Rachmat Sumantri

Sub Division of Hematology Medical Oncology Department of Internal Medicine Padjadjaran University Hasan Sadikin Hospital

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 cellular bone marrow with increased quantities of one or more cellular lineages in the peripheral blood

The Clinical Variants of The CMPDs may share, to varying extents :

1. 2. 3. 4. 5. 6. 7. 8. 9. Affects middle aged and older groups Asymptomatic onset Panhyperplasia of bone marrow Extra medullary hematopoesis Fibroblast proliferation and reticulin / collagen formation in bone marrow Frequent transitions between these disorders, with overlapping manifestation Terminating in acute leukemia Elevation of platelet count ; Giant or bizzare platelets, or both Hemorrhagic and thrombotic complications

OTHERS :
1. CYTOGENETIC ABNORMALITIES 2. ABNORMAL P53 genes Apoptosis induced by the P53 ,
in the presence of altered or absent p53 apoptosis does not occur, resulting in continued proliferation.

RELATIONSHIP BETWEEN THE VARIOUS MPDS

1 2% ET PV
10 15%

15 20%
1 2%

2 5%

AML
60 70%

IMF ALL
25%

1 2%

5%

CML

CHRONIC MPD
1. Polycythemia Vera 2. Chronic Myelogenous Leukemia 3. Idiopathic Myelofibrosis 4. Essential Thrombocytosis

POLYCYTHEMIA VERA
PV is a hematopoietic stem cell disorder predominantly characterized by accelerated erythropoiesis, proliferation of myeloid and megakaryocytic elements of the bone marrow.

ELEVATED HEMATOCRIT 50%

Absolute Erythrocytosis (Increased RC Volume)

Relative Erythrocytosis (Normal RC Volume)

POLYCYTHEMIA VERA

SECONDARY ERYTHROCYTOSIS

DEHYDRATION STRESS POLYCYTEMIA (Gaisbock syndr.)

PATHOGENESIS
Abnormal Pluripotent Cell Erythroid colonies grow independently from EPO

EPI DEMIOLOGY
2 Cases per 100,000 population Median age 60 years

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

LABORATORY FEATURES
Elevation of RBC, HB, HT are the most important 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

PV
Splenomegaly Hepatomegaly Heart or lung + 75% + 35% 80%

Sec Eryth

Relative Eryth

+ + Normal

Normal Normal

Dis
Cyanosis Red Cell Mass WBC

Platelet
B12 O2 saturation

50%
75% Normal

normal
Normal

Normal
Normal Normal

PV STUDY GROUP CRITERIA

MAYOR CRITERIA 1. Elevated Red Cell Mass 2. Normal Arterial O2 Saturation 3. Splenomegaly MINOR CRITERIA 1. Leukocytosis 2. Thrombocytosis 3. Elevated Leukocyte Alkaline Phosphatase 4. Increased serum Vit. B12 ALL from mayor or elevated red cell mass + two minor criteria

 SECONDARY ERYTHROCYTOSIS
COPD Cyanotic congenital heart disease Cirrhosis Pickwickian Syndrome High Altitude Smoking

RELATIVE ERYTHROCYTOSIS
Dehydration GAISBOCKS Syndrome (Hypertensive, Obese, smoking)

TREATMENT
PHLEBOTOMY CHEMOTHERAPY : Hydroxyurea, Busulphan, 32p

PROGNOSIS
Survival rate 8 15 years Thrombohemorrhagic Events : 40% of deaths 10 15% : Malignant Transformation to AML

ESSENTIAL THROMBOCYTOSIS
MAYOR CAUSES OF THROMBOCYTOSIS
1. CLONAL

- Essential (Primary) Thrombocytosis - Polycythemia Vera - Chronic Myelogenous Leukemia - Myelofibrosis (Myeloid Metaplasia)
2. FAMILIAL

Autosomal Dominant

Cont.
3. REACTIVE (SECONDARY) THROMBOCYTOSIS A. Transient Reactive Processes - Acute Blood Loss - Rebound - Acute Infection, Inflammation - Response to Exercise B. Sustained Processes - Iron Deficiency - Post Splenectomy - Malignancy - Chronic Inflammatory and Infection Diseases - Hemolytic Anemia - Response to Drug (Vincristine, Epinephrine, ATRA, Growth Factors)

PATHOGENESIS
Clonal : Multipotensial Hematopoietic Cell
Chromosome Abnormality (17)

JAK2 Gene : A Tyrosine kinase for signaling from cell membrane receptor

 Splenomegaly in 40%
Complications BLEEDING OR THROMBOSIS

DIAGNOSTIC CRITERIA
1. Platelet > 600.000/mm3 2. Normal Red Cell Mass

< 36 ml/kg < 32 ml/kg

3. Stainable iron in marrow or failure of iron trial 4. No Philadelphia Chromosome 5. Collagen fibrosis of marrow : Absent or < 1/3 biopsy area without splenomegaly nor leukoerythroblastic reaction 6. No known cause for reactive thrombocytosis 7. Megakaryocytes in clumps

CLINICAL RISK OF THROMBOHEMORRHAGIC

THROMBOSIS
INCREASED RISK

BLEEDING Aspirin or NSAID > 1.500.000

Previous History of Thrombosis Cardiovascular Risk Factors Especially Smoking Age > 60 Inadequate Control of Thrombocytosis

CLINICAL FEATURES
CLONAL THROMBOCYTOSIS Splenomegaly 40% Platelet morphology Giant platelet Platelet function Often abnormal Thrombotic complications REACTIVE Normal Normal

Digital, cerebral, large vessel arterial or venous No thrombosis

THERAPY
CYTOREDUCTION HYDROXYUREA NON ALKYLATING MYELOSUPPRESIVE AGENT ANAGRELIDE RECOMBINANT - INTERFERON ANTIPLATELET ASPIRIN

PROGNOSIS
Terminates by converting to acute leukemia, myelodysplasia or myelofibrosis Better overall prognosis than other MPDs 5 years survival : 80%

IDIOPATHIC MYELOFIBROSIS
History: First reported in 1879 by Heuck Synonyms : Agnogenic myeloid metaplasia Myelosclerosis Osteosclerosis Chronic Erythroblastosis Myelofibrosis with Myeloid Metaplasia (MMM) CHARACTERIZED BY : Fibrosis of the marrow Extramedullary hematopoesis Leukoerythroblastosis and teardrops

INCIDENCE AND ETIOLOGY

Annual incidence is 0.6 per 100,000 Male to female ratio = 2 : 1 Age distribution : 50 70 Etiology : Mayority is unknown Exposure to radiation, toxins

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

CLINICAL PICTURES
Insidious, symptoms free for many years Splenomegaly, hepatomegaly Anemia 10% bleeding secondary to thrombocytopenia or thrombocytosis Bone pain Hypermetabolism Gout

LABORATORY FINDINGS
Leukoerythroblastic Teardrop formation 50% WBC increased, 35% WBC normal, 15% WBC below normal Platelet : normal, elevated or decreased Bone marrow aspiration : Dry Tap Histologic : Reticulin, Fibroblast and collagen increased

DIFFERENTIAL DIAGNOSIS
Must be distinguished from other disease of the CMPDs, as well as differentiated from fibrosis secondary 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)

TREATMENT
TO IMPROVE QUALITY OF LIFE PALLIATIVE TRANSFUSION STEROID ANDROGEN SPLENECTOMY ALLOPURINOL

PROGNOSIS

Median survival 5 years Cause of death : Hemorrhage, infection

CASE STUDY
60 Y O MAN ADMITTED WITH PAIN AND SWELLING OF LEFT LIMB,2 DAYS EARLIER HE CAME TO EMG WITH HEADACHE,BLURRED VISION,TINNITUS AND PRURITUS ESPECIALLY AFTER BATHING. He had been treated for gout for the past 2 months Physical examination : flushed face,engorged retinal veins,ecchymosis on the legs,splenomegaly,no hepatomegaly

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

comment
History and physical findings : presumptive diagnosis of PV Headache and blurred vision: hyperviscosity As well as thrombotic episode. Plethora , engorged retinal veins : blood vessels congestion Generalized pruritus occurs in 30% Phlebotomy and cytoreduction therapy must be initiated