CML Flashcards
What is the cause of CML?
Myeloproliferative neoplasm involving hematopoietic stem cells that results in over expression of cells of myeloid lineage, especially granulocytes.
What is the median age of onset?
50-60 years old
What are the risk factors for CML?
Idiopathic (most cases)
Ionising radiation (eg secondary to therapeutic radiation)
Aromatic hydrocarbons (especially benzene)
What is the pathophysiology behind CML?
Reciprocal translocation between chromosomes 9 and 22 forms the Philadelphia chromosome t(9;22) -> fusion of the ABL1 gene (on chromosome 9) with the BCR gene (on chromosome 22) -> formation of the BCR-ABL gene > encodes a BCR-ABL non receptor tyrosine kinase with increased enzyme activity. Result is it inhibits physiologic apoptosis and increases mitosis rate -> uncontrolled proliferation of functional granulocytes.
What causes CML to progress from chronic to accelerated phase and into acute leukaemia?
Additional chromosomal changes sand mutations of tumour suppressor genes and oncogenes (p53, Rb1, Ras)
What are the clinical features of CML in the chronic phase?
Often sub clinical
When symptomatic - weight loss, fatigue, fever, splenomegaly, lymphadenopathy not typical in CML
What clinical features does CML have in the accelerated phase?
Erythropenia - anaemia
Neutropenia - infection and fever
Extreme pleocytosis - infarctions of spleen and heart, retinal vessel occlusion, leukaemic priapism. Terminal phase - myelofibrosis.
Extreme splenomegaly
What is the blast crisis in CML?
The terminal stage of CML
What clinical features are present during the blast crisis of CML?
Symptoms similar to acute leukaemia (due to anaemia - fatigue, pallor, weakness, due to thrombocytopenia - epistaxis, bleeding gums, petechia, purpura, due to immature leukocytes - frequent infections, fever)
Hepatosplenomegaly
Rapid progressions of bone marrow failure -> pan trope is, bone pain
Sever malaise
Which lab findings should clinicians look out for?
Severe leukocytosis on routine lab tests
Splenomegaly
Constitutional symptoms eg - malaise, fatigue with non specific signs of bone marrow suppression eg anaemia, thrombocytopenia.
What should be the initial diagnostic work up for CML?
CBC
Peripheral blood smear
Bone marrow aspiration and biopsy
How do you confirm the diagnosis of CML?
Identification of Philadelphia chromosome and or BCR-ABL1 fusion gene
What will the CBC and blood smear show for CML?
Leukocytosis with mid stage progenitor cells (eg myelocytes) and mature cells (eg neutrophils)
Thrombocytes is
Basophils and eosinophilia
Blast cells in peripheral blood can indicate trainstion to AP-CML (accelerated phase)
Anaemia
Which further tests should be carried out for CML?
Leukocyte alkaline phosphatase - low LAP is a typical finding for CML
Flow cytometry - assess the type and maturity of leukocytes in order to detect progression to advanced phases of CML
What will a cryogenic test confirm?
Presence of BCR-ABL1 fusion gene and or Philadelphia chromosome.
What is present during the accelerated phase of CML?
Increased proportion of blast cells and additional genetic mutations are often present
What is present during the blast phase of CML?
Higher proportion of blast cells compared with AP-CML
extramedullary blast proliferation
Often resistant to targeted therapy due to presence of multiple genetic mutations
What is the treatment for the chronic phase of CML?
Tyrosine kinase inhibitors first and second line treatment
Haematopoietic stem cell transplant may also be considered if other treatments fail
Which treatment is done for accelerated phase of CML?
Begin with tyrosine kinase inhibitors
Consider systemic chemotherapy or transplant if patient is eligible
Which treatment is given for blast phase of CML?
Aggressive systemic chemotherapy in combination with tyrosine kinase inhibitors
Transplant if patient is eligible
Which agents should be used for targeted therapy with tyrosine kinase inhibitors?
First generation TKI’s (Imatinib)
Second generation TKI’s (Dasatinib, Nilotinib)
Third generation TKI’s (Ponatinib)
What are the indications for first generation TKI’s?
Indicated in low risk CP-CML with comorbidities or older patients
What are the indications for second generation TKI’s?
In AP-CML
What are the indications for third generation TKI’s?
Especially effective in patients with additional mutations
What is the mechanism of action with TKI’s?
Selective inhibition of tyrosine kinases (by blocking its ATP binding site). Inhibits tyrosine phosphorylation of downstream signalling proteins.
Disruption of BCR-ABL1 pathway - inhibits proliferation and induces apoptosis in BCR-ABL1 positive scells
What are further treatment options for CML?
Adjunctive medical therapy - hydroxyurea or Interferon alpha to reduce leukocyte counts and control Compton’s associated with extreme leukocytosis or thrombocytosis.
Systemic chemotherapy - indicated in BP-CML and certain case if AP-CML
stem cell transplant in patients with TKI-resistant CML
What is the differential diagnosis for CML?
Polycythemia Vera
Primary myelofibrosis
Essential thrombocytopenia
Chronic myeloid leukaemia
Leukemoid reaction
Acute myelogenous leukaemia
Reactive thrombocytosis and granulocytosus secondary to infection
What is the prognosis for CML?
Survival rate without treatment - chronic phase - 3.5-5 years
Blast phase - 3-6 months
Most patients life expectancy goes up with targeted therapy with imatinib.
