Makindo Medical Notes

Related Subjects: |Leukaemias in General |Acute Promyelocytic Leukaemia |Acute Myeloblastic Leukaemia (AML) |Acute Lymphoblastic Leukaemia (ALL) |Chronic Lymphocytic leukaemia (CLL) |Chronic Myeloid Leukaemia (CML) |Hairy Cell Leukaemia |Differentiation syndrome |Tretinoin (All-trans-retinoic acid (ATRA) ) |Haemolytic anaemia |Immune(Idiopathic) Thrombocytopenic Purpura (ITP)

The BCR-ABL fusion protein is the proto-oncogene from the Philadelphia chromosome, found in Chronic Myeloid Leukaemia (CML). It is a potent tyrosine kinase that stimulates signal transduction and mitosis.Imatinib (a tyrosine kinase inhibitor, TKI) is first-line treatment for the chronic phase of CML.

About

• A myeloproliferative stem cell disorder predominantly involving granulocytes.
• Typically seen in patients aged 35-75 years.

Aetiology

• Cytogenetic analysis reveals the t(9;22) Philadelphia chromosome.
• This forms the BCR-ABL fusion gene, which codes for a 210 kDa protein.
• The BCR-ABL protein has tyrosine kinase activity, acting as an oncogene.

Stages of CML

• Chronic phase: Can last up to 5 years, often prolonged with Imatinib treatment.
• Accelerated phase: A more aggressive phase that may develop after the chronic phase.
• Blast crisis: CML can progress to either Acute Myeloid Leukaemia (AML) or Acute Lymphoblastic Leukaemia (ALL). This phase is more difficult to treat and has become less frequent due to TKI therapy.

Clinical Features

• Typically seen in later middle age.
• Symptoms include fever, night sweats, weight loss, and occasionally priapism.
• Abdominal pain or ulcer disease (due to histamine release from increased basophil cell mass).
• Massive splenomegaly, which may cause acute abdominal pain from splenic infarction.
• Lymphadenopathy is uncommon, except during blast crisis.
• CML may progress to AML or myelofibrosis over time.
• Bone marrow failure can occur in later stages.

Investigations

• Full Blood Count (FBC): WCC may exceed 50-400 x 10⁹/L, predominantly neutrophils, myelocytes, and metamyelocytes. High platelet counts may also be observed.
• BCR-ABL oncogene: Detected by reverse transcriptase PCR (Philadelphia chromosome).
• Leukocyte Alkaline Phosphatase (LAP) score: Low in leukaemia.
• Bone Marrow: Hypercellular, with greatly increased WCC production.
• Lactate Dehydrogenase (LDH): Elevated in CML due to increased cell turnover.
• Uric Acid Levels: Elevated due to increased cell breakdown.

Prognosis: depends on several factors:

• Age at diagnosis.
• Phase of CML at the time of diagnosis.
• Number of blasts in the blood and bone marrow.
• Size of the spleen at diagnosis.
• General health of the patient.

Management

• Tyrosine Kinase Inhibitors (TKIs): Imatinib and newer TKIs are the mainstay of treatment, achieving a 95% success rate in the chronic phase.
• Imatinib: Blocks the action of the BCR-ABL fusion protein and leads to the disappearance of the Philadelphia chromosome in about 90% of cases.
• Patients are monitored by measuring BCR-ABL transcript levels to track treatment response. Some may develop resistance to TKIs, requiring first or second-line TKIs.
• Allogeneic Hematopoietic Stem Cell Transplant (HSCT): Reserved for patients who fail TKI therapy.
• Blast Crisis: Combination of TKI and chemotherapy is given during this phase.
• Palliative Treatments: Hydroxycarbamide and low-dose cytarabine may be used in older patients for palliation.