Myeloproliferative disorders

Introduction
 Hemopoietic stem cell disorder
 Clonal
 Characterized by proliferation
 Granulocytic
 Erythroid
 Megakaryocytic
 Interrelationship between
 Polycythaemia
 Essential thrombocythaemia
 myelofibrosis
Introduction / haemopoiesis
 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
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)
 Differential diagnosis
Features distinguishing MPD from MDS, MDS/MPD & AML
Disease cellularity
BM
% Maturation Morphology Haemato- Blood Large
marrow poiesis
counts organs
blasts

MPD Increase
d
Normal
or
Present Normal Effectiv
e
One or
more
Common

< 10% myeloid

increased

MDS Usually
increased
Normal
or <
Present Abnorma
l
In-
effective
Low one
or more
Un-
common
20% cytopeni
a

MDS/ Usually Normal Present Abnorma Effective Variable Common

increased or <20% l or in-
MPD effective

AML Usually
increased
Increase
d >20%
Minimal Dysplasia
can be
In-
effective
Variable Un-
common
present
 Clonal evolution
Clonal evolution & stepwise progression to fibrosis, marrow failure or
acute blast phase
Incidence and epidemiology
 Disease of adult

 Peak incidence in 7th decade

 6-9/100,000
 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
Prognosis
 Depends on the proper diagnosis
and early treatment
 Role of
 IFN
 BMT
 Tyrosine kinase inhibitors
 Myeloproliferative disorders
 Clonal haematopoeitic disorders
 Proliferation of one of myeloid lineages
 Granulocytic
 Erythroid
 Megakaryocytic
 Relatively normal maturation
 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
Myeloproliferative disorders

MPD
•PRV CML AML
•ET
•MF

CMML

MDS
•RA
•RARS
•RAEB I
•RAEB II
 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
 Bone marrow stem cell
Clonal
abnormality

Granulocyte Red cell Megakaryocytes Reactive

precursors precursors fibrosis

Chronic myeloid Polycythaemia Essential Myelofibrosis

leukemia rubra vera thrombocytosis
(PRV) (ET)

10% 10%
70% AML
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 –may be massive

Pt . maybe asymptomatic
 The Philadelphia Chromosome

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X Y
The Philadelphia Chromosome: t(9;22) Translocation

9 9+

Philadelphia
22 chromosome
Ph

bcr
bcr-abl

abl Fusion protein

with tyrosine
kinase activity
 Clinical Course: Phases of CML

Advanced phases
Chronic phase
Accelerated phase Blastic phase (blast crisis)

Median 4–6 years Median duration Median survival

stabilization up to 1 year 3–6 months
Terminal phase
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……
 CML Treatment

•Chemotherapy to reduce WCC - Hydroxyurea

•Interferon based treatment

•Allogeneic bone marrow transplant

•Molecular therapy - Imatinib

 CML- CP survival post BMT
(IBMTR 1994-1999)
Probability %

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
Imatinib
P
ATP P
P

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 1.5% 7%
disease
 Evolution of treatment goals

HR MCR CCR PCR -

HU

IFN

Imatinib

BMT
 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 Start Imatinib at

well-matched donor 400mg/day

Poor response or
Initial response Good response
Cosider for Allograft
Followed by maintained
Loss of response

Add or substitute
Other agents Continue Imatinib
Allo SCT
Allo-SCT indefinitely
Auto
 Polycythemia

 True / Absolute
 Primary Polycythemia
 Secondary Polycythemia
 Epo dependent
 Hypoxia dependent
 Hypoxia independent
 Epo independent
 Apparent / Relative
 Reduction in plasma volume
 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
 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
 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
 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
 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
 Polycythaemia vera
(Polycythaemia rubra vera)

Erythromelalgia
 Hepatosplenomegaly

 Erythromelalgia

 Increased skin temp Liver

40%
 Burning sensation
 Redness Spleen
70%
 Polycythaemia vera
(Polycythaemia rubra vera)
Bone marrow in PV

 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
Polycythaemia vera
(Polycythaemia rubra vera)

 Treatment

 To decrease PVC (HCT)

 Venesection
 Chemotherapy

 Treatment of complications
 Clinical features
 Plethora
 Persistent leukocytosis
 Persistent thrombocytosis
 Microcytosis secondary to iron deficiency
 Splenomegaly
 Generalized pruritus (after bathing)
 Unusual thrombosis (e.g., Budd-Chiari syndrome)
 Erythromelalgia (acral dysesthesia and erythema)
 Clinical features

 Hypertention
 Gout
 Leukaemic transformation
 Myelofibrosis
 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

 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
 Causes of secondary polycythemia

 ERYTHROPOIETIN (EPO)-MEDIATED
 Hypoxia-Driven
 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)
 Malignant tumors
 Hepatocellular carcinoma
 Renal cell cancer
 Cerebellar hemangioblastoma
 Nonmalignant conditions
 Uterine leiomyomas
 Renal cysts
 Postrenal transplantation
 Adrenal tumors
 Causes of secondary polycythemia

 EPO RECEPTOR–MEDIATED
 Activating mutation of the erythropoietin
receptor
 DRUG-ASSOCIATED
 EPO Doping
 Treatment with Androgen Preparations
 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
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)
Relative polycythaemia
 Apparent polycythaemia or
pseudopolycythaemia due to
plasma volume contraction

 Causes
 Stress
 Cigarette smoker or alcohol intake
 Dehydration
 Plasma loss- burn injury
 Differentiation of PV, Secondary
PV and Relative Erythrocytosis
Features PV 2ndary Rel.
PV Erythro
organo- present absent absent
megaly
O2 Sat Normal Dec. Normal
RBC mass Inc Inc Normal
EPO Dec Inc Normal
WBC Inc Normal Normal
 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
 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
 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
 Investigations
ET is a diagnosis of exclusion
 Rule out other causes of elevated platelet count
 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
Therapy of ET based on the risk of thrombosis
 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.
 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
 Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis

 Clinical features

 Haemorrhage
 Microvascular occlusion
 TIA, gangrene
 Splenic or hepatic vein
thrombosis
 Hepatosplenomegaly
Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis

 Treatment
 Anticoagulant
 Chemotherapy
 Role of aspirin

 Disease course and prognosis

 25 % develops myelofibrosis
 Acute leukemia transformation
 Death due to cardiovascular complication
 Agnogenic Myeloid Metaplasia
 Stem cell mutation causes
hematopoietic abnormalities
 Extramedullary hematopoiesis
 BM fibrosis:uncontrolled production of
fibroblasts from degenerating platelets result
in dense thread-like scar tissue: dry BM tap
 Differences from CML
 LAP inc., Ph neg, nRBC, splenomegaly,
tear drop cell
Myelofibrosis
 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
 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)
 Myelofibrosis
Chronic idiopathic myelofibrosis

 Progressive fibrosis of the marrow & increase

connective tissue element

 Agnogenic myeloid metaplasia

 Extramedullary erythropoiesis
 Spleen
 Liver

 Abnormal megakaryocytes
 Platelet derived growth factor (PDGF)
 Platelet factor 4 (PF-4)
 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
 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