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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 –maybe 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, 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)
Years
Pro
babi
lity
%
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
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
• EPO RECEPTOR–MEDIATED– Activating mutation of the erythropoietin receptor
• DRUG-ASSOCIATED– EPO Doping– Treatment with Androgen Preparations
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
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 CriteriaA1 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
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
Thrombophilia
Barry White
National Haemophilia Director
Director, National Centre for Hereditary Coagulation Disorders,
St James’s Hospital
Virchow’s Triad
• Disorder of blood vessel wall
• Disordered blood flow (stasis)
• Abnormality of blood constituents
Venous thrombosis - a multifactorial disease
• Acquired risk factors pregnancy, surgery, hormonal therapy, malignancy
• Inherited risk factors single gene defects e.g. antithrombin multigenic defects e.g. antithrombin + FV
leiden
Thrombophilia
• Inherited or acquired predisposition to venous thrombosis
• Laboratory abnormalities
Increased procoagulants
• FVIII
• FIX
• FXI
• Prothrombin 20210A
• Fibrinogen
• Thrombin activator fibrinolysis inhibitor (TAFI)
Decreased anticoagulants
• Antithrombin deficiency
• Protein C deficiency
• Protein S deficiency
• Activated PC resistance (FV Leiden)
Unknown mechanism
• Antiphospholipid syndrome
• Hyperhomocysteinemia
Activated protein C resistance
• Activated protein C resistance• Factor V leiden (R506Q) in 90% of cases• Coagulation based assay (+/-FV def plasma)• PCR based assay• 2%-15% • 2.0 –2.3% of Irish population are heterozygous FVL
Livingstone et al 2000
• 20% of unselected VTE• Relative risk 3-8 fold for heterozygotes
APC Factor V (normal)
APC Factor V Leiden
Prothrombin G20210A
• Poort 1996
• Mutation in 3’ UTR associated with increased prothrombin levels
• 1.3% of Irish population heterozygous (Keenan et al 2000)
• 6-8% of unselected VTE
• 16% of familial VTE
Hyperhomocysteinemia
• Definite risk factor for arterial vascular disease
• >18.5 mol/l in 5% of normal population
• >18.5 mol/l in 10% of VTE
• Homozygous MTHFR (C677T) - 10% Irish population
• Acquired B12, folate, B6 deficiency
Antiphospholipid syndrome
• Venous, arterial or small vessel except superficial venous thrombosis
• 3 consecutive unexplained fetal loss
• Severe pre-eclampsia or placental insufficiency leading to prematurity (<34w)
• Unexplained single fetal loss >10 wks with normal morphology
APLS - laboratory diagnosis
• ACL IgG or IgM (> 3SD above normal)
• Lupus anticoagulant
• Need 2 positive tests (either test will do) at least 6 weeks apart
• Anti B2-Glycoprotein I
Hormonal therapy
• OCP risk of VTE increased x 2-3 fold (baseline risk 1:10,000)
• FVL risk of VTE increased x 3-7 fold• OCP + FVL risk of VTE increased x 33 fold
(30:10,000 = 0.3%)• Need to screen 2 million to save one life• Similar synergistic interaction with other
thrombophilic defects• HRT likely to be similar
Pregnancy and Virchow’s triad
• Venous stasis - changes in tone and obstruction
• Vascular damage at time of delivery APTT, PS (free and total), APCr FVIII:C, VWF, Fibrinogen PAI-1 and PAI-2
Pregnancy and venous thromboembolic disease
• Pregnancy increases risk x 5-10 fold• 0.86/1000 deliveries• 0.71/1000 (DVT) : 0.15/1000 (PE)• Left leg >80%• Ileofemoral more common than calf vein
(72% versus 9%)• Increased with age, caesarian section, bed
rest and prior history of DVT/PE
Clinical practice – DVT/PE
• Diagnosis DVT – doppler ultrasound primarily (venogram gold
standard)PE – ventilation perfusions scan primarily (pulmonary
angiogram is gold standard)
• TreatmentHeparin x 5-10 days until at least 5 days of warfarinWarfarin x 6 months ( indefinite for second
thrombosis)