Myeloproliferative diseases by dr kamal e higgy consultant haematologist
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MYELOPROLIFERATIVE DISEASES By DR. KAMAL E. HIGGY CONSULTANT HAEMATOLOGIST. Myeloid Disorders Usual Features at Diagnosis. WHO Classification Chronic Myeloproliferative Disease

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MYELOPROLIFERATIVE DISEASES By DR. KAMAL E. HIGGY CONSULTANT HAEMATOLOGIST

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MYELOPROLIFERATIVEDISEASESByDR. KAMAL E. HIGGYCONSULTANT HAEMATOLOGIST


Myeloid DisordersUsual Features at Diagnosis


WHO Classification

Chronic Myeloproliferative Disease

---------------------------------------------------------------------------------------------------------------------------

  • Chronic Myelogenous Leukaemia

    [Ph chromosome, t(9;22)(q34;q11) , BCR/ABL- positive ]

  • Chronic Neutrophilic Leukaemia

  • Chronic Eosinophilic Leukaemia

    (and the hypereosinophilic syndrome)

  • Polycythaemia Vera

  • Chronic Idiopathic Myelofibrosis

    (with extramedullary haematopoiesis)

  • Essential Thrombocythaemia

  • Chronic Myeloproliferative Disease, Unclassifiable


WHO Classification

Myelodysplastic / Myeloproliferative Diseases

-----------------------------------------------------------------

  • Chronic Myelomonocytic Leukaemia

  • Atypical Chronic Myeloid Leukaemia

  • Juvenile Myelomonocytic Leukaemia

  • Myelodysplastic/Myeloproliferative Disease, Unclassifiable


Myeloproliferative DiseaseRecurring Genetic Abnormalities and Their Frequency (%)at diagnosis


Polycythaemia Vera

----------------------------------------------------------------------------------------------------------------------------------------------------------------------

  • Hb: Males >17.5 gm/dl

    Females > 15.5 gm/dl

  • RBC: Males > 6.0 X 1012/L

    Females > 5.5X1012/L

  • PCV: Males > 51%

    Females > 48%

  • TRCV : Males > 36 ml/kg (25-35)

    Females > 32 ml/kg (22-32)

  • TPV: 40 – 50 ml/kg


Classification of Erythrocytosis

Raised PCV (female >0.48; male>0.51)

RCM

(Interpreted using ICSH reference values)

Increased RCMNormal RCM

Absolute erythrocytosisApparent erythrocytosis

Abbreviations: PCV = Packed Cell Volume; RCM = red cell mass;

ICSH = International Council for Standardization in Haematology;


Primary Erythrocytosis

Congenital #

Truncation of the EPO receptor*

Acquired

Polycythaemia Vera*

Secondary Erythrocytosis

Congenital #

e.g., high oxygen affinity Hb,

autonomous high EPO production

Acquired

e.g., hypoxemia, renal disease

# Sometimes familial

* The only condition to be defined in this category at present

EPO = erythropoietin


Polycythaemia Vera

Causes

----------------------------------------------------------------------------------------------------------------------------------------------------------------------

  • Primary : Polycythaemia Vera

  • Secondary:

    1.Erythropoietin Compensatory Increase:

    High Altitude

    C.V. disease

    Pulmonary disease

    High Affinity Hb

    Heavy smoking

    Methaemoglobinaemia

    2.Abnormal Erythropoietin Production:

    Renal diseases.

    Massive uterine fibromatosis

    Hepatocellular Carcinoma

    Cerebellar Haemangioblastoma

  • Relative: Stress, Dehydration, Plasma Loss.


Polycythaemia Vera

Clinical Features

----------------------------------------------------------------------------------------------------------------------------------------------------------------------

  • Headache, Lethargy, Dyspnea

  • Weight Loss, Night Sweats

  • Generalized pruritis (Increase after hot bath)

  • Plethoric Appearance

  • Haemorrhage & Thrombosis

  • Hypertension (In about 1/3rd of the patients)

  • Gout (Increased Uric Acid)

  • Peptic Ulcers (In 5 – 10% of the patients)

  • Splenomegaly (In 2/3rd of patients)

  • Accidental Discovery (On Routine exam)


Polycythaemia Vera

Laboratory Investigations

----------------------------------------------------------------------------------------------------------------------------------------------------------------------

  • C.B.C

  • Neutrophil Alkaline Phosphatase (N.A.P.)

  • Serum B12 & B12 binding capacity

  • Bone Marrow- Blood Viscosity

  • Uric Acid Level- Hb Electrophoresis

  • Arterial Oxygen Tension -T.R.C.V.

  • I.V. Pyelography, CT & US - JAK2:74 – 97 % (PV)

  • Erythropoietin Assay 33 – 57 % (ET)

    35 – 50 % (MF)


Polycythaemia Vera

Classic Polycythaemia Vera Study Group

Diagnostic Criteria

--------------------------------------------------------------------------------------------------------------------------------------------------------------------------

A1 ↑ Red Cell MassB1Thrombocytosis

Male ≥36 ml/kg Platelet count >400,000/µl

Female ≥32ml/kgB2Leukocytosis >12,000/µl

(No fever or infection)

A2Normal ArterialB3↑ Leukocyte Alkaline

O2 Saturation ≥92%Phosphatase score >100

(No fever or infection)

A3Splenomegaly ↑ Serum B12 (>900pg/ml)

or

↑ Unbound B12 binding

capacity (>2200pg/ml)

--------------------------------------------------------------------------------------------------------------------------------------------------------------------------

  • Diagnosis is acceptable if the following combinations are present: A1 + A2 + A3 or A1 + A2 + any two from Category B.


Polycythaemia Vera

Proposed diagnostic criteria

-------------------------------------------------------------------------------------------------------------------------------

A1 Raised red cell mass B1 Thrombocytosis

(>25% above mean normal Platelet count>400X109/1

predicted value)

A2 Absence of a cause of B2 Neutrophil leukocytosis

Secondary Polycythaemianeutrophil count >10X109/1

A3 Palpable splenomegalyB3 Splenomegaly demonstrated

by isotope/ultrasound scanning

A4 Clonality marker B4 Characteristic BFU-E growth

e.g. - abnormal marrow karyotypeor reduced serum erythropoietin

- JAK2

------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

A1 + A2 + A3 or A4 establishes PV

A1 + A2 + Two of B establishes PV


Polycythaemia Vera

Treatment

--------------------------------------------------------------

  • Venesecton

  • Radioactive Phosphorus (P32)

  • Chemotherapy:

    e.g. Hydroxyurea


Chronic Idiopathic MyelofibrosisPrefibrotic Stage


Chronic Idiopathic MyelofibrosisFibrotic Stage


Essential ThrombocythaemiaDiagnostic Criteria

Positive Criteria

  • Sustained platelet count ≥600X109/L

  • Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes

    Criteria of exclusion

  • No evidence of polycythaemia vera (PV)

    - Normal red cell mass or Hb <18.5g/dl in men, 16.5g/dl in women

    - Stainable iron in marrow, normal serum ferritin or normal MCV

    - If the former condition is not met, failure of iron trial to increase red cell

    mass or Hgb levels to the PV range

  • No evidence of CML

    - No Philadelphia chromosome and no BCR/ABL fusion gene


Essential ThrombocythaemiaDiagnostic criteria(Continued)

  • No evidence of chronic idiopathic myelofibrosis

    - Collagen fibrosis absent

    - Reticulin fibrosis minimal or absent

    4.No evidence of myelodysplastic syndrome

    - No del(5q), t(3;3)q21;q26), inv(3)(q21q26)

    - No significant granulocytic dysplasia, few if any

    micromegakaryocytes

  • No evidence that thrombocytosis is reactive due to:

    - Underlying inflammation or infection

    -Underlying neoplasm

    -Prior splenectomy


Giant Plat


Megakaryocytes

in Clusters


Chronic Myelogenous Leukaemia

Presenting Manifestations

Common

Anaemia

Splenomegaly

Less Common

Symptoms due to the raised metabolic rate

Haemorrhagic Manifestations, especially bruising


Chronic Myelogenous Leukaemia

Presenting Manifestations (Cont…)

Occasional

  • Acute abdominal pain

  • Bone or joint pains

  • Menstrual disturbances

  • Neurological symptoms

  • Priapism

  • Gout

  • Skin disorder

  • Disturbances of vision or hearing

  • Accidental discovery on routine blood examination


Chronic Myelogenous Leukaemia

Evolution of the disease

Chronic Phase

Accelerated Phase

Blastic Transformation

(AML) (ALL)


Chronic Myelogenous Leukaemia

Laboratory Investigations

  • CBC


Chronic Myelogenous Leukaemia

Laboratory Investigations (Cont…)

  • Neutrophil Alkaline Phosphatase

  • Bone Marrow Examination.

  • Serum B12 & B12 binding capacity

  • Cytogenetic Studies

    (Ph1) chromosome [ t ( 9 : 22 ) ]

  • DNA restriction enzyme analysis

    BCR-ABL (Breakpoint Cluster Region)


Chronic Myelogenous LeukaemiaAccelerated Phase

  • Blasts 10% to 19% of peripheral blood white cells or bone marrow cells

  • Peripheral blood basophils at least 20%

  • Persistent thrombocytopenia (<100X109/L) unrelated to therapy or persistent thrombocytosis (> 1000X109L) unresponsive to therapy

  • Increasing spleen size and increase WBC count unresponsive to therapy


Chronic Myelogenous LeukaemiaAccelerated Phase (Cont…)

  • Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML)

  • Megakaryocytic proliferation in sizable sheets and clusters, associated with marked reticulin or collagen fibrosis, and/or severe granulocytic dysplasia, should be considered as suggestive of CML-AP

    These findings have not yet been analyzed in large clinical studies, however, so it is not clear if they are independent criteria for accelerated phase. They often occur simultaneously with one or more of the other features listed


Chronic Myelogenous LeukaemiaBlastic Phase (BP)

Diagnosis is established if one or more of following is present:

  • Blasts 20% or more of peripheral blood white cells or bone marrow cells

  • Extramedullary blast proliferation

  • Large foci or clusters of blasts in bone marrow biopsy


Chronic Myelogenous LeukaemiaChronic Phase (BP) Treatment

  • Hydroxyurea (HU):

    WBC/ulHU (mg/kg BW/DAY)

    >50,00050

    15-50,00030 – 40

    <15,00025

  • Busulphan

  • Alpha – Interferon:

    5 MU/DAY

    7.5 MU/DAY if WBC > 10,000/mcl

    10 MU/DAY if WBC > 20,000/mcl

    3 MU/DAY if cytopenia develops

  • BMT, ABMT & STEM CELL HARVEST

  • Gleevec


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