Myeloid Malignancy Flashcards by Annie Caldwell

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Pathology of AML

Leukemic cells do not differentiate

Bone marrow failure

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Prognosis of AML

Rapidly fatal if untreated

Potentially curable

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Subgroups of acute leukaemia

Acute myeloblastic leukaemia (AML)

Acute lymphoblastic leukaemia (ALL)

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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

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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

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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

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Pathology of CML

Leukaemic cells retain ability to differentiate

Proliferation without bone marrow failure

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Prognosis of CML

Survival for a few years historically

Long term survival / possible cures with modern therapy

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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

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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

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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

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What are myelodysplastic syndromes?

Acquired clonal disorders of the bone marrow

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What age are myelodysplastic syndromes common?

Elderly

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Presentation of myelodysplastic syndromes

Macrocytic anaemia
Pancytopenia
Neutropenia
Bone marrow often hypercellular but the cells are not released into the blood

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What is myelodysplastic syndromes in relation to leukaemia?

Pre-leukaemic

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Prognosis of myelodysplastic syndromes

Pre-leukaemic

Fatal as result of progression to bone marrow failure or AML

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Treatment of myelodysplastic syndromes

Supportive

Stem cell transplantation for the few younger patients

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Types of myeloproliferative neoplasms (MPN)

Polycythaemia Vera (PV)
Essential thrombocythemia (ET)
Idiopathic myelofibrosis (IM)

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Mutations in myeloproliferative neoplasms

JAK2V617F mutation in > 98% of PV
PV in 50% of ET and myelofibrosis
CALR mutation in 25% of ET

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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

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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

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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

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Prognosis of PV

Stroke and other arterial or venous thromboses if poorly controlled
Bone marrow failure from development of secondary myelofibrosis
Transformation to AML

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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?

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?

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?

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