CML

Question 1

What is the cause of CML?

Answer 1

Myeloproliferative neoplasm involving hematopoietic stem cells that results in over expression of cells of myeloid lineage, especially granulocytes.

Question 2

What is the median age of onset?

Answer 2

50-60 years old

Question 3

What are the risk factors for CML?

Answer 3

Idiopathic (most cases)
Ionising radiation (eg secondary to therapeutic radiation)
Aromatic hydrocarbons (especially benzene)

Question 4

What is the pathophysiology behind CML?

Answer 4

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.

Question 5

What causes CML to progress from chronic to accelerated phase and into acute leukaemia?

Answer 5

Additional chromosomal changes sand mutations of tumour suppressor genes and oncogenes (p53, Rb1, Ras)

Question 6

What are the clinical features of CML in the chronic phase?

Answer 6

Often sub clinical
When symptomatic - weight loss, fatigue, fever, splenomegaly, lymphadenopathy not typical in CML

Question 7

What clinical features does CML have in the accelerated phase?

Answer 7

Erythropenia - anaemia

Neutropenia - infection and fever

Extreme pleocytosis - infarctions of spleen and heart, retinal vessel occlusion, leukaemic priapism. Terminal phase - myelofibrosis.

Extreme splenomegaly

Question 8

What is the blast crisis in CML?

Answer 8

The terminal stage of CML

Question 9

What clinical features are present during the blast crisis of CML?

Answer 9

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

Question 10

Which lab findings should clinicians look out for?

Answer 10

Severe leukocytosis on routine lab tests
Splenomegaly
Constitutional symptoms eg - malaise, fatigue with non specific signs of bone marrow suppression eg anaemia, thrombocytopenia.

Question 11

What should be the initial diagnostic work up for CML?

Answer 11

CBC
Peripheral blood smear
Bone marrow aspiration and biopsy

Question 12

How do you confirm the diagnosis of CML?

Answer 12

Identification of Philadelphia chromosome and or BCR-ABL1 fusion gene

Question 13

What will the CBC and blood smear show for CML?

Answer 13

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

Question 14

Which further tests should be carried out for CML?

Answer 14

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

Question 15

What will a cryogenic test confirm?

Answer 15

Presence of BCR-ABL1 fusion gene and or Philadelphia chromosome.

Question 16

What is present during the accelerated phase of CML?

Answer 16

Increased proportion of blast cells and additional genetic mutations are often present

Question 17

What is present during the blast phase of CML?

Answer 17

Higher proportion of blast cells compared with AP-CML
extramedullary blast proliferation
Often resistant to targeted therapy due to presence of multiple genetic mutations

Question 18

What is the treatment for the chronic phase of CML?

Answer 18

Tyrosine kinase inhibitors first and second line treatment
Haematopoietic stem cell transplant may also be considered if other treatments fail

Question 19

Which treatment is done for accelerated phase of CML?

Answer 19

Begin with tyrosine kinase inhibitors
Consider systemic chemotherapy or transplant if patient is eligible

Question 20

Which treatment is given for blast phase of CML?

Answer 20

Aggressive systemic chemotherapy in combination with tyrosine kinase inhibitors
Transplant if patient is eligible

Question 21

Which agents should be used for targeted therapy with tyrosine kinase inhibitors?

Answer 21

First generation TKI’s (Imatinib)
Second generation TKI’s (Dasatinib, Nilotinib)
Third generation TKI’s (Ponatinib)

Question 22

What are the indications for first generation TKI’s?

Answer 22

Indicated in low risk CP-CML with comorbidities or older patients

Question 23

What are the indications for second generation TKI’s?

Answer 23

In AP-CML

Question 24

What are the indications for third generation TKI’s?

Answer 24

Especially effective in patients with additional mutations

Question 25

What is the mechanism of action with TKI’s?

Answer 25

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

Question 26

What are further treatment options for CML?

Answer 26

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

Question 27

What is the differential diagnosis for CML?

Answer 27

Polycythemia Vera
Primary myelofibrosis
Essential thrombocytopenia
Chronic myeloid leukaemia
Leukemoid reaction
Acute myelogenous leukaemia
Reactive thrombocytosis and granulocytosus secondary to infection

Question 28

What is the prognosis for CML?

Answer 28

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.