Myeloid Malignancy Flashcards
What are the Myeloid Malignancies?
Acute myeloid Leukaemia (AML)
Chronic Myeloid Leukaemia (CML)
Myelodysplastic syndromes (MDS)
Myeloproliferative neoplasms (MPN)
Pathology of AML
Leukemic cells do not differentiate
Bone marrow failure
Prognosis of AML
Rapidly fatal if untreated
Potentially curable
Subgroups of acute leukaemia
Acute myeloblastic leukaemia (AML)
Acute lymphoblastic leukaemia (ALL)
Presentation of Acute myeloblastic leukaemia
Bone marrow failure
- anaemia
- thrombocytopenic bleeding (purpura and mucosal)
- infection because of neutropenia (predominately bacterial and fungal)
Splenomegaly
Bone pain
Investigations of acute myeloblastic leukaemia
Blood count and blood film
Bone marrow aspirate / trephine
Cytogenetics (karyotype) from leukaemic blasts
Immunophenotyping of leukaemic blasts
CSF exam if symptoms
Targeted molecular genetics for associated gene mutations e.g. FLT3
Treatment of acute myeloblastic leukaemia
Supportive
Anti-leukaemic chemotherapy
- daunorubicin and cytosine arabinoside
Allogenic stem cell transplantation
All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in low risk acute promyelocytic anaemia
Targeted treatment - midostaurin in FLT3 mutated AML
Pathology of CML
Leukaemic cells retain ability to differentiate
Proliferation without bone marrow failure
Prognosis of CML
Survival for a few years historically
Long term survival / possible cures with modern therapy
Presentation of CML
Often no symptoms Low grade fever / sweating Malaise Anaemia Splenomegaly, often massive - left upper quadrant fullness / leading to abdominal discomfort Weight loss Hyperleukostasis - fundal haemorrhage and venous congestion - altered consciousness - resp failure Gout
CML blood features
High WCC (can be VERY high)
Low Hb
High Platelets or may be reduced due to big spleen
High neutrophils
Anaemia
Blood film shows all stages of white cell differentiation with increased basophils
Bone marrow hypercellular
Increased mature granulocytes (basophils, eosinophils, neutrophils) so there is no immunosuppression
High or low red cell count due to the big spleen
Decreased leukocyte alkaline phosphatase
Treatment of CML
Tyro kinase inhibitors (TKIs)
- Imatinib - 1st line
Allogenic transplantation (few now) only in TKI failures
Bone marrow transplant only possible cure
Hydroxyurea
Interferon alpha
What are myelodysplastic syndromes?
Acquired clonal disorders of the bone marrow
What age are myelodysplastic syndromes common?
Elderly
Presentation of myelodysplastic syndromes
Macrocytic anaemia
Pancytopenia
Neutropenia
Bone marrow often hypercellular but the cells are not released into the blood
What is myelodysplastic syndromes in relation to leukaemia?
Pre-leukaemic
Prognosis of myelodysplastic syndromes
Pre-leukaemic
Fatal as result of progression to bone marrow failure or AML
Treatment of myelodysplastic syndromes
Supportive
Stem cell transplantation for the few younger patients
Types of myeloproliferative neoplasms (MPN)
Polycythaemia Vera (PV) Essential thrombocythemia (ET) Idiopathic myelofibrosis (IM)
Mutations in myeloproliferative neoplasms
JAK2V617F mutation in > 98% of PV
PV in 50% of ET and myelofibrosis
CALR mutation in 25% of ET
Presentation of Polycythaemia Vera
Headaches Itch - intense - after exposure to hot water or hot and humid weather Vascular occlusion Thrombosis (e.g. DVT) TIA, stroke Splenomegaly 20% will suffer from gout
Lab features of polycythaemia vera
Elevated red cells
Elevated platelets in 50%
Raised Hb and haematocrit
Tendency to have raised WCC and platelet count
A raised uric acid
True increase in red cell mass when blood volume measured
Treatment of PV
Venesection to keep the haematocrit level below 0.45 in men and 0.43 in women
Aspirin
Hydroxcarbamide (HC)
Ruxolitnib (JAK2 inhibitor) in HC failures with systemic symptoms
Prognosis of PV
Stroke and other arterial or venous thromboses if poorly controlled
Bone marrow failure from development of secondary myelofibrosis
Transformation to AML
What is Essential thrombocythaemia (ET)?
Myeloproliferative disease with predominant feature of raised platelet count
Mutations of ET
50% +ve for JAK2V617F mutation
25% positive for calreticulin (CALR) mutuation
Presentation of ET
Symptoms of arterial and venous thrombosis Digital ischaemia Gout Headache Mild splenomegaly
Treatment of ET
Aspirin
Hydroxycarbamide or anagrelide
What can ET progress to?
Myelofibrosis
AML
What mutation causes > 98% of primary polycythaemia?
JAK2
Causes of haematological malignancy
Radiation Non therapeutic Chemo Smoking Chemicals e.g. benzene HIV HTLV1 and EBV Immunosuppressants Downs syndrome
Who is AML most common in?
Elderly
What is prognosis related to in AML?
Classification and cytogenic changes
How is chemotherapy given in AML?
Blocks intensive for 10 days 2 - 3 week break intensive chemo for 8 days 2 - 3 week break intensive chemo for 8 days 2 - 3 week break May have a 4th dose
AML success in under 60 y/o
80% success with ‘good chromosomal genes’
50% success for no or neutral chromosomal changes
20% success with ‘bad chromosomes’
When is bone marrow transplant given in AML/ALL?
Not in remission post induction chemotherapy
High relapse risk (as assessed by chromosomes)
Relapsed disease
Can parents be a bone marrow donor?
No
How much of siblings statistically match for bone marrow transplant?
25%
Why is rejection unlikely in bone marrow transplant?
Patients immune system has been ‘killed’ by the conditioning chemo +/- radiotherapy and will be replaced by the donors immune system
Why do recipients of bone marrow transplant need immunosuppression?
To reduce the risk of graft versus host disease
What is graft vs host disease?
New immune system from the donors bone marrow rejects recipients own tissue
Who does CML effect?
More common in adults but effects everyone
What chromosomal abnormality is seen in CML?
Philadelphia chromosome - t(9;22)
The Philadelphia chromosome has a translocation between which chromosomes?
9 and 22
What does the Philadelphia chromosome changes produce?
2 oncogenes BCR and ABL brought together to form
A new RNA sequence - creating tyrosine kinase
What transcript is active in creating tyrosine kinase?
BCR-ABL
Effects of BCR-ABL
Creates a new RNA sequence - tyrosine kinase
Activates proteins that speed up the cell cycle and inhibit DNA repair, increasing the risk of other mutations
What can CML transform into?
AML (80%)
ALL(20%)
If CML does transform into an acute leukaemia, what is the prognosis?
poor - 3 months
How many blast cells in the marrow are normal?
5%
How many blasts in the bone marrow is classed as leukaemia?
> 20%
How many blasts in the bone marrow are classed as myelodysplastic syndrome?
5 - 19%
What can myelodysplastic syndromes progress to?
Acute myeloid leukaemia
What questions should be asked relating to tiredness?
How is it affecting life?
All the time?
Any reason for not sleeping?
What features of feeling an abdominal mass would make you think that is was splenomegaly?
Can’t get above it
Moves with inspiration
May feel a splenic notch
What is a feature of a mass that would indicate it was a kidney mass?
Ballotable
What can be elevated in people with lymphomas?
LDH
What level of melanocytes are usually in the peripheral blood?
None
What type of cells are found in acute leukaemia?
Immature cells
How fast does acute leukaemia come on?
Quickly - weeks - a month
What blood result is often found to be VERY high in both CML and CLL?
WCC
What test should be done usually if blood results are abnormal?
Bone marrow biopsy
Would a bone barrow biopsy be done if for example the bloods weren’t effected in e.g. lymphoma?
No
IMPORTANT INVESTIGATION I ALWAYS FORGET
Blood film
What is cytogenetics used to analyse?
Chromosomes
What is FISH?
Florescent marker attached to chromosome
What is the 9 marker in CML when looking at FISH?
BCR
What is the 11 marker in CML when looking at FISH?
ABL
How do you test for the Philadelphia chromosome?
PCR
Cytogenetics
FISH
What levels are tracked in CML to monitor treatment?
BRC-ABL
Pathology of blast crisis in CML
Chronic phase -> accelerated phase -> AML
What are the cancers that spread to bone?
Prostate Lung Breast Renal Thyroid
What test should be done if concerned about K+ levels?
ECG
How to bring down high K levels?
Salbutamol
Calcium gluconate if very high
Insulin dextrose (insulin and glucose)
How to bring down high Ca levels?
IV fluids to rehydrate
Biphosphonates
What is the issue when using bisphosphonates?
They can worsen renal failure
What is the most common form of leukaemia in adults?
AML
Poor prognostic features for AML
> 60 yo
20% blasts after first round of chemo
Cytogenetics - deletion of chromosome 5 or 7
What classification system is used for AML?
FAB - French American british
Describe the FAB classification of AML
M0 - undifferentiated M1 - without maturation M2 - with granulocytic maturation M3 - acute promyelocytic M4 - Granulocytic and monocytic maturation M5 - monocytic M6 - eyrthroleukaemia M7 - megakaryoblastic
Describe acute promyelocytic leukaemia (M3)
Associated with t(15;17)
Fusion on PML and RAR-alpha genes
Presents in younger people as opposed to other types of AML - average is 25 y/0
What is often seen at presentation of acute promyelocytic leukaemia?
DIC
Thrombocytopenia
What are seen on myeloperoxidase stain in acute promyelocytic leukaemia?
Auer rods
Prognosis of acute promyelocytic leukaemia
Good
