Myeloproliferative disorders

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Myeloproliferative disorders

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Introduction

• Hemopoietic stem cell disorder
• Clonal
• Characterized by proliferation
• Granulocytic
• Erythroid
• Megakaryocytic
• Interrelationship between
• Polycythaemia
• Essential thrombocythaemia
• myelofibrosis

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Introduction / haemopoiesis
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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

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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)

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Differential diagnosisFeatures distinguishing
MPD from MDS, MDS/MPD AML
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Clonal evolutionClonal evolution stepwise
progression to fibrosis, marrow failure or acute
blast phase
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Incidence and epidemiology

• Disease of adult
• Peak incidence in 7th decade
• 6-9/100,000

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Pathogenesis

• Dysregulated proliferation
• No specific genetic abnormality
• CML (Ph chromosome t(922) 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-ß Platelet like growth factor

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Prognosis

• Depends on the proper diagnosis and early
  treatment
• Role of
• IFN
• BMT
• Tyrosine kinase inhibitors

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Myeloproliferative disorders

• Clonal haematopoeitic disorders
• Proliferation of one of myeloid lineages
• Granulocytic
• Erythroid
• Megakaryocytic
• Relatively normal maturation

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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

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Myeloproliferative disorders
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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

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Bone marrow stem cell
Clonal abnormality
Essential thrombocytosis (ET)
Polycythaemia rubra vera (PRV)
Myelofibrosis
Chronic myeloid leukemia
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10
70
AML
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Epidemiology of CML

• Median age range at presentation 45 to 55 years
• Incidence increases with age
• 12 - 30 of patients are gt60 years old
• At presentation
• 50 diagnosed by routine laboratory tests
• 85 diagnosed during chronic phase

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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
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Presentation
Insidious onset Anorexia and weight
loss Symptoms of anaemia Splenomegaly may be
massive Pt . maybe asymptomatic
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The Philadelphia Chromosome
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The Philadelphia Chromosome t(922)
Translocation
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Philadelphia chromosome
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Ph
bcr
bcr-abl
Fusion proteinwith tyrosinekinase activity
abl
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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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Treatment of Chronic Myeloid leukemia
Arsenic Lissauer, 1865 Radiotherapy Pusey,
1902 Busulfan Galton, 1953 Hydroxyurea Fishb
ein 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 OBrien et al,
200
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CML Treatment

• Chemotherapy to reduce WCC - Hydroxyurea
• Interferon based treatment
• Allogeneic bone marrow transplant
• Molecular therapy - Imatinib

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

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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

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Mechanism of Action of Imatinib
Goldman JM. Lancet. 20003551031-1032.
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Imatinib compared with interferon and low
dose Cytarabine for newly diagnosed
chronic-phase Chronic Myeloid leukemia S.G.
OBrien et al New England Journal of
Medicine Vol. 348 March 2003
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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
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Evolution of treatment goals
HR MCR CCR PCR -
HU IFN Imatinib BMT
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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

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CML
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Polycythemia

• True / Absolute
• Primary Polycythemia
• Secondary Polycythemia
• Epo dependent
• Hypoxia dependent
• Hypoxia independent
• Epo independent
• Apparent / Relative
• Reduction in plasma volume

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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 0.81.2

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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

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Polycythaemia vera(Polycythaemia rubra vera)

• Definition of polycythemia
• Raised packed cell volume (PCV / HCT)
• Male gt 0.51 (50)
• Female gt 0.48 (48)
• Classification
• Absolute
• Primary proliferative polycythaemia
  (polycythaemia vera)
• Secondary polycythaemia
• Idiopathic erythrocytosis
• Apparent
• Plasma volume or red cell mass changes

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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

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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

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Polycythaemia vera(Polycythaemia rubra vera)
Erythromelalgia

• Hepatosplenomegaly
• Erythromelalgia
• Increased skin temp
• Burning sensation
• Redness

Liver 40
Spleen 70
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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

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Polycythaemia vera(Polycythaemia rubra vera)

• Treatment
• To decrease PVC (HCT)
• Venesection
• Chemotherapy
• Treatment of complications

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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)

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Clinical features

• Hypertention
• Gout
• Leukaemic transformation
• Myelofibrosis

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Diagnostic Criteria

• A1 Raised red cell mass
• A2 Normal O2 sats and EPO
• A3 Palpable spleen
• A4 No BCR-ABL fusion
• B1 Thrombocytosis gt400 x 109/L
• B2 Neutrophilia gt10 x 109/L
• B3 Radiological splenomegaly
• B4 Endogenous erythroid colonies
• A1A2either another A or two B establishes PV

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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 gt1,500,000/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

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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

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Causes of secondary polycythemia

• EPO RECEPTORMEDIATED
• Activating mutation of the erythropoietin
  receptor
• DRUG-ASSOCIATED
• EPO Doping
• Treatment with Androgen Preparations

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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

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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)

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Relative polycythaemia

• Apparent polycythaemia or pseudopolycythaemia due
  to plasma volume contraction
• Causes
• Stress
• Cigarette smoker or alcohol intake
• Dehydration
• Plasma loss- burn injury

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Differentiation of PV, Secondary PV and Relative
Erythrocytosis
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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

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Essential Thrombocythaemia (ET)

• Clonal MPD
• Persistent elevation of Pltgt600 x109/l
• Poorly understood
• Lack of positive diagnostic criteria
• 2.5 cases/100000
• MF 21
• Median age at diagnosis 60, however 20 cases
  lt40yrs

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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

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Investigations

• ET is a diagnosis of exclusion
• Rule out other causes of elevated platelet count

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Diagnostic criteria for ET

• Platelet count gt600 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 lt0.48
• Presence of stainable iron in a bone marrow
  aspiration
• No evidence of myelofibrosis
• No evidence of MDS

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Therapy of ET based on the risk of thrombosis
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Essential thrombocythaemiaPrimary thrombocytosis
/ idiopathic thrombocytosis

• Clonal myeloproliferative disease of
  megakaryocytic lineage
• Sustained thrombocytosis
• Increase megakaeryocytes
• Thrombotic or/and haemorrhage episodes
• Positive criteria
• Platelet count gt600 x 109/L
• Bone marrow biopsy large and increased megas.

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Essential thrombocythaemiaPrimary 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

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Essential thrombocythaemiaPrimary thrombocytosis
/ idiopathic thrombocytosis

• Clinical features
• Haemorrhage
• Microvascular occlusion
• TIA, gangrene
• Splenic or hepatic vein thrombosis
• Hepatosplenomegaly

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Essential thrombocythaemiaPrimary thrombocytosis
/ idiopathic thrombocytosis

• Treatment
• Anticoagulant
• Chemotherapy
• Role of aspirin
• Disease course and prognosis
• 25 develops myelofibrosis
• Acute leukemia transformation
• Death due to cardiovascular complication

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Agnogenic Myeloid Metaplasia

• Stem cell mutation causes hematopoietic
  abnormalities
• Extramedullary hematopoiesis
• BM fibrosisuncontrolled 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

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• Myelofibrosis

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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 tissuereplacing normal marrow

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Myelofibrosis

• Extramedullary hematopoeisishepatic 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)

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MyelofibrosisChronic 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)

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MyelofibrosisChronic idiopathic myelofibrosis

• Insidious onset in older people
• Splenomegaly- massive
• Hypermetabolic symptoms
• Loss of weight, fever and night sweats
  MyelofibrosisChronic idiopathic myelofibrosisc
• Bleeding problems
• Bone pain
• Gout
• Can transform to acute leukaemia in 10-20 of
  cases

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MyelofibrosisChronic 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