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Which one of the following is the most important component in the pathogenesis of β thalassaemia? 
A. Iron overload. 
B. α/β globin chain imbalance. 
C. Ineffective erythropoiesis. 
D. Dysfunctional β globin. 
E. Haemolytic anaemia.  

B. α/β globin chain imbalance. 

Excess alpha chains are unstable and precipitate - RBC membrane damage (target cell)

Results in:
- Intramedullary and peripheral haemolysis
- Erythroid hyperplasia, 
- Ineffective erythropoeisis due to intramedullary destruction of erythroid cells.


1.  What are the three different kinds of haemoglobin?

2.  Which forms the majority of adult Hb?

3.  On what genes are haemoglobin alpha and beta located?

HBA (A2B2)- a tetramer of two alpha and two beta chains 
HBA2 (a2δ2) tetramer forms - 1-2% adult Hb
HBF - a2γ2 tetramer forms - fetal Hb but <1% of adult Hb

2.  98% adult Hb primarily HBa

2 alpha-globin genes - Cr16, w/ no substitutes.
B-globin gene - Cr11, adjacent to B-like glob in genes delta δ and gamma γ


In the context of thalassaemia, define the following terms:

1.  Trait
2.  Intermedia
3.  Major

1.  Trait - lab features, no clinical impact
2.  Intermedia - occastional transfusion requirement
3.  Major - life threatening or transfusion dependent - most die of iron overload.


Describe the pathogenesis of alpha-thalassaemia

Alpha thalassaemia - Cr16 x 2
- due to gene deletions —> reduced a-globin chain synthesis
- each gene produces 1/4 of total alpha-globin quantity
- all adult Hb are alpha containing, so there will never be any change in percentage distribution of it on Hb EPG.
- Severe forms:  excess B chains will form B2B2 tetramer (H bodies), or HbH which are highly unstable.


Describe the clinical features of alpha thalassaemia

Southeast Asians and Chinese

- aa/a- : silent carrier
- aa/— or a-/a- : Clinically normal, mild microcytic anaemia
- a-/— : HbH disease - chronic haemolytic anaemia of variable severity (minor or intermedia) with pallor and splenomegaly.  Intermittent transfusions only (infection / stress or by RBC production shutdown (aplastic crisis) by certain viruses (i.e. parvovirus).)
- —/— : Hydrops fetalis (no normal Hb is produced only Bart’s y4) - fetus is stillborn


Describe the lab findings for alpha-thalassaemia trait and HbH disease.

Trait - MCV (60-75)
- normal or increased RBC count
- smear:  microcytes, hypochromia, occ target cells, acanthocytes.
- retic and iron counts normal
- Hb EPG:  no change in percent HbA2/F/or HbH
- dx of exclusion

HbH disease
- marked anaemia HCT 22-32%
- very low MCV 60-70
- smear:  hypochromia, microcytosis, target cells, poikilocytosis (annoying term that means ‘varied’!)
- elevated retics, elevated/normal RBC count
- Hb EPG: fast migrating haemoglobin (HbH) accounting for 10-40% of the Hb.
- Can stain smear with supra vital dye to show HbH


Describe the pathogenesis of beta-thalassaemia

Beta thalassamia - Cr 11 point mutation
- little to no B-Hb --> more HBA2 & HbF on EPG
- excess alpha chains precipitate --> RBC membrane damage
- intramedullary and peripheral haemolysis, erythroid hyperplasia
Absent b-chains:  B0
Reduced b-chains:  B+ (variable severity)

Severe disease
- marrow expansion --> bone deformities, osteopaenia, path fractures


Describe the clinical manifestations of all forms of beta-thalassaemia

Homozygotes (B0/B0 or B+/B+)
- thal major
- normal @ birth, severe tfusion dependence at 6/12 (HbF-->HbA)
- Stunted growth
- Bony deformities (frontal bossing, chipmunk facies, path fractures)
- Hepatosplenomegaly
- Cirrhosis, jaundice (due to gallstones), thrombophilia
- Iron overload (due to transfusion) --> heart failure & arrythmias, cirrhosis, endocrinopathies, pseudoxanthoma elasticum - calcification of epithelial cells of skin, retina, CVS) due to inability to excrete iron.  Poor survival.

Homozygosity for milder B+/B+: chronic haemolytic anaemia, transfusions only during aplastic crises.  May still develop iron overload, hepatosplenomegaly and bony deformities but survive into adulthood.

Heterozygosity for B/B0 or B/B+ : thalassaemia minor, clinically insignificant microcytic anaemia


What are the lab findings for beta-thal major and minor?

B-thal minor:
- Modest anaemia - HCT 28-40%, MCV 55-75
- RBC count normal or increased
- Retic count - normal or slightly elevated
- Smear:  Hypochromia, microcytosis, target cells, basophilic stippling
- Hb EPG: Increased HBA2 to 4-8%, occ increased HbF - 1-5%

B-thal major:
- severe anaemia - HCT to
- smear:  severe poikilocytosis, hypochromia, microcytosis, target cells, basophilic stiplling,  nucleated RBCs.
- HbEPG - little to no HbA, variable amt HBa2, major Hb present is HbF


How do you differentiate thalassaemia from iron deficiency anaemia?

How is the diagnosis of b-thal and a-thal made?

Compared to Fe+ deficiency anaemia
 - lower MCV
 - normal or elevated RBC count
 - more abnormal smear at modest lvld anaemia
 - normal or elevated transferrin sat/ferritin (or both)

Dx of b-thal made with above plus HbEPG showing elevated HbA2 and F (assuming iron replete)
Dx of a-thal is one of exclusion since HbEPG levels of a-globin remains the same.
Other microcytic anaemia with normal or elevated RBC count is Fe+ deficiency + PCV


Describe the treatment for all forms of thalassaemia

Mild a or b - no treatment but need identification so they don’t keep getting investigated for Fe deficiency anaemia!
HbH - Folic acid, avoid medicinal iron and oxidative drugs (sulphonamides)
Severe thalassaemia - regular transfusion, folic acid and iron chelation.

Allogeneic SCT - treatment of choice for B-thal major, only cure, and in kids w/o Fe+ overload or chronic organ toxicity - long term survival of >80%.


Which one of the following occurs most frequently in the α thalassaemia syndromes? 
A. Mental retardation. 
B. Reduced mean corpuscular volume. 
C. Gene deletions. 
D. Haemoglobin H inclusion bodies. 
E. Reduced haemoglobin. 

C. Gene deletions. 


AMP 1999 Question 30 
 In which one of the following conditions has initial therapy with imatinib been shown to cause the best improvement in survival? 
A. Multiple myeloma. 
B. Low grade non-Hodgkin’s lymphoma. 
C. Chronic myeloid leukaemia. 
D. Chronic lymphocytic leukaemia. 
E. T-cell acute lymphocytic leukaemia. 


TKIs (Imatinib, Dasatinib, Nilotinib, Ponatinib) • specific competitive binders in the ATP-pocket of BCR-ABL tyrosine kinase.  Associated with >80% progression free at 8 years.


What is the pathogenesis of CML?

Chromosomal abnormality
Reciprocal translocation of Cr9 to 22
Cr9q Abl protoncogene fused to BCR on Cr22q


Molecular abnormality
Fusion gene deregulates abl tyrosine kinase activity —> autophosphyrlation, altered adhesion, inhibition of apoptosis


Myeloid proliferation


What are the clinical findings of CML?

• Middle aged, more men
• May be asymptomatic - discovered incidentally on an FBC with elevated WCC
• Hyper metabolic sx; night sweats, low-grade fever caused by overproduction of white cells
• May have splenomegaly and or sternal tenderness from marrow overexpansion
• Rarely; leukostasis:  blurred vision, resp distress, priapism (usually w/ very high white cell counts
• Acceleration:  Fever in absence of infection, bone pain and splenomegaly.


What are the lab findings in CML?

• Early CML:  normal BM function, normal WBCs, normal neutrophils
• Untreated:  accelerated then acute blast phase - indistinguishable from acute leukaemia
• Median WBC count >150
• Blood film: Left-shifted (immature cells present) with cells present in proportion to their degree of maturation (i.e. blasts <5%), normal RBC morphology, normal or elevated platelets (abnormal megakaryocytes)
• Basophilia and eosinophilia of granulocytes is pathognomic
• Peripheral blood PCR (required for diagnosis):  Increased levels of BCR-ABL gene.
• BM:  Hypercellular w/ left shift myelopoesis


What is the diagnostic criteria for CML?

• Peripheral blood:  bcr/able gene present on PCR - hallmark of the disease – this is diagnostic criterai
• BMB is NOT necessary for dx but useful for prognosis and detecting additional chromosomal abnormalities


How is the blast phase of CML defined?

What is it associated with?

One or more of:
o Blasts composing >20% of nucleated bone marrow cells.
o Extramedullary blast proliferation 
o Large foci or clusters of blasts in the bone marrow biopsy 

Evolution to a blast cell crisis in CML associated w/:
o Non-random secondary chromosomal changes 
o Mutations or deletions of tumour suppressor genes


How do you differentiate CML from infection and other blood disorders?

• Infection - no splenomegaly, WBC <50, no bcr/abl gene
• Other blood disorders - normal RBCs, no nucleated RBCs, definitive finding of bcr/abl gene


Define the types and goals of therapy in CML

• Untreated progresses from chronic phase (3-5 years) to blast crisis
• Chronic-phase CML:  TKI aiming for complete remission w/ normalisation of blood count and splenomegaly within 3 months initiation. Aim for MAJOR molecular response in 1 year.
• Blast/accelerated phase:  ASCT + myelosuppressive therapy
• Hyperleukocytosis (priapism, respiratory distress, visual blurring, altered mental state):  emergency leukapheresis + myelosuppressive therapy.


What do the terms major molecular response, and complete molecular response refer to in the context of CML?

Major molecular response
- 3-log reduction of bcr/abl transcript on PCR within a year (corresponds to bcr/abl RATIO (compared to alb) of <0.01).
- Goal is to achieve MMR within a year
- excellent prognosis - up to 100% progression-free at 8 years.

Complete MR = >4.5 log reduction ie undetectable


What is the mechanism of action of tyrosine kinase inhibitors?

What are the side effects?

Tyrosine Kinase Inhibitors
• specific competitive binders in the ATP-pocket of BCR-ABL tyrosine kinase
• Imatinib:  first line, MMR @ 30% at 1 year in chronic phase.  SEs:  NV, chronic diarrhea, intolerable fatigue
• Dasatinib: pleural effusions esp. in the elderly, pneumonitis, pulmonary hypertension, bleeding, possibly increased infection risk
• Nilotinib: cardiac SEs:  esp IHD, CVA, PAD (inc limb ischaemia, claudication), also increases cholesterol and LDL
• 3rd gen agents may be more effective - can salvage 90% of patients who do not respond to imatinib.  Are now approved as first line agents.


What is the mechanism of tyrosine kinase inhibitor resistance?

How is it managed in CML?

• Due to:
- drug influx/efflux due to low OCT-1 expression
- amplification and over expression of BCR-ABL
- Mutations of BCR-ABL kinase domain (found in 50-90% w/ secondary resistance)

• can increase dose with variable response (depends on mutation
• or use alternative TKIs


How is disease progression in CML monitored?

Peripheral blood PCR, if it increases on therapy check compliance, check for a new abl mutation, may be able to get away with increased dose of Imatinib, otherwise switch to a new inhibitor.


What is the course and prognosis of CML?

Course & Prognosis
• 80% w/o progression at 9 years w/ TKIs
• essentially 100% survival at 9 years if good molecular response
• Complete (undetectable bcr/abl) response lasting > 2years may be able to cease therapy all together.

• Untreated progresses from chronic phase (3-5 years) to blast crisis


What is the pathogenesis of CLL?

• B Cell lymphocytosis w/ coexpression of CD19, CD5 (pathognomic:  aberrant T-cell marker) on lymphocytes.
• indolent, long lived small (unactivated) lymphocytes
• immunoincompetent, poorly antigenic responsive

• immunosuppression, 
• BM failure
• organ infiltration with lymphocytes
• inadequate antibody production
• damage due to direct tissue introduction


What is the epidemiology of CLL?

- 25% of all leukemias (2.7/100,000) , increasing
- Unknown aetiology
- Increased other malig (SCC)
- Only leukemia NOT linked to radiation
- M:F=2:1, less in Asian’s
- Disease of old age - median at presentation is age 70


What are the clinical findings in CLL?

Clinical Findings
• incidental:  lymphocytosis - usually indolent
• symptomatic:  fatigue or lymphadenopathy
• 80% will have lymphadenopathy, 50% splenomegaly
• subtype prolymphocytic leukaemia (larger and more immature cells) is more aggressive but rare
• maybe complicated by AIHA or autoimmune thrombocytopaenia
• 5% of systemic cases may have an isolated lymph node transform into an aggressive large cell lymphoma (Richter syndrome)


What is the Rai staging system used for?  Can you describe it?

Used to stage CLL

Staging - Rai
Stage 0 - lymphocytosis (low-risk)
Stage II - organomegaly (low risk)
Stage III - anaemia (high risk)
Stage IV - thrombocytopaenia (high risk)


What is the diagnostic criteria for CLL?

Diagnostic criteria
Peripheral absolute B lymphocyte count > 5 x 109/L w/ mainly morphologically mature lymphocytes
Flow cytometry: clonality of circulating B-lymphocytes w/ low levels of  SmIg and either kappa or lambda (not both) and expression of B-cell antigens (CD19, 20, 23), and expression of T-Cell associated antigen CD5.