Clonal haematopoeitic disorders Proliferation of one of myeloid lineages Relatively normal maturation

Myeloproliferative disorders
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Clonal haematopoeitic disorders
Proliferation of one of myeloid lineages
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Granulocytic
Erythroid
Megakaryocytic
Relatively normal maturation
Myeloproliferative disorders
WHO Classification of CMPD
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Ch Myeloid leukemia
Ch Neutrophillic leukemia
Ch Eosinophillic leukemia / Hyper Eo Synd
Polycythemia Vera
Essential Thrombocythemia
Myelofibrosis
CMPD unclassifiable
Myeloproliferative disorders
MPD
•PRV
•ET
•MF
CML
CMML
MDS
•RA
•RARS
•RAEB I
•RAEB II
AML
Myeloproliferative disorders
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Ch Myeloid leukemia (BCR-ABL positive)
Polycythemia Vera
Essential Thrombocythemia
Myelofibrosis
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Specific clincopathologic criteria for diagnosis and distinct
diseases, have common features
Increased number of one or more myeloid cells
Hepatosplenomegaly
Hypercatabolism
Clonal marrow hyperplasia without dysplasia
Predisposition to evolve
Bone marrow stem cell
Clonal abnormality
Granulocyte
precursors
Chronic myeloid
leukemia
Red cell
precursors
Polycythaemia
rubra vera
(PRV)
10%
70%
AML
Megakaryocytes
Reactive
fibrosis
Essential
thrombocytosis
(ET)
Myelofibrosis
10%
30%
Epidemiology of CML
 Median age range at presentation: 45 to 55 years
 Incidence increases with age
 12% - 30% of patients are >60 years old
 At presentation
 50% diagnosed by routine laboratory tests
 85% diagnosed during chronic phase
Epidemiology of CML
Ionizing radiation
Latent Period
Atomic bomb survivors
11 years ( 2-25)
Ankylosing spondylitis pts
3.6 years (1-6)
No evidence of other genetic factors
Chemical have not been associated with CML
Incidence 1-1.5/100,000 population
Male predominance
Presentation
Insidious onset
Anorexia and weight loss
Symptoms of anaemia
Splenomegaly –maybe massive
Pt . maybe asymptomatic
The Philadelphia Chromosome
1
2
3
6
7
8
13
14
15
19
20
9
21
4
5
10
11
12
16
17
22
X
18
Y
The Philadelphia Chromosome: t(9;22) Translocation
9
9+
Philadelphia
Ph
chromosome
22
bcr
bcr-abl
abl
Fusion protein
with tyrosine
kinase activity
Clinical Course: Phases of CML
Advanced phases
Chronic phase
Median 4–6 years
stabilization
Accelerated phase
Blastic phase (blast crisis)
Median duration
up to 1 year
Median survival
3–6 months
Terminal phase
Treatment of Chronic Myeloid leukemia
Arsenic
Radiotherapy
Busulfan
Hydroxyurea
Autografting
Allogeneic BMT (SD)
Interferon
Allogeneic BMT (UD)
Donor Leukocytes
Imatinib
Imatinib/Combination therapy
Lissauer, 1865
Pusey, 1902
Galton, 1953
Fishbein et al, 1964
Buckner et al, 1974
Doney et al, 1978
Talpaz et al, 1983
Beatty et al, 1989
Kolb et al, 1990
Druker et al, 1998
O’Brien et al, 200……
CML Treatment
•Chemotherapy to reduce WCC - Hydroxyurea
•Interferon based treatment
•Allogeneic bone marrow transplant
•Molecular therapy - Imatinib
CML- CP survival post BMT
Probability %
(IBMTR 1994-1999)
Years
Issues related to BMT
• 70% long term cure rate
• Donor Availability
• Age of patient
• Length/stage of disease
• Treatment related mortality
• Long term sequalae – infertility, cGVHD
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
Mechanism of Action of Imatinib
Bcr-Abl
Bcr-Abl
Substrate
Substrate
P
P
P
ATP
Imatinib
Y = Tyrosine
P = Phosphate
P
Goldman JM. Lancet. 2000;355:1031-1032.
Imatinib compared with interferon and low dose
Cytarabine for newly diagnosed chronic-phase
Chronic Myeloid leukemia
S.G. O’Brien et al
New England Journal of Medicine
Vol. 348 March 2003
Imatinib vs Interferon in newly diagnosed CP
Chronic Myeloid leukemia (18 months)
Imatinib 400mg
Interferon and Ara-C
CHR
96%
67%
MCR
83%
20%
CCR
68%
7%
Intolerance
0.7%
23%
Progressive
disease
1.5%
7%
Evolution of treatment goals
HR
HU
IFN
Imatinib
BMT
MCR
CCR
PCR -
Issues related to Imatinib
• Very few molecular responses (5-10%)
• Resistance in some patients
• Lack of response in some patients
• Expensive
• Long term toxicity/side effects unknown
CML
Diagnosis
Young with a
well-matched donor
Start Imatinib at
400mg/day
Cosider for Allograft
Poor response or
Initial response
Followed by
Loss of response
Good response
maintained
Allo SCT
Add or substitute
Other agents
Allo-SCT
Auto
Continue Imatinib
indefinitely
Polycythemia
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True / Absolute
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Primary Polycythemia
Secondary Polycythemia
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Epo dependent
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Hypoxia dependent
Hypoxia independent
Epo independent
Apparent / Relative
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Reduction in plasma volume
Causes of secondary polycythemia
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ERYTHROPOIETIN (EPO)-MEDIATED
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Hypoxia-Driven
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Chronic lung disease
Right-to-left cardiopulmonary vascular shunts
High-altitude habitat
Chronic carbon monoxide exposure (e.g., smoking)
Hypoventilation syndromes including sleep apnea
Renal artery stenosis or an equivalent renal pathology
Hypoxia-Independent (Pathologic EPO Production)
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Malignant tumors
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Nonmalignant conditions
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Uterine leiomyomas
Renal cysts
Postrenal transplantation
Adrenal tumors
EPO RECEPTOR–MEDIATED
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Hepatocellular carcinoma
Renal cell cancer
Cerebellar hemangioblastoma
Activating mutation of the erythropoietin receptor
DRUG-ASSOCIATED
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EPO Doping
Treatment with Androgen Preparations
POLYCYTHEMIA VERA
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Chronic, clonal myeloproliferative disorder
characterized by an absolute increase in number
of RBCs
2-3 / 100000
Median age at presentation: 55-60
M/F: 0.8:1.2
POLYCYTHEMIA VERA
JAK2 Mutation
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JAK/STAT: cellular proliferation and cell
survival
deficiency in mice at embryonic stage is lethal due
to the absence of definitive erythropoiesis
Abnormal signaling in PV through JAK2 was
first proposed in 2004
a single nucleotide JAK2 somatic mutation
(JAK2V617F mutation) in the majority of PV
patients
Clinical features
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Plethora
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Persistent leukocytosis
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Persistent thrombocytosis
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Microcytosis secondary to iron deficiency
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Splenomegaly
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Generalized pruritus (after bathing)
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Unusual thrombosis (e.g., Budd-Chiari syndrome)
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Erythromelalgia (acral dysesthesia and erythema)
Clinical features
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Hypertention
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Gout
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Leukaemic transformation
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Myelofibrosis
Diagnostic Criteria
A1
A2
A3
A4
B1
B2
B3
B4
Raised red cell mass
Normal O2 sats and EPO
Palpable spleen
No BCR-ABL fusion
Thrombocytosis >400 x 109/L
Neutrophilia >10 x 109/L
Radiological splenomegaly
Endogenous erythroid colonies
A1+A2+either another A or two B establishes PV
Treatment
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The mainstay of therapy in PV remains phlebotomy to keep the
hematocrit below 45 percent in men and 42 percent in women
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Additional hydroxyurea in high-risk pts for thrombosis (age over 70,
prior thrombosis, platelet count >1,500,000/microL, presence of
cardiovascular risk factors)
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Aspirin (75-100 mg/d) if no CI
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IFNa (3mu three times per week) in patients with refractory pruritus,
pregnancy
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Anagrelide (0.5 mg qds/d) is used mainly to manage thrombocytosis in
patients refractory to other treatments.
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Allopurinol
Essential Thrombocythaemia (ET)
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Clonal MPD
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Persistent elevation of Plt>600 x109/l
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Poorly understood
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Lack of positive diagnostic criteria
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2.5 cases/100000
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M:F 2:1
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Median age at diagnosis: 60, however 20% cases <40yrs
Clinical Features
 Vasomotor
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Headache
Lightheadedness
Syncope
Erythromelalgia (burning pain of the hands or
feet associated with erythema and warmth)
Transient visual disturbances (eg, amaurosis
fujax, scintillating scotomata, ocular migraine)
Thrombosis and Haemorrhage
Transformation
Investigations
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ET is a diagnosis of exclusion
Rule out other causes of elevated platelet count
Diagnostic criteria for ET
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Platelet count >600 x 109/L for at least 2 months
Megakaryocytic hyperplasia on bone marrow
aspiration and biopsy
No cause for reactive thrombocytosis
Absence of the Philadelphia chromosome
Normal red blood cell (RBC) mass or a HCT <0.48
Presence of stainable iron in a bone marrow
aspiration
No evidence of myelofibrosis
No evidence of MDS
Therapy of ET based on the risk of thrombosis