3. Bahan Kuliah Myeloproliferative Disorders

7/28/2019 3. Bahan Kuliah Myeloproliferative Disorders

1/36

Rachmat SumantriSub Division of Hematology Medical Oncology

Department of Internal Medicine

Padjadjaran University

Hasan Sadikin Hospital


2/36

MPDs divided into two groups : ACUTE and CHRONIC

ACUTE : Acute non lymphocytic leukemia (ANLL)

CHRONIC : Chronic myelocytic leukemia

Polycythemia vera

Idiopathic myelofibrosis

Essential thrombosis

Characterized by a hyper cellularbone marrow with increasedquantities of one or more cellular

lineages in the peripheral blood


3/36

The Clinical Variants of The CMPDs

may share, to varying extents :

1. Affects middle aged and older groups

2. Asymptomatic onset

3. Panhyperplasia of bone marrow

4. Extra medullary hematopoesis5. Fibroblast proliferation and reticulin / collagen formation in

bone marrow

6. Frequent transitions between these disorders, withoverlapping manifestation

7. Terminating in acute leukemia

8. Elevation of platelet count ; Giant or bizzare platelets, or both

9. Hemorrhagic and thrombotic complications


4/36

OTHERS :

1. CYTOGENETIC ABNORMALITIES

2. ABNORMAL P53

genesApoptosis induced by the P53 ,

in the presence of altered or absent p53

apoptosis does not occur, resulting in

continued proliferation.


5/36

RELATIONSHIP BETWEEN

THE VARIOUS MPDS

IMFET

PV

AML

CML

ALL

1 2%

10 15%

15 20%

60 70%25% 5%1 2%

2 5%

1 2%


6/36

CHRONIC MPD

1. Polycythemia Vera

2. Chronic Myelogenous Leukemia3. Idiopathic Myelofibrosis

4. Essential Thrombocytosis


7/36

POLYCYTHEMIA VERA

PV is a hematopoietic stem cell disorder

predominantly characterized by

accelerated erythropoiesis, proliferation

of myeloid and megakaryocytic

elements of the bone marrow.


8/36

ELEVATED HEMATOCRIT 50%

Absolute Erythrocytosis

(Increased RC Volume)

Relative Erythrocytosis

(Normal RC Volume)

POLYCYTHEMIA VERA

SECONDARY ERYTHROCYTOSISDEHYDRATION

STRESS POLYCYTEMIA

(Gaisbock syndr.)


9/36

PATHOGENESIS

Abnormal Pluripotent Cell

Erythroid colonies grow independentlyfrom EPO

2 Cases per 100,000 population

Median age 60 years

EPI DEMIOLOGY


10/36

CLINICAL PICTURES

Insidious onset

Symptoms related to increased red cell volume or hyperviscocity

Cerebral circulatory disturbances : headache, dizzy, vertigo,

visual phenomena

Hemorrhage

Thrombosis

Splenomegaly, modest hepatomegaly

Reddish purple color or the face, nose, ears, lips (PLETHORA)

Itching

Fever

Gout


11/36

LABORATORY FEATURES

Elevation of RBC, HB, HT are the mostimportant findings

HT > 58% in men > 52% in women

Red cell mass 36 ml/mg in men

32 ml/kg in women

Elevation of WBC is moderate

(12 25. 109/L)

Thrombocytosis (450 1000 x 109 /L)

O2

saturation normal


12/36

PV Sec Eryth Relative Eryth

Splenomegaly + 75%

Hepatomegaly + 35%

Heart or lung +

Dis

Cyanosis +

Red Cell Mass NormalWBC 80% Normal NormalPlatelet 50% normal NormalB12 75% Normal NormalO

2saturation Normal Normal


13/36

PV STUDY GROUP CRITERIA

MAYOR CRITERIA1. Elevated Red Cell Mass

2. Normal Arterial O2 Saturation

3. Splenomegaly

MINOR CRITERIA

1. Leukocytosis

2. Thrombocytosis

3. Elevated Leukocyte Alkaline Phosphatase4. Increased serum Vit. B12

ALL from mayor

or elevated red cell mass + two minor criteria


14/36

SECONDARY ERYTHROCYTOSIS

COPD

Cyanotic congenital heart disease

Cirrhosis

Pickwickian Syndrome

High Altitude

Smoking

RELATIVE ERYTHROCYTOSIS

Dehydration

GAISBOCKS Syndrome (Hypertensive,Obese, smoking)


15/36

TREATMENT

PHLEBOTOMY

CHEMOTHERAPY : Hydroxyurea,

Busulphan, 32p

PROGNOSIS

Survival rate 8 15 years

Thrombohemorrhagic Events : 40% of deaths

10

15% : Malignant Transformation to AML


16/36

ESSENTIAL

THROMBOCYTOSIS

1. CLONAL

- Essential (Primary) Thrombocytosis

- Polycythemia Vera

- Chronic Myelogenous Leukemia

- Myelofibrosis (Myeloid Metaplasia)2. FAMILIAL

Autosomal Dominant

MAYOR CAUSES OF THROMBOCYTOSIS


17/36

Cont.

3. REACTIVE (SECONDARY) THROMBOCYTOSIS

A. Transient Reactive Processes- Acute Blood Loss

- Rebound

- Acute Infection, Inflammation

- Response to ExerciseB. Sustained Processes

- Iron Deficiency

- Post Splenectomy

- Malignancy- Chronic Inflammatory and Infection Diseases

- Hemolytic Anemia

- Response to Drug (Vincristine, Epinephrine,

ATRA, Growth Factors)


18/36

PATHOGENESIS

Clonal : Multipotensial Hematopoietic

Cell

Chromosome Abnormality (17)

JAK2 Gene : A Tyrosine kinase forsignaling from cell membrane receptor


19/36

Splenomegaly in 40%

Complications BLEEDING OR

THROMBOSIS


20/36

DIAGNOSTIC CRITERIA

1. Platelet > 600.000/mm3

2. Normal Red Cell Mass

< 36 ml/kg

< 32 ml/kg3. Stainable iron in marrow or failure of iron trial4. No Philadelphia Chromosome

5. Collagen fibrosis of marrow :

Absent or < 1/3 biopsy area withoutsplenomegaly nor leukoerythroblastic reaction

6. No known cause for reactive thrombocytosis

7. Megakaryocytes in clumps


21/36

CLINICAL RISK OF

THROMBOHEMORRHAGIC

THROMBOSIS BLEEDING

INCREASED

RISK Previous History

of Thrombosis Cardiovascular

Risk Factors

Especially Smoking

Age > 60

Inadequate Control

of Thrombocytosis

Aspirin or

NSAID

> 1.500.000


22/36

CLINICAL FEATURES

CLONALTHROMBOCYTOSIS

REACTIVE

Splenomegaly

Platelet morphology

Platelet function

Thrombotic

complications

40%

Giant plateletOften abnormal

Digital, cerebral, large

vessel arterial or venous

thrombosis

NormalNormal

No


23/36

THERAPY

CYTOREDUCTION

HYDROXYUREA

NON ALKYLATING MYELOSUPPRESIVEAGENT

ANAGRELIDE

RECOMBINANT - INTERFERON ANTIPLATELET

ASPIRIN


24/36

PROGNOSIS

Terminates by converting to acuteleukemia, myelodysplasia or

myelofibrosis

Better overall prognosis than other

MPDs 5 years survival : 80%


25/36

IDIOPATHIC MYELOFIBROSIS

History : First reported in 1879 by HeuckSynonyms : Agnogenic myeloid metaplasia

Myelosclerosis

OsteosclerosisChronic Erythroblastosis

Myelofibrosis with Myeloid Metaplasia (MMM)

CHARACTERIZED BY :

Fibrosis of the marrow

Extramedullary hematopoesis

Leukoerythroblastosis and teardrops


26/36

INCIDENCE AND ETIOLOGY

Annual incidence is 0.6 per 100,000

Male to female ratio = 2 : 1Age distribution : 50 70

Etiology : Mayority is unknownExposure to radiation,toxins


27/36

PATHOGENESIS

STEM - CELL DEFECT

Mutation of multipotensial stem-cell

Bone marrow fibrosis occur

secondary, non neoplastic process

MARROW FIBROSIS :

Platelet derived growth factor

fibroblast collagen production

myelofibrosis


28/36

CLINICAL PICTURES

Insidious, symptoms free for many years

Splenomegaly, hepatomegaly

Anemia

10% bleeding secondary to thrombocytopenia or

thrombocytosis

Bone pain

Hypermetabolism

Gout


29/36

LABORATORY FINDINGS

Leukoerythroblastic

Teardrop formation

50% WBC increased, 35% WBCnormal, 15% WBC below normal

Platelet : normal, elevated or decreased

Bone marrow aspiration : Dry Tap Histologic : Reticulin, Fibroblast and

collagen increased


30/36

DIFFERENTIAL DIAGNOSIS

Must be distinguished from other disease of theCMPDs, as well as differentiated from fibrosissecondary to infiltratif disorders

CML considered most frequently 15 20% patients PV undergo a transition to terminal

myelofibrosis with marked anemia, bone marrow

fibrosis and splenomegaly Secondary myelofibrosis : Metastatic carcinoma,

leukemia, granulomatous disorders (TBC,Histoplasmosis, Sarcoidosis)


31/36

TREATMENT

TO IMPROVE QUALITY OFLIFE

PALLIATIVE

TRANSFUSION

STEROID ANDROGEN

SPLENECTOMY

ALLOPURINOL


32/36

PROGNOSIS

Median survival 5 years Cause of death : Hemorrhage,

infection


33/36

CASE STUDY

60 Y O MAN ADMITTED WITH PAIN ANDSWELLING OF LEFT LIMB,2 DAYS EARLIER HE

CAME TO EMG WITH HEADACHE,BLURRED

VISION,TINNITUS AND PRURITUS ESPECIALLYAFTER BATHING. He had been treated for gout for the

past 2 months

Physical examination : flushed face,engorged retinal

veins,ecchymosis on the legs,splenomegaly,nohepatomegaly


34/36

Lab : Hb 18.8 gr% WBC 20.300

RBC 7.53x10/L

Platelet 870.000 Hct 58% O2 saturation 94%

Bone marrow:panhyperplasia and large

megakaryocyte,reticulin content slightly

increased


35/36

comment

History and physical findings : presumptive

diagnosis of PV

Headache and blurred vision: hyperviscosityAs well as thrombotic episode. Plethora , engorged

retinal veins : blood vessels congestion

Generalized pruritus occurs in 30%

Phlebotomy and cytoreduction therapy must be

initiated


36/36

Documents

3. Bahan Kuliah Myeloproliferative Disorders