Chronic Myeloid Leukemia (CML)

Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a fairly slow growing cancer that starts in the bone marrow. It"s a type of leukemia that affects the myeloid cells -- cells that form blood cells, such as red blood cells, platelets, and many types of white blood cells. In CML, leukemia cells tend to build up in the body over time. In many cases, people don't have any symptoms for at least a few years. CML can also change into a fastgrowing, acute leukemia that invades almost any organ in the body. Most cases of CML occur in adults, but it is also very rarely found in children. As a rule, their treatment is the same as for adults.

Definition

Leukemia is a type of cancer of the blood. There are different forms of leukemia depending on what type of blood cell is affected. "Chronic" describes a gradual or slow progression, and "myeloid" denotes the origin from myeloid cells, which are immature cells that normally become mature red blood cells, white blood cells, or platelets. In chronic myeloid leukemia, the bone marrow produces too many myeloid blood cells which are at various maturation stages including cells known as immature granulocytes, metamyelocyte, and myeloblasts. Platelets and basophils (different myeloid cells responsible, in part, for the allergic response) are also often overproduced at diagnosis. Excess production of myleloid blood cells in the bone marrow ultimately prevents the normal production of red blood cells, which are important in delivering oxygen to all cells in the body, and can also decrease production of platelets or thrombocytopenia. Platelets play a critical role to stop bleeding.

Different phases of CML

• Chronic Phase
• Accelerated Phase
• Blast crisis Phase

Causes

This specific genetic abnormality is an abnormal rearrangement of genetic material. Two chromosomes exchange a portion of their genes with genes on the other chromosome. This is known as a translocation. For CML, specifically, genes from chromosomes 9 are swapped with genes from chromosome 22. Translocation of the Abelson murine leukemia gene (ABL) on chromosomes 9 and the breakpoint cluster region (BCR) on chromosome 22 resulting in the Philadelphia chromosome (translocation of chormosomes 9 and 22, t(9;22)) can be detected in 95% of patients with CML either from cells circulating in the blood or in the bone marrow. The Philadelphia chromosome encodes a dysregulated tyrosine kinase (an enzyme in cells), which results in an abnormal behavior of the cells affected. This includes the formation of immortalized cells, increased cell turnover and proliferation, and abnormal cell maturation.

Risk Factors

• Exposure to high-dose radiation can increase the risk of CML. Atomic bomb and nuclear reactor accident survivors as well as radiology technicians prior to 1950 (when protective shielding was first introduced) are at inceased risk of developing CML
• The risk of developing CML increases with age but as people get older the risk is still very small. CML also occurs slightly more often in men than in women.
• People exposed to pesticides or benzenes as part of their work seem to have a moderate increased risk of developing CML.

Diagnosis

• Typical findings in the blood and bone marrow
• Requires the detection of the Ph chromosomal or its product, the BCR-ABL1 fusion mRNA and the BCR-ABL1 protein
  • Conventional cytogenetic analysis (karyotyping) – The first method
  • Florence and in situ hybridization (FISH) analysis
  • RT-PCR (The BEST)
  • Southern blot techniques – rarely used
  • Western Blotting – low sensitivity and labor intensive

Differential Diagnosis

• Leukemoid reaction
• Juvenile myelomonocytic leukemia (JMML)
• Chronic myelomonocytic leukemia (CMML)
• Atypical CML
• Chronic eosinophilic leukemia
• Chronic neutrophilic leukemia
• Other myeloproliferative neoplasms
• Other Ph chromosome positive malignancies

Symptoms and clinical manifestations

• Splenomegaly
• Fatigue
• Bleeding
• Asymptomatic in 20-50% of patients
• Fatigue 34%, weight loss 20%, excessive sweating 15%, abdominal fullness 15%, bleeding episodes 21% (platelet dysfunction).
• Abdominal pain in the LUQ (enlarged spleen)
• Tenderness over the lower sternum.
• Acute gouty arthritis
• Findings: Splenomegaly, anemia, WBC > 100,000, platelet count > 600,000
• Leukocytosis (median of 100,000)
• Differentiation shows virtually all cells of neutrophilic series
• Blasts < 2%
• Myelocytes more than metamyelocytes (a classic finding in CML)
• Neutrophils cytochemistry is abnormal – low LAP score
• Basophilia in 90% of cases
• Thrombocytosis. If low platelets – consider an other

Treatments

• Transplantation is the only known cure.
• Chemo Therapy
• Imatinib (STI-571)
• BMS-354825 and AMN107 (still under study)
• Busulphan
• Alkylating agent
• Preferred in older pts (not candidate for transplant)

Side effect

• prolonged myelosuppression
• Pulmonary fibrosis
• Skin pigmentation
• infertility

Bone Marrow Pathology

• Granulocytic maturation pattern same as in the peripheral blood
• Increased reticulin fibrosis and vascularity
• Erythroid islands are reduced in number and size
• Dwarf megakaryocytes
• Pseudo-Gaucher's cells and Sea Blue histiocytes (markers of increased cell turnover)
• Iron-laden macrophages are reduced or absent