CML

Question 1

Types of haematological malignancies

Answer 1

Acute myeloid leukaemia AML
chronic myeloid leukaemia CML
Myeloproliferative neoplasia MPN
Myelodysplasic syndromes MDS

Acute lymphoid leukaemia ALL
Chronic lymphoid leukaemia CLL
Lymphoma
Myeloma

Question 2

CML facts

Answer 2

Rare
10-15% of all leukaemia 
Disease of middle age ~53
Men more than women 
Cause unknown radiation has been implicated 
BRCABL translocation

Question 3

CML used as a model for understanding molecular genetics leading to a development of targeted therapy

Answer 3

Patient -> semitotics study of signs and symptoms of the patent -> pathology study of the disease morphology , mechanisms and aetiology -> discovery of abnormal genes -> discovery of new drugs -> back to the patient

Question 4

Clinical diagnostic approach

Answer 4

History
Physical exam - IPPA - large spleen

Investigations

Question 5

Investigations

Answer 5

Blood film morphology - cells at varying stages of differentiation - immature myelocytes & basophils mature granulocytes and neutrophils
Bone marrow diagnosis - aspirate and trephine morphology, lots of immature myelocytes and megakaryocytes
Cytogenetics - Philadelphia chromosome diagnosed by FISH - fluorescent in situ hybridisation where each protein gieven and fluorescent tag 2 seen together hybrid chimearisation and QPCR quantitative real time polymerase chain reaction - BCR-ABL transcripts present

Question 6

Phases of CML

Answer 6

Chronic phase -> advanced phase -> blasted transformation -> myeloid/lymphoid leukaemia
Aim of treatment is to treat in the chronic phase

Question 7

Current treatment

Answer 7

Imatinib
Inhibits the binding of ATP to the ABL tyrosine kinase
Inhibits the survival of CML cells
Only curative option is allogenic haematopoietic stem cell transplant however only 30% of patients are eligible

Question 8

Conclusions regarding imatinib

Answer 8

Well tolerated 
Orally available 
Effective 1st line treatment 
Reduces risk of relapse to 10% 
97% of patients with a compete cytogenic response did not progress to the acute or blast phase within 54months

Question 9

Problems with imatinib

Answer 9

Variability is response
Predictor of how well the response is - the degree of reduction in disease burden and time taken to get this reduction

Drug resistance: mutations in BRC-ABL

Failure to eradicate primitive stem cell populations

Question 10

Second generation TKI

Answer 10

More potent but have more side effect profiles

Dasatinib 500x more potent

Question 11

JAK what is it and how is it implicated in treatment

Answer 11

JAK2 an intracellular component of cytokines receptors it transducers signal from outside the cell to inside the cell
It is identified in myeloproliferative neoplasia - different group of myeloid diseases

Question 12

What is being trialled as a treatment against JAK mutations

Answer 12

Ruxolitinib
Myelofibrosis
Does not eradicate the disease. It slows disease progression and inc survival
Eradicates constitutional symptoms of myelofibrosis and increases QOL