Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. The overwhelming majority is due to a characteristic chromosomal translocation termed the Philadelphia chromosome. It is traditionally treated with chemotherapy, interferon and bone marrow transplantation, although a specific inhibitor (imatinib mesylate) has radically changed the management.

Contents

1 Signs and symptoms 2 Diagnosis 3 Pathophysiology 4 Epidemiology 5 Treatment 5.1 Chronic phase 5.2 Blast crisis 6 Prognosis 7 References

Signs and symptoms

The disease is often without symptoms, and may be detected on a routine full blood count. Symptoms may include: malaise, low grade fever, increased susceptibility to infections, anemia and thrombocytopenia with resultant bruising (although an increased platelet count, thrombocytosis, may be a feature).

The disease may remain dormant for years, but a proportion proceed to accelerated phase (in which the diseases progresses rapidly) or overt blast crisis, which has the symptoms and risks of acute myelogenous leukemia (AML).

Diagnosis

CML is often suspected on the basis on the full blood count, which shows increased granulocytes of all types (including basophils). When the index of suspicion is high, a bone marrow biopsy is required to distinguish CML from other diseases that feature the same symptoms.

Ultimately, CML is diagnosed by detecting the Philadelphia chromosome (a translocation between the 9th and 22nd chromosome leading to an abberant protein that drives cell division). This translocation leads to bcr-abl fusion and activation of protein tyrosine kinase cascade.

Disease activity can be determined on the basis of the bone marrow examination, cytogenetics and by quantitative PCR.

Pathophysiology

CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation named Philadelphia chromosome, in 1960. The fusion of two genes on chromosomes 9 and 22, termed abl and bcr respectively, leads to a protein that propels mitosis and causes genomic instability (leading to further mutations).

CML progresses to accelerated phase, and then blast crisis, when additional genetic abnormalities speed up the rate at which new malignant cells are produced in the bone marrow. A second Philadelphia chromosome may appear, as well as deletions of (parts of) chromosomes.

Epidemiology

CML occurs in all age groups, but most commonly in the middle-aged and elderly.

Treatment

Chronic phase

Chronic-phase CML is treated with:

• Hydroxyurea (hydroxycarbamide)
• Alkylating agents (cytarabine)
• Interferon alfa 2b and steroids
• Imatinib mesylate (STI-571, Gleevec®, Glivec®) - this new agent specifically targets the abnormality caused by the Philadelphia chromosome.

Various combinations of the different treatment modalities are being explored, such as interferon and imatinib together.

Blast crisis

Blast crisis carries all the symptoms and characteristics of acute myelogenous leukemia, and has a very high mortality rate. This stage can most effectively be treated by a bone marrow transplant after high-dose chemotherapy. In young patients with accelerated phase, this may also be an option.

Prognosis

The prognosis of CML depends on a number of different parameters. Two different scoring systems are in use: one by Sokal et al (1984) and one by Hasford et al (1998).

References

• Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in good risk chronic granulocytic leukemia. Blood 1984;63:789-799. PMID 6584184.
• Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998;90:850-858. PMID 9625174.

Health science - Medicine - Hematology

Hematological malignancy and White blood cells

Lymphoma (Hodgkin's disease, NHL) - Leukemia (ALL, AML, CLL, CML) - Multiple myeloma - MDS - Myelofibrosis - Myeloproliferative disease (Thrombocytosis, Polycythemia) - Neutropenia

Red blood cells

Anemia - Hemochromatosis - Sickle-cell anemia - Thalassemia - G6PD - other hemoglobinopathies

Coagulation and Platelets

Thrombosis - Deep venous thrombosis - Pulmonary embolism - Hemophilia - ITP - TTP