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)