML) Guidelines. Chronic Myelogenous Leukemia (CML) Guidelines. New York, NY: WebMD. http://emedicine.medscape.com/article/2243078-overview. Updated: December 23, 2016. Accessed: April 14, 2017.
10. Key Statistics for Chronic Myeloid Leukemia. https://www.cancer.org/cancer/chronic-myeloid-leukemia/about/statistics.html. Updated: June 19, 2018. Accessed: March 19, 2020.