Cancers of Myeloid Cell Origin Flashcards
What is CML
Proliferation and differentiation of leukaemic stem cells
Increased end cells / monocytosis
Most commonly neutrophil affected
Present without bone marrow failure as no blocked differentiation
Proliferation of bone marrow that makes mature end-cells so lots of granulocytes
What is prognosis
Survival for a few years
Long term now achievable with modern therapy - attacking Philadelphia chromosome
CLL a bit behind
What is +Ve in majority of CML and what is important
Philadelphia chromosome t(9:22)(q34:q11)
Translocation 9-22
Give rise to mutant BCL-ABL on chromosome creating tyrosine kinase
Leads to uncontrolled cell cycling
Genetically unique as only require this one mutation to get disease rather than multiple hits
More +Ve prognosis in CML.
Dx by FISH / molecular testing
How does CML present
Insidious
WCC increasing = leucocytosis
Classicaly neutrophils + basophils
Can sometimes get thrombocytosis
Anaemia chronic disease - lethargy
Slight bone marrow failure (no neutropenia or thrombocytopenia)
Massive splenomegaly
B symptoms - Weight loss /fever / night sweats due to hyper metabolism
Anorexia due to spleen compressing stomach
Hyperleukostasis
Gout as high cell turnover
Increased viscosity due to increased cells
Have granulocytes at different stages
What do they not have
Neutropenia - raised
Thrombocytopenia - can get thrombocytosis
What causes weight loss
Hypermetabolic state
What does hyperleukostasis cause
Fundal haemorrhage
Venous congestion
Altered consciousness
Resp failure
What is important not to do due to increased viscosity
DO NOT TRANSFUSE
Anaemia is the only thing that is keeping viscosity at bay
What are lab features of CML
High WCC - extremely
Variable platelet - can be high due to inflammation
Whole spectrum of myeloid cells at different stages of maturation
Urate and B12 increased
Anaemia
What does blood film show
Increased cells and different types of white cells at different stages
What will bone marrow and blood cells contain
Philadelphia chromosome
What is diagnostic
Bloods
Blood film -
Philadelphia +Ve
Bone marrow = diagnostic
What is 1st line Rx in CML
Tyrosine kinase inhibitor (direct inhibitor of BCR-ABL on Philadelphia chromosome)
Known as Imaticinib
Normal life expectancy if maintain remission
Either take tablet for years or life
Other Rx options
Interferon alpha
Allogenic stem cell transplant - do this if relapse
Chemo NOT effective as can never get rid of all cells (used to be only option so used to be incurable)
What is most common leukaemia in adults
AML
How does it occur
Primary - Down's - RT ' Chemo - Fanconi Secondary transformation of myeloproliferative disorder
What happens in AML
Leukaemic cells do not differnetiate
Just proliferate
Leads to bone marrow failure
Rapid aggressive and fatal
What are features of AML
Bone marrow failure Infiltration - HSM Bone pain Skin involvement CNS = rare Usually elderly
What suggests poor prognosis
> 60
20% blasts after chemo
Do not differentiate into different cell lines
Certain cytogenetics
APML t(15,17) can present in medical emergency
- DIC
- Haemorrhage
- Continuous therapy needed in these patients
How do you Dx / essential investigation
Blood count + film Bone marrow aspiration = diagnostic Cytogenetics/ immunophenotype to guide Rx CSF - more in ALL as CSF spread Targeted genetics Increased use of NGS myeloid gene panels
What will blood count and film show
AUER RODS WCC - high or low (usually high) Neutropenia Thrombocytopenia Anaemia Circulating leukaemic cells
What confirms Dx
Bone marrow aspirate
Blasts >20% = Dx
If 15% = myelodysplasia
If infiltrate CNS what do you get
Headache
CN palsy
More common in ALL
What genes and what do they suggest about prognosis
FLT3 = worse but drugs to target NPM1 = better IDH1 = drugs to target
How do you treat
Supportive
Chemotherapy
Allogenic stem cell to consolidate remission and cure
What is supportive care
Blood transfusion
Platelet support
Suport neutropenic sepsis risk
What is remission
Blood count returned to normal state
Blasts <5%
What are new treatments
ATRA - All trans retinoic acid - Continuous therapy against t(15,17) of RAR gene - APML type of AML ATO Targeted Ab against cell receptors New delivery systems
What is myelodysplastic syndromes
Acquired clonal disorders of bone marrow common in elderly
Bone marrow trying to produce mature cells but never quite make it to maturity
Blasts >15% but less than <20%
Pre-leukaemic
RF = smoking / previous chemo or RT
How does it present
Classically present with low blood count / cytopenia in peripheral blood but busy bone marrow full of pre-cursor
Bone marrow failure Macrocytic anaemia Pancytopenia HSM Will progress to AML
How do you Rx
Supportive - transfusion
Few effective therapies
Chemo
Stem cell transplant in the younger
What are myeloproliferative disorders
Stem cell disorder that results in certain type of end cell / mature cell
What is linked to myeloproliferative disorders and what do they have potential to do
JAK2 mutation as means can produce cells e.g. red cells without EPO
Turns of the stop button so just over proliferative
Now used to Dx and patients no longer require bone marrow aspirate
Pre-malignant
Transform to AML
What are types of myeloproliferative disroder
Polycythermia vera - red cell
Essential thrombocythaemia - platelet
Idiopathic myelofibrosis - haemopoetic stem cell
CML - WBC
What is polycythaemia vera
Clonal proliferation of marrow stem cell leading to excess red cells
Often neutrophils and platelet increased as well
How does it present
Itch and headache = very common Raised Hb Hyperviscosity Headache Plethroic appearance Itch Painful hands and feet Vascular occlusion / thrombosis Splenomegaly causing feeling. of abdominal fullness Gout Low ESR Hypertension Haemorrhage
What is big risk
TIA / stroke
What causes haemorrhage
Abnormal platelets
How do you investigate
FBC / film
U+E, LFT, ferritin, urate, LDH
JAK2 +ve
Cytogenetics to differentiate from CML
What does FBC show
Raised Hb + haematocrit
Tend to have raised WCC / platelet
MCV may be low as iron deficiency + low ferritin
What should you look for if raised Hb
Other causes
Low sats
Smoker
COPD / lung disease
What is standard Rx
Venesection + aspirin
What is aim
To keep haematocrit below 0.45 in M and 0.43 in F
To prevent stroke and MI
What are other options
Hydroxycarbamide - suppress platelet
Ruxolitinimb - JAK2 inhibitor
What are complications
Stroke
Bone marrow failure if secondary myelofibrosis occurs
Transformation to AML
What are other causes of polycythaemia (cause same Sx)
COPD / lung disease / low sats - look for this
Altitiude
OSA
Excessive erythropoetin - can be caused by renal tumour
Dehydration / alcohol / diuretics causes relative
How do you differentiate between true polycythaemia and relative
Red cell mass studies - will be high if true
If JAK2 -ve and no obvious 2 cause for polycythameia what should you do
ABG ABdo USS Serum eryhropoetin Bone marrow aspiration Cytogenetics
What is essential thrombocythaemia
Raised platelets
What mutation
JAK2
CARL
What symptoms
Arterial and venous thrombosis Digital ischaemia Gout Mild splenomegaly Normal ferritin
How do you Rx
Manage vascular RF
Aspirin + hydroxycarbamide to get platelet down as high risk of thrombosis
What can it progress too
Secondary myelofibrosis
AML
What is idiopathic myelofibrosis
Fibrosis of bone marrow due to hyperplasia of abnormal megakaryocytic / cell lines
Cytokines cause release of platelet derived growth factor and stimulation of fibroblast
Can be primary or secondary to polycythaemia or essential thrombocythaemia
What does this lead too
Haemotopoeisis developing in liver and spleen as can’t occur in marrow
Can cause HSM + portal hypertension
How does it present
Bone marrow failure - Anaemia - Low WCC Elderly + extreme fatigue Massive splenomegaly Hypermetabolic - weight loss / night sweats Symptoms of cytopenia Thrombotic events
What are lab results
Anaemia Can get high or low WCC depending on disease High or low platelet High urate High LDH
What can you not too
Bone marrow biopsy as fibroses so just get dry tap
Trephine will be fibrotic and hyper cellular
What is seen on film
Tear drop poikilocytes
How do you Rx
Transfusion + supportive
Hydroxycarbamide
Ritoxicilinum - JAK2 inhibitor
Allogenic stem cell transplant = only curative
How do you assess raised Hb / haematocrit
History Examination Bloods JAK2 USS to look for splenomegaly EPO Red cell mass studies Bone marrow = rarely done
What is important in the Hx
Any reasons for polycythaemia e.g. smoking
Any symptoms suggestive of polycythamia vera
Assess thrombotic risk
What do you look for in examination
Splenomegaly
Chest signs
O2 sats
What bloods
Repeat FBC, U+E, LFT, urate, LDH, ferritin
What confirms myelproliferative disorder
+ve JAK2 mutations
What does EPO tell you
If low = primary polycythaemia
Normal = unhelpful
If high = secondary
What are red cell mass studies useful for
Work out if true or apparent polycythaemia
What causes primary thrombocytosis
Overproduction in bone marrow usually due to myeloproliferative disorder Essential thrombocytosis Myelofibrosis Ppolycythaemia CML
What causes secondary
Systemic response to infection Inflammation - RA Tissue damage - post surgery Malignancy Iron or B12 deficiency
What could you ask in history
Infection Surgery Bleeding Weight loss Joint pain Pruritus
What do you look for in examination
Splenomegaly
Signs of malignancy / inflammation / infection
What investigations
FBC, film, U+E, LFT, urate, LDH CRP/. ESR Ferritin JAK2 USS/. CT
What can help differentiate
Primary patient usually well
- Itch / thrombosis / splenomegaly often associated
Secondary patient usually unwell
Background
OK
Where are myeloid precursor cells supposed to liver
In BM = only place
What happens if begins to grow out of control e.g AML / myelodysplasia
Very busy bone marrow
Increasing cells in blood count as leak out
Abnormal cells in BM expand in number and crowd out normal precursor
BM starts to fail in ability to produce normal cells = cytopenia
Abnormal cells leak out into blood and can see leukaemia cells
What can AML purely present with
Cytopenia
May just be neutropenic but will eventually get all
Overproliferation of immature cells
AML
Overproliferation of mature cells
ET
Similarity between myeloproliferative and myelodysplasia
Both myeloid
Both slow moving
Both oveproliferation of myeloid precursor
Difference
Myeloproliferative
- Cells still normal enough to make it to maturity of whatever lineage
- Leads to too many blood cells
- Aim to get cell count down
Myelodysplasitc
- Cells proliferate but do not survive
- BM can look similar as full of precursor but blood count low / cytopenia
How does CML overlap with both
Proliferation of WCC - neutrophilic / monocytosis
Get loss of mature RBC and platelet formation
Often a leucocytosis with anaemia / thrombocytopenia or both
What can result from myeloproliferative / dysplasia
Secondary AML
Cells already have a genetic abnormality so more likely to transform
More difficult to Rx if secondary as more mutations
