Myeloproliferative disorders

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Myeloproliferative disorders
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Myeloproliferative disorders
Acute
Acute Myeloid Leukaemia (AML)
Chronic
Chronic Myeloid Leukaemia (CML)
Polycythaemia rubra vera (PRV)
Esential thrombocytosis (ET)
Idiopathic Myelofibrosis
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Acute Myeloid Leukaemia
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AML ALL

10-15 childhood leukemia ? with increasing
age median age 60 years
85 of childhood leukemia Commonest 2-10
years 20 ? after 40 years
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Leukemia Aetiology

• Chemicals/toxins
• Radiation
• Viruses

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Chance
Etiology
Genetic Modifiers MHC/Immune Sx. Carcinogen
metabolism DNA Repair Inherited mutated alleles
Stem cells
Environmental exposures Genotoxic Ionizing
Radiation Solvents Proliferative Stress
Infection Toxins Diet Transforming viruses
Mutations
Chance
Chance
dominant clone
Acquired Modifiers Diet Infection
Immunosuppression
Leukemia
Chance
Greaves, Lancet
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Presentation

• Acute leukemia always serious and life
  threatening
• Anemia Pallor, lethargy, dyspnoea
• Leucopenia Infection - mouth, skin, perianal
  region
• Thrombocytopenia -bruising, menorrhagia, gum
  bleeding
• Hepatosplenomegaly is common
• Gum hypertrophy,skin infiltration

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Investigations
FBC Usually shows ? HB and platelets (maybe
lt20) WCC can vary lt1.0 - gt 200 x 109/l,
Abnormal differential Coag. Screening Maybe
abnormal esp. APML Chemistry LDH reflects
tumor burden, renal failure,hyperuricemia
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Leukaemia diagnosis
Morphology Immunophenotype Cytogenetics Molecular
genetics
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Abnormalities seen in at least 50 of
cases Karyotype is of major prognostic
significance Used in planning treatment
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Cytogenetic risk groups in AML
Favourable t (821), t (1517)
inv(16) Intermediate Normal 8, 21,
22 del (7q), del (9q) Abnormal
11q23 Others Adverse -5, -7, del
(5q) Abnormal 3q Complex
Grimwade et al, Blood 92 (1998)
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Prognostic significance of cytogenetics in AML
Still alive
Still alive
Years from entry
Years from entry
Grimwade et al, Blood 92 (1998)
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Treatment
Supportive Care Red cell transfusion for
anaemia Platelets transfusion for
thrombocytopenia Vigorous treatment of
infection Social and psychological support
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How does chemotherapy work?
Inhibit proliferation Induce apoptosis
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Treatment
Remission induction Consolidation Autologous
bone marrow transplantation Allogeneic bone
marrow transplantation
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Outcomes of remission induction treatment by age
100
Induction death
Complete remission
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Remission
Resistant disease
0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70
Age groups
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Treatment for Younger Adults in First Remission
of AML
LFS at 5 years Intensive chemotherapy
30-40 Autologous BMT
40-50 Allogeneic BMT (sibling donor)
50-60
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Acute leukaemia Standard of care
Lessons from paediatric leukaemia Rigorous
diagnostic assessment Population-based
registration Clinical trial as first option
Agreed protocols for non-trial patients
Built-in prospective quality assurance
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Myeloproliferative disorders
Malignant transformation of the multipotential
stem cell
Essential thrombocytosis (ET) - excess production
of platelets Polycythaemia rubra vera (PRV) -
excess production of RBC Chronic myeloid
leukaemia (CML) - excess production of
WBC Myelofibrosis - excess fibrosis
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Bone marrow stem cell
Clonal abnormality
Essential thrombocytosis (ET)
Polycythaemia rubra vera (PRV)
Myelofibrosis
Chronic myeloid leukaemia
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10
70
AML
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Chronic myeloid leukaemia
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Chronic Myeloid Leukemia (CML)

• CML
• Proliferative disorder of hematopoietic stem
  cells
• Well-characterized clinical course
• Philadelphia chromosome
• Unique chromosome abnormality
• Bcr-Abl tyrosine kinase
• Single molecular abnormality causes
  transformation
• to a malignant clone

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The Philadelphia Chromosome t(922)
Translocation
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9
Philadelphia chromosome
22
Ph
bcr
bcr-abl
Fusion proteinwith tyrosinekinase activity
abl
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p210Bcr-Abl Fusion Protein Tyrosine Kinase

Faderl S. N Engl J Med. 1999341169.
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Epidemiology of CML

• Median age range at presentation 45 to 55 years
• Incidence increases with age
• 1230 of patients are gt60 years old
• At presentation
• 50 diagnosed by routine laboratory tests
• 85 diagnosed during chronic phase

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Presentation
Insidious onset Anorexia and weight
loss Symptoms of anaemia Splenomegaly maybe
massive Pt . maybe asymptomatic
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Clinical Course Phases of CML
Advanced phases
Chronic phase Median 46 yearsstabilization
Accelerated phase Median durationup to 1 year
Blastic phase (blast crisis) Median survival36
monthsTerminal phase
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CML Treatment
Chemotherapy to reduce WCC - Hydroxyurea Interfer
on based treatment Allogeneic bone marrow
transplant Molecular therapy -Imatinib
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The Ideal Target for Molecular Therapy

• Present in the majority of patients with a
  specific disease
• Determined to be the causative abnormality
• Has unique activity that is
• Required for disease induction
• Dispensable for normal cellular function

Courtesy of BJ Druker, MD
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Mechanism of Action of STI571
Goldman JM. Lancet. 20003551031-1032.
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Bone marrow stem cell
Clonal abnormality
Essential thrombocytosis (ET)
Polycythaemia rubra vera (PRV)
Myelofibrosis
Chronic myeloid leukaemia
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10
70
AML
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Polycythaemia - Erythrocytosis
Absolute
Relative
Dehydration plasma loss -burns Cigarette
smoking stress polycythaemia
10 Polycythaemia PRV

• 20 Polycythaemia
• Tissue hypoxia causing
• EPO production
• Lung disease
• Cardiovascular disease
• Renal disease
• Living high altitude

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PRV Clinical Features
Disease of older ages. MF Symptoms develop
gradually Headaches , dizziness Generalised
pruritus Bleeding episodes Plethoric
appearance Splenomegaly in 75 of
patients Gout Thrombotic episodes
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Causes of High platelet count
Endogenous
Reactive
Haemorrhage Trauma Chronic iron
deficiency Malignancy Chronic infections Post-oper
ative Connective tissue disease
Essential thrombocytosis Other
myeloproliferative disorders
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Myelofibrosis
Progressive generalised fibrosis of the bone
marrow Development of haematopoiesis in spleen
and bone marrow Fatigue Pain 20 massive
splenomegaly Hypermetabolic symptoms Anaemia Mass
ive hepatosplenomegaly Classical laboratory
findings Leucoerythroblastic blood picture
Teardrop poikilocytes
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