Makindo Medical Notes.com

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 CML. It is a potent tyrosine kinase which stimulates signal transduction and hence mitosis.

About

• A myeloproliferative stem cell disorder predominantly involving granulocytes
• Seen in Age range mainly of 35-75

Aetiology

• Cytogenetics reveal t(9:22) Philadelphia chromosome
• Forms a BCR ABL fusion gene which codes for a 210 kDa protein
• This has tyrosine kinase activity, which acts as an oncogene
• Imatinib (tyrosine kinase inhibitor) is first-line for the treatment of the chronic phase

Stages

• 1. Chronic phase for up to 5 years which can be prolonged by Imatinib
• 2. An accelerated phase may be seen
• 3. Blast crisis to ether AML or ALL which is difficult to treat which has reduced in frequency by Imatinib. This happens after a chronic course of 2-5 years unless treated and transforms into acute leukaemia, myeloblastic or lymphoblastic as a terminal event.

Clinical

• Typically seen in later middle age
• Fevers, sweats and weight loss and even priapism can be a presenting feature
• Abdominal pain - Ulcer disease (Increased Basophil cell mass release histamine)
• Massive splenomegaly or even acute abdomen due to splenic infarction
• Lymphadenopathy is not common until there is a blast crisis
• CML can rapidly develop into AML or Myelofibrosis
• May progress over the years from Chronic? Accelerated? Blast crisis
• Bone marrow failure

Investigations

• FBC: WCC may be > 50-400 x 10⁹/L mostly neutrophils + myelocytes and metamyelocytes. High platelet count may also be seen
• BCR-ABL oncogene detectable by reverse transcriptase PCR (Philadelphia Chromosome)
• LAP score is low in leukaemia (LLL)
• Bone marrow is hypercellular with greatly increased WCC production
• Blood LDH levels is elevated
• High uric acid level due to increased cell breakdown.

Prognosis depends on

• Age at onset of the disease
• Phase of CML at time of diagnosis
• Number of blasts in the blood and bone marrow at time of diagnosis
• Size of the spleen at the time of diagnosis
• Patient's general overall health

Management

• Mainstay of treatment is the TKIs. There is Imatinib and several other new Tyrosine kinase inhibitors which give a 95% in the chronic phase.
• Imatinib and other TKIs block the action of the BCR-ABL fusion protein and leads to the disappearance of the Philadelphia chromosome in 90%.
• Patients are monitored by measuring and monitoring the BCR ABL transcript levels from baseline. Some develop resistance to the TKIs and there are now first and second-line TKIs
• Allogeneic HSCT is now reserved for patients who fail Tyrosine Kinase Inhibitor therapy.
• Blastic crises a combination of TKI and chaemotherapy is given
• Hydroxycarbamide and low dose cytarabine can be used palliatively in older patients.