Myeloproliferative disorders
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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

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Myeloproliferative disorders
Myeloproliferative disorders

  • Clonal haematopoeitic disorders

  • Proliferation of one of myeloid lineages

    • Granulocytic

    • Erythroid

    • Megakaryocytic

  • Relatively normal maturation


Myeloproliferative disorders1
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 disorders2

AML

CML

CMML

  • MDS

  • RA

  • RARS

  • RAEB I

  • RAEB II

Myeloproliferative disorders


Myeloproliferative disorders3
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


Granulocyte

precursors

Red cell

precursors

Megakaryocytes

Reactive

fibrosis

Bone marrow stem cell

Clonal abnormality

Chronic myeloid

leukemia

Polycythaemia

rubra vera

(PRV)

Essential

thrombocytosis

(ET)

Myelofibrosis

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 radiationLatent 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 –maybe massive

Pt . maybe asymptomatic


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


The Philadelphia Chromosome: t(9;22) Translocation

9

9+

Philadelphia

chromosome

22

Ph

bcr

bcr-abl

abl

Fusion proteinwith tyrosinekinase activity


Clinical Course: Phases of CML

Advanced phases

Chronic phase

Median 4–6 yearsstabilization

Accelerated phase

Median durationup to 1 year

Blastic phase (blast crisis)

Median survival3–6 monthsTerminal 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


Bcr-Abl

Bcr-Abl

Substrate

Substrate

Imatinib

P

ATP

P

P

Y = Tyrosine

P = Phosphate

P

Mechanism of Action of Imatinib

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



Polycythemia
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
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
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 vera1
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
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 features1
Clinical features

  • Hypertention

  • Gout

  • Leukaemic transformation

  • Myelofibrosis


Diagnostic criteria
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
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
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 features2
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
Investigations

ET is a diagnosis of exclusion

  • Rule out other causes of elevated platelet count


Diagnostic criteria for et
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



Thrombophilia

Thrombophilia

Barry White

National Haemophilia Director

Director, National Centre for Hereditary Coagulation Disorders,

St James’s Hospital


Virchow s triad
Virchow’s Triad

  • Disorder of blood vessel wall

  • Disordered blood flow (stasis)

  • Abnormality of blood constituents


Venous thrombosis a multifactorial disease
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


Thrombophilia1
Thrombophilia

  • Inherited or acquired predisposition to venous thrombosis

  • Laboratory abnormalities


Increased procoagulants
Increased procoagulants

  • FVIII

  • FIX

  • FXI

  • Prothrombin 20210A

  • Fibrinogen

  • Thrombin activator fibrinolysis inhibitor (TAFI)


Decreased anticoagulants
Decreased anticoagulants

  • Antithrombin deficiency

  • Protein C deficiency

  • Protein S deficiency

  • Activated PC resistance (FV Leiden)


Unknown mechanism
Unknown mechanism

  • Antiphospholipid syndrome

  • Hyperhomocysteinemia


Activated protein c resistance
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
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
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
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
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
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
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 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
Clinical practice – DVT/PE

  • Diagnosis

    DVT – doppler ultrasound primarily (venogram gold standard)

    PE – ventilation perfusions scan primarily (pulmonary angiogram is gold standard)

  • Treatment

    Heparin x 5-10 days until at least 5 days of warfarin

    Warfarin x 6 months ( indefinite for second thrombosis)


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