4. Introduction
Normal maturation (effective)
Increased number of
Red cells
Granulocytes
Platelets
(Note: myeloproliferation in myelodysplastic syndrome is ineffective)
Frequent overlap of the clinical, laboratory &
morphologic findings
Leucocytosis, thrombocytosis, increased
megakaeryocytes, fibrosis & organomegaly blurs
the boundaries
Hepatosplenomegaly
Sequestration of excess blood
Extramedullary haematopoiesis
Leukaemic infiltration
5. Rationale for classification
Classification is based on the
lineage of the predominant
proliferation
Level of marrow fibrosis
Clinical and laboratory data (FBP,
BM, cytogenetic & molecular
genetic)
6. Differential diagnosis
Features distinguishing MPD from MDS, MDS/MPD & AML
Disease cellularity
BM
%
marrow
blasts
Maturation Morphology Haemato-
poiesis
Blood
counts
Large
organs
MPD Increase
d
Normal
or
< 10%
Present Normal Effectiv
e
One or
more
myeloid
increase
d
Common
MDS Usually
increased
Normal
or <
20%
Present Abnorma
l
In-
effective
Low one
or more
cytopeni
a
Un-
common
MDS/
MPD
Usually
increased
Normal
or <20%
Present Abnorma
l
Effective
or in-
effective
Variable Common
AML Usually
increased
Increase
d >20%
Minimal Dysplasia
can be
present
In-
effective
Variable Un-
common
9. Pathogenesis
Dysregulated proliferation
No specific genetic abnormality
CML (Ph chromosome t(9;22) BCR/ABL)
Growth-factor independent proliferation
PV, hypersensitiviy to IGF-1
Bone marrow fibrosis in all MPD
Fibrosis is secondary phenomena
Fibroblasts are not from malignant clone
TGF-β & Platelet like growth factor
10. Prognosis
Depends on the proper diagnosis
and early treatment
Role of
IFN
BMT
Tyrosine kinase inhibitors
11. Myeloproliferative disorders
Clonal haematopoeitic disorders
Proliferation of one of myeloid lineages
Granulocytic
Erythroid
Megakaryocytic
Relatively normal maturation
12. Myeloproliferative disorders
WHO Classification of CMPD
Ch Myeloid leukemia
Ch Neutrophillic leukemia
Ch Eosinophillic leukemia / Hyper Eo Synd
Polycythemia Vera
Essential Thrombocythemia
Myelofibrosis
CMPD unclassifiable
14. Myeloproliferative disorders
Ch Myeloid leukemia (BCR-ABL positive)
Polycythemia Vera
Essential Thrombocythemia
Myelofibrosis
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
15. Bone marrow stem cell
Clonal abnormality
Granulocyte
precursors
Red cell
precursors
Megakaryocytes Reactive
fibrosis
Essential
thrombocytosis
(ET)
Polycythaemia
rubra vera
(PRV)
Myelofibrosis
AML
Chronic myeloid
leukemia
70%
10% 10%
30%
16. 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
17. 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
Epidemiology of CML
21. The Philadelphia Chromosome: t(9;22) Translocation
bcr-abl
Fusion protein
with tyrosine
kinase activity
22
bcr
abl
Ph
9 9+
Philadelphia
chromosome
22. Clinical Course: Phases of CML
Chronic phase
Median 4–6 years
stabilization
Accelerated phase
Median duration
up to 1 year
Blastic phase (blast crisis)
Median survival
3–6 months
Terminal phase
Advanced phases
23. Treatment of Chronic Myeloid leukemia
Arsenic Lissauer, 1865
Radiotherapy Pusey, 1902
Busulfan Galton, 1953
Hydroxyurea Fishbein et al, 1964
Autografting Buckner et al, 1974
Allogeneic BMT (SD) Doney et al, 1978
Interferon Talpaz et al, 1983
Allogeneic BMT (UD) Beatty et al, 1989
Donor Leukocytes Kolb et al, 1990
Imatinib Druker et al, 1998
Imatinib/Combination therapy O’Brien et al, 200……
24. CML Treatment
•Chemotherapy to reduce WCC - Hydroxyurea
•Interferon based treatment
•Allogeneic bone marrow transplant
•Molecular therapy - Imatinib
26. 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
27. 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
28. Mechanism of Action of Imatinib
Goldman JM. Lancet. 2000;355:1031-1032.
Bcr-Abl
ATP
Substrate
Imatinib
Y = Tyrosine
P = Phosphate
Bcr-Abl
Substrate
P
P
P
P
29. 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
32. 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
33. CML
Diagnosis
Young with a
well-matched donor
Start Imatinib at
400mg/day
Cosider for Allograft
Allo SCT
Poor response or
Initial response
Followed by
Loss of response
Add or substitute
Other agents
Allo-SCT
Auto
Good response
maintained
Continue Imatinib
indefinitely
35. POLYCYTHEMIA VERA
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
36. POLYCYTHEMIA VERA
JAK2 Mutation
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
37. Polycythaemia vera
(Polycythaemia rubra vera)
Definition of polycythemia
Raised packed cell volume (PCV / HCT)
Male > 0.51 (50%)
Female > 0.48 (48%)
Classification
Absolute
Primary proliferative polycythaemia (polycythaemia
vera)
Secondary polycythaemia
Idiopathic erythrocytosis
Apparent
Plasma volume or red cell mass changes
38. Polycythaemia vera
(Polycythaemia rubra vera)
Polycythaemia vera is a clonal stem cell disorder
characterised by increased red cell production
Abnormal clones behave autonomous
Same abnormal stem cell give rise to granulocytes and
platelets
Disease phase
Proliferative phase
“Spent” post-polycythaemic phase
Rarely transformed into acute leukemia
39. Polycythaemia vera
(Polycythaemia rubra vera)
Clinical features
Age
55-60 years
May occur in young adults and rare in childhood
Majority patients present due to vascular
complications
Thrombosis (including portal and splenic vein)
DVT
Hypertension
Headache, poor vision and dizziness
Skin complications (pruritus, erythromelalgia)
Haemorrhage (GIT) due to platelet defect
41. Polycythaemia vera
(Polycythaemia rubra vera)
Laboratory features and
morphology
Hb, PCV (HCT), and Red
cell mass increased
Increased neutrophils
and platelets
Normal NAP
Plasma urate high
Circulation erythroid
precursors
Hypercellular bone
marrow
Low serum
erythropoietin
Bone marrow in PV
45. Diagnostic Criteria
A1 Raised red cell mass
A2 Normal O2 sats and EPO
A3 Palpable spleen
A4 No BCR-ABL fusion
B1 Thrombocytosis >400 x 109/L
B2 Neutrophilia >10 x 109/L
B3 Radiological splenomegaly
B4 Endogenous erythroid colonies
A1+A2+either another A or two B establishes PV
46.
47. Treatment
The mainstay of therapy in PV remains phlebotomy to keep the
hematocrit below 45 percent in men and 42 percent in women
Additional hydroxyurea in high-risk pts for thrombosis (age over
70, prior thrombosis, platelet count >1,500,000/microL, presence of
cardiovascular risk factors)
Aspirin (75-100 mg/d) if no CI
IFNa (3mu three times per week) in patients with refractory
pruritus, pregnancy
Anagrelide (0.5 mg qds/d) is used mainly to manage
thrombocytosis in patients refractory to other treatments.
Allopurinol
49. Causes of secondary polycythemia
EPO RECEPTOR–MEDIATED
Activating mutation of the erythropoietin
receptor
DRUG-ASSOCIATED
EPO Doping
Treatment with Androgen Preparations
50. Secondary polycythaemia
Polycythaemia due to known causes
Compensatory increased in EPO
High altitude
Hulmonary diseases
Heart dzs eg- cyanotic heart disease
Abnormal hemoglobin- High affinity Hb
Heavy cigarette smoker
Inappropriate EPO production
Renal disease-carcinoma, hydronephrosis
Tumors-fibromyoma and liver carcinoma
51. Secondary polycythaemia
Arterial blood gas
Hb electrophoresis
Oxygen dissociation curve
EPO level
Ultrasound abdomen
Chest X ray
Total red cell volume(51Cr)
Total plasma volume(125 I-
albumin)
52. Relative polycythaemia
Apparent polycythaemia or
pseudopolycythaemia due to
plasma volume contraction
Causes
Stress
Cigarette smoker or alcohol intake
Dehydration
Plasma loss- burn injury
53. Differentiation of PV, Secondary
PV and Relative Erythrocytosis
Features PV 2ndary
PV
Rel.
Erythro
organo-
megaly
present absent absent
O2 Sat Normal Dec. Normal
RBC mass Inc Inc Normal
EPO Dec Inc Normal
WBC Inc Normal Normal
54. Essential Thrombocytosis
Clonal stem cell disorder
characterized by marked
thrombocytosis and abnormal
platelet function
Plt count 600-2500 X 109/L
Abnormal plt aggregation studies
55. Essential Thrombocythaemia (ET)
Clonal MPD
Persistent elevation of Plt>600 x109/l
Poorly understood
Lack of positive diagnostic criteria
2.5 cases/100000
M:F 2:1
Median age at diagnosis: 60, however 20% cases <40yrs
56. Clinical Features
Vasomotor
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
57. Investigations
ET is a diagnosis of exclusion
Rule out other causes of elevated platelet count
58. Diagnostic criteria for ET
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
63. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
Clonal myeloproliferative disease of
megakaryocytic lineage
Sustained thrombocytosis
Increase megakaeryocytes
Thrombotic or/and haemorrhage episodes
Positive criteria
Platelet count >600 x 109/L
Bone marrow biopsy; large and increased megas.
64. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
Criteria of exclusion
No evidence of Polycythaemia vera
No evidence of CML
No evidence of myelofibrosis (CIMF)
No evidence of myelodysplastic syndrome
No evidence of reactive thrombocytosis
Bleeding
Trauma
Post operation
Chronic iron def
Malignancy
Chronic infection
Connective tissue disorders
Post splenectomy
69. Myelofibrosis
Myeloproliferative disorder (monoclonal stem cell
disorder) in which increased marrow fibrosis is
dominant feature
Rare
50-70 yrs
Clinical: fatigue, weakness, malaise, fever/night
sweats, abdominal pain, anorexia/wt loss,
nasuea/vomiting
May be primary or secondary (breast cancer,
prostate cancer, Hodgkin's disease, non-Hodgkin's
lymphoma, autoimmune diseases)
Hematopoietic stem cells grow out of control,
producing both immature blood cells and excess
fibrous tissue—replacing normal marrow
70. Myelofibrosis
Extramedullary hematopoeisis—hepatic and
splenic enlargement, thoracic paravertebral
masses
Bones
Uniform or heterogeneous increased density
Spine (“sandwich sign” or diffuse density),
pelvis, skull, ribs, proximal femur/humerus
Cortical thickening in long bones
Decreased T1 and T2 marrow signal
Bone marrow bx needed to confirm dz
Progressive bone marrow failure = severe anemia
/ thrombocytopenia/leukopenia
risk of bleeding/infection
Slowly progressive dz leading to death
No available tx to effectively reverse progression;
possible cure with bone marrow or stem cell
transplantation (significant risks)
72. Myelofibrosis
Chronic idiopathic myelofibrosis
Insidious onset in older
people
Splenomegaly- massive
Hypermetabolic symptoms
Loss of weight, fever and
night sweats Myelofibrosis
Chronic idiopathic myelofibrosisc
Bleeding problems
Bone pain
Gout
Can transform to acute
leukaemia in 10-20% of
cases
73. Myelofibrosis
Chronic idiopathic myelofibrosis
Anaemia
High WBC at presentation
Later leucopenia and
thrombocytopenia
Leucoerythroblastic blood
film
Tear drops red cells
Bone marrow aspiration-
Failed due to fibrosis
Trephine biopsy- fibrotic
hypercellular marrow
Increase in NAP score