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Introduction / haemopoiesis
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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 diagnosisFeatures distinguishing MPD from MDS, MDS/MPD & AML
Disease cellularity BM
% marrow blasts
Maturation Morphology Haemato-poiesis
Blood counts
Large organs
MPD Increased
Normal or
< 10%
Present Normal Effective
One or more
myeloid increase
d
Common
MDS Usually increase
d
Normal or < 20%
Present Abnormal
In-effective
Low one or more cytopeni
a
Un-common
MDS/MPD
Usually increase
d
Normal or <20%
Present Abnormal
Effective or in-
effective
Variable Common
AML Usually increase
d
Increased >20%
Minimal Dysplasia can be present
In-effective
Variable Un-common
Clonal evolutionClonal 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•ET•MF
AML
MDS•RA•RARS•RAEB I•RAEB II
CMML
CML
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 cellClonal
abnormality
Granulocyte precursors
Red cell precursors
Megakaryocytes Reactive fibrosis
Essentialthrombocytosis
(ET)
Polycythaemia rubra vera
(PRV)
Myelofibrosis
AML
Chronic myeloid leukemia
70%10% 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
Ionizing radiation Latent Period
Atomic bomb survivors 11 years ( 2-25)
Ankylosing spondylitis pts 3.6 years (1-6)
No evidence of other genetic factorsChemical have not been associated with CML
Incidence 1-1.5/100,000 populationMale predominance
Epidemiology of CML
Presentation
Insidious onset
Anorexia and weight loss
Symptoms of anaemia
Splenomegaly –may be massive
Pt . maybe asymptomatic
The Philadelphia Chromosome
2 3 4 51
7 8 9 10 11 126
13 14 15 16 17 18
20 21 22 X Y19
The Philadelphia Chromosome: t(9;22) Translocation
bcr-abl
Fusion proteinwith tyrosine
kinase activity
22
bcr
abl
Ph
9 9+
Philadelphia chromosome
Clinical Course: Phases of CML
Chronic phase
Median 4–6 yearsstabilization
Accelerated phase
Median durationup to 1 year
Blastic phase (blast crisis)
Median survival3–6 months
Terminal phase
Advanced phases
Treatment of Chronic Myeloid leukemia
Arsenic Lissauer, 1865Radiotherapy Pusey, 1902Busulfan Galton, 1953Hydroxyurea Fishbein et al, 1964Autografting Buckner et al, 1974Allogeneic BMT (SD) Doney et al, 1978Interferon Talpaz et al, 1983Allogeneic BMT (UD) Beatty et al, 1989Donor Leukocytes Kolb et al, 1990Imatinib Druker et al, 1998Imatinib/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)
Years
Prob
abili
ty %
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
Goldman JM. Lancet. 2000;355:1031-1032.
Bcr-Abl
ATP
Substrate
Imatinib
Y = TyrosineP = Phosphate
Bcr-Abl
Substrate
PPP
P
Imatinib compared with interferon and low doseCytarabine for newly diagnosed chronic-phase
Chronic Myeloid leukemia
S.G. O’Brien et al
New England Journal of MedicineVol. 348 March 2003
Imatinib vs Interferon in newly diagnosed CP Chronic Myeloid leukemia (18 months)
CHR 96% 67%
MCR 83% 20%
CCR 68% 7%
Intolerance 0.7% 23%
Progressive 1.5% 7%disease
Imatinib 400mg Interferon and Ara-C
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 well-matched donor
Start Imatinib at400mg/day
Cosider for Allograft
Allo SCT
Poor response or Initial response
Followed byLoss of response
Add or substituteOther agents
Allo-SCTAuto
Good response maintained
Continue Imatinib indefinitely
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)
Hepatosplenomegaly
Erythromelalgia
Increased skin temp Burning sensation Redness
Liver40%
Spleen70%
Erythromelalgia
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
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 massA2 Normal O2 sats and EPOA3 Palpable spleenA4 No BCR-ABL fusionB1 Thrombocytosis >400 x 109/LB2 Neutrophilia >10 x 109/LB3 Radiological splenomegalyB4 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 2ndaryPV
Rel.Erythro
organo-megaly
present absent absent
O2 Sat Normal Dec. NormalRBC mass Inc Inc NormalEPO Dec Inc NormalWBC 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 thrombocythaemiaPrimary 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 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
Essential thrombocythaemiaPrimary thrombocytosis / idiopathic thrombocytosis
Clinical features
Haemorrhage Microvascular occlusion
TIA, gangrene Splenic or hepatic vein
thrombosis Hepatosplenomegaly
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
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)
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)
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
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