Chronic Myeloproliferative

Neoplasies (CMPN)

Myeloid NeoplasiesWHO Classification

• Myeloproliferative neoplasies (MPN)• Myelodysplastic syndromes (MDS)• Myelodysplastic /Myeloproliferative

neoplasies – Chronic myelomonocytic leukemia (CMML)– Juvenile myelomonocytic leukemia (JMML)– Atypical Chr.. Myeloid Leukemia (BCR/ABL -)

• Eosinophilia and PDGFRA/PDGFRB or FGFR1 mutation + myeloid or lymphoid neoplasies

• Acute myeloid neoplasies

• Chronic myelocytic leukemia (CML) (Bcr-abl +)

• Chronic Neutrophylic Leukemia• Polycythemia Vera• Primary Myelofibrosis• Essential Thrombocythemia• Chronic Eosinophylic Leukemia• Mastocytosis• Unclassified types

Chronic Myeloproliferative Neoplasies (MPN)

Systemic mastocytosis

Polycythemia (rubra) vera

Essential thrombocytemia

Hypereosinophylic syndrome

Myeloproliferative Neoplasies

Chronic myeloid leukemia

Chronic myelomonocytic leukemiaMyelofibrosis with myeloid metaplasia

CMPN -concepts• Clonal disorders of hemopoietic stem

cell• Overproduction of one or more cell lines• Extramedullary hematopoesis, myelofibrosis and

leukemic transformation can occur• Increased risk of thrombosis

Polycythemia

Cells (RBC)

plasma

Blood

6

Hct: b/aNormal

Dehydration Hct: elevated

1 2 3

True polycythemia

a

b

Polycythemia–Relative

• Dehydration• Gaisbock’s syndr

(Nephropathy, Hypertension, Erythrocytosis)• Stress polycythemia

–Absolute/true• Secondary• Primary

– PRV– Familial

KidneyBone marrow

Erythropoetin

Increased red cell productionHypoksia

Oxygen transport capacity of the blood increases

Increased Hb level

Anemia

KidneyBone marrow

Erythropoetin

Increased red cell productionCauses of

hypoksia other than anemia Erythrocytosis

(Polycythemia)

CO intoxicationHigh altitudeHigh O2 affinity HbMethemoglobinemiaLung diseaseRespir. center dysfunction

Sleep apneaRight to left shunts

Bone marrowIncreased red cell production

Increased EPO levels without hypoxia

Erythrocytosis(Polycythemia)

High EPO due to Renal disease Renal cysts Hydronephrosis R.Artery stenosis Renal transplantation Focal glomerulonephritis Bartter’s syndromeInappropriate EPO productionEPO production by Tumors Hypernephroma Hepatoma Cerebellar hemangioblastoma Adrenal adenoma Pheocromocytoma Meningioma Uterine fibromyomaAndrogen therapyEPO administrationOther

Congenital /familial erythrocytosisEg: EPO receptor hypersensitivity

Bone marrow

Overproduction of RBCs + WBCs+ Platelets

Stem cell disease

Polycythemia vera

PV (PRV)• First described by Vaquez in 1892• Epidemiology:

– Incidence:2/100.000-year– Median age: 60

(may occur in younger also, 7% < 40 y)– M/F: 1-2:1

• General characteristics:– Erytrocytosis,leukocytosis,thrombocytosis– Thrombosis,– Bleeding– Transformation:

• Myelofibrosis/acute leukemia

PRV: Etiology-Pathophysiology• PRV erythroid progenitors are

resistant to apoptosis induced by EPO deprivation.

• Non-EPO dependent overproduction of erythroid lineage

• Increased sensitivity to cytokines or HGF :

eg: IL-3, GM-CSF, SCF, TPO, IGF-1,• JAK-2 mutation !!!!!!!!!!!!!

• Progenitors in PRV gain clonal predominance and supress the proliferation of normal progenitor cells.

• During the later stages of the disease myelofibrosis and extramedullary hematopoesis (in the liver , spleen and lymph nodes) may occur.

PRV: Etiology-Pathophysiology

PRV:Etiology-Pathophysiology

• JAK2 mutations (chr 9p):TK activity: 97%*

• Increased levels of PRV-1 mRNA in granulocytes

*Kenneth Kaushansky, On the Molecular Origins of the Chronic Myeloproliferative Disorders: It All Makes Sense.ASH Education Book 2005,p 533-537

EPO related signal EPO unrelated signal

Campbell P and Green A. N Engl J Med 2006;355:2452-2466 JAK2 mutation (Chr 9p): 97 % of cases !!!!!!!

• Asymptomatic• Plethora,cyanosis,• Vertigo • Tinnitus• Headache• Visual disturbances• Paresthesias• Systolic hypertension• Erythromelalgia • Pruritus (aggravated by bath)• Weight loss• Arthralgia

• Decreased exercise capacity,• Dyspnea• Excessive sweating• Vascular occlusion

• TIA , stroke,MI• Venous thrombosis

• Digital ischemia• Easy bruising • GI bleeding• Splenomegaly (70%)• Gout or/and kidney stones• Pulmonary hypertension

PRV: Clinical features

• Late stage disease – Secondary bone marrow fibrosis and

extramedullary hematopoesis• Increased spleen size and/or hepatomegaly• Decreasing red cell mass• Leuko-erythroblastic blood picture with tear

drop poikilocytosis• Bone marrow fibrosis

PRV: Clinical features

Blood counts of a PV case

Disease presentation:• Some cases have isolated

erythrocytosis• Some may have trilinegae

hyperplasia– erythrocytosis – leukocytosis – thrombocytosis

• Some cases may present with isolated lekocytosis or thrombocytosis in the beginning of the disease followed by erythrocytosis .

PRV• Hct > 60% in men and > 55% in

women usually indicates red cell mass increase

• Iron deficiency or hypersplenism may cause an underestimation of red cell mass due to a decreased Hct

• Serum levels of– LDH– Uric acid – Vit B12 or B12 binding capacity may

increaseand – EPO is decreased

• Leukocyte alkaline phosphatase level increases

• JAK2 (+)• Red cell mass is increased• Bone marrow is

– hypercellular (trilineage hyperplasia, red cell and megakaryocytic lineage may be prominent) and ,

– iron strores may be decreased.– fibrosis may be a late finding

Diagnosis• Exclude other causes of

polycythemia• Search for the criteria for

the diagnosis of PRV

PV 2008 WHO Diagnostic Criteria– Major criteria1. Increased RBC mass

• Hgb>18.5 g/dL (male)• >16.5 g/dL (female)or• Hgb ya da Hct >99 percentile or• Increased RBC mass (> % 25 of normal)(Cr51)

2. JAK2V617F (%90-95) or JAK2 exon 12 mutation (%5-10)

– Minor criteria• Bone Marrow: Proliferation of all three cell lines • Serum EPO: Decreased• Endogenous erythroid colonies

• 2 major and 1 minör or

• First major and 2 minor criteria are needed for diagnosis

Complications• Myelofibrosis• Acute leukemia• Peptic ulcer• Vascular occlusions:Arterial or venous• Bleeding:Platelet defects , acquired vWD• Splenic infarction• Increase in uric acid levels and gout or renal

stones

PRV: Prognosis• Proliferative phase followed by

postpolycythemic myelofibrosis and extramedullary hematopoesis

• Life expectancy: > 10 years– Less than normal age/sex group

• Thrombosis• Transformation

– AML– MF

PRV Treatment• Venesection to keep Hct: < %45• Low dose aspirin (if it’s not contraindicated)• Prevent/control reversible thrombotic risk

factors– EG:Hypertension,smoking, obesity,

hypercholesterolemia,DM etc• Myelosupressive treatment : If there is;

– Thrombosis– Age > 60– Intolerance to phlebotomy– Prominent thrombocytosis – Symptomatic/progressive splenomegaly

Myelosupressive agents:– Hydroxyurea– IFN– Busulphan– Radioactive “P” (32P)– Anegrelide (only to supress platelet

production)

PV: TreatmentRisk group Treatment

High risk patients:– Thrombosis history+– Age > 60– Platelets > 1.500.000/mm3

Intermediate risk– Without high/low risk features

Low risk:– Age < 40– Without any risk factor

VenesectionLow dose aspirin +Hydroksyurea (anegrelide or interpheron)

Low dose aspirin + VenesectionMyelosupressive treatment if CVS risk factors are present.

Low dose aspirin + Venesection

Peter J. Campbell and Anthony R. Green. Management of Polycythemia Vera andEssential Thrombocythemia,ASH Education Book 2005,p201-208

Causes of thrombocytosis• ET and other MPD• Iron deficiency anemia• Splenectomy or hyposplenism• Malignancy• Collagen vascular disease• Infection• Hemolysis or bleeding• Myelodysplastic Syndrome• Surgery • Drugs,etc

• First described by Epstein and Goedel in 1934 as “haemorrhagic thrombocytemia”

• In 1951 Dameshek defined it as a MPD

Essential Thrombocytemia(ET)

Essential Thrombocytemia (ET)

• 1-2/100.000- year• Age: Median:50-60

– Second peak at age 30 (mostly female)

• M/F:slight female predominance• Median survival > 10 years• Etiology : unknown

– JAK2 mutation: 57 %

ET: Clinical• Some patients may be asymptomatic• Vasomotor symptoms:

– Visual disturbances– Lightheadedness– Headaches– Palpitations– Atypical chest pain– Erythromelalgia– Livedo reticularis– Acral paresthesias

ET: Clinical• Thrombosis:

– At presentation or during the course of the disease– Deep Vein Thrombosis , Pulmonary

Embolism– Digital ischemia– Portal vein thrombosis– CVA– Coronary ischemia

• Bleeding:– Most common : GIS– NSAID increase the risk– Major bleeding:5%

• Splenomegaly : 20-25%

Diagnosis of ET: WHO 2008– 4 criteria must be present

1. Thrombocytosis > 450 x 10^9/L – More than two months on more than two

occasions 2. Megakaryocytic proliferation without

granulocytic and erythroid proliferation 3. Without diagnostic criteria of

CML,PV,IMF,MDS and other CMPN4. JAK2V617F (50%) or cMPL mutation

(MPLW515L and MPLW515K) + or no evidence of reactive thrombocytosis

– Exclude other causes of thrombocytosis • Reactive

– Anemias » Iron deficiency» Hemolytic» Acute blood loss

• Post splenectomy • Inflammation

– Bone marrow findings• Normo-Hypercellular with megakaryocytic

hypeplasia• Normal iron score • Normal erythropoesis• Without significant fibrosis

Diagnosis of ET: WHO 2008 (2)

Prognosis• Myelofibrosis: (spent phase)• Acute leukemia:• Mortality: mostly because of

thrombosis or bleeding

ET: Treatment• Prevent/Manage cardiovascular risk

factors• Low dose aspirin

– if there is no contra-indication• Myelosupressive treatment:

– High risk patients • > 60 y, • prior thrombosis,• plt > 1500000/mm3

• Thrombopheresis– Rapid reduction of very high plt counts

ET: TreatmentRisk group Treatment

High risk patients:– Thrombosis history+– Age > 60– Platelets > 1.500.000/mm3

Intermediate risk– Age: 40-60– Without high risk features

Low risk:– Age < 40– Without any risk factor

Low dose aspirin +Hydroksyurea (anegrelide or interpheron)

Low dose aspirin +Myelosupressive treatment if CVS risk factors are present.

Low dose aspirin +

Reference: Peter J. Campbell and Anthony R. Green. Management of Polycythemia Vera andEssential Thrombocythemia,ASH Education Book 2005,p201-208

Causes of myelofibrosisIdiopathic myelofibrosis and PRV ,ET,

CML, MDS Lymphoma,M MyelomaA.Leukemia (ANLL-M7,ALL)Hairy cell leukemia Metastatic carcinomaInfection :eg: Tbc,Fungal inf. SLE,Systemic sclerosisSystemic MastocytosisHypovit. D , renal osteodystrophyHypoparathyroidism,Hyperparathyroidism etc

Etiology : Unknown (radiation ? other?)Epidemiology: 0.4 – 1.3 / 100000-yearAge: Median 60-65 (wide age distribution)

Survival: median:3-5 years

Myelofibrosis with myeloid metaplasia (Idiopathic myelofibrosis)

(Idiopathic Myelofibrosis)(Myelofibrosis with Myeloid Metaplasia)

bone

IMF• Fibroblasts are not part of the clonal

process• Megakaryocyte derived cytokines

– PDGF– TGF-Beta are the cause of fibrosis

• There is extramedullary hematopoesis• Cytogenetic abnormalities are found in

50%• 13 q- , 20q- , 12p- , trisomy 8, trisomy 9• JAK2 mutation (50%) (or other . Eg MPL)

• Symptoms related to anemia or marrow failure

• Hypermetabolic state– Sweating– Weight loss– Low grade fever

• Oedema• Abdominal fullness/organomegaly

(splenomegaly and or hepatomegaly) • Portal hypertension• Splenic infarction (sudden LUQ pain)• Effusions • LAP

IMF:Clinical

IMF: LAB• Anemia• WBC : normal / leukopenia /

leukocytosis• Plt : normal /thrombocytosis

/thrombocytopenia• Blood smear :

– Red cell poikilocytosis with teardrop shapes

– Leuko-erythroblastic : erythroblasts + young myeloid cells*

*(promyelocytes, myelocytes , meta , band and polys.)

IMF: LAB• LDH , uric acid: increased • Bone marrow :

–Aspiration : Dry tap–Biopsy: Increased fibrosis and

megakaryopoesis JAK2 mutation:50%**

** Kenneth Kaushansky, On the Molecular Origins of the Chronic Myeloproliferative Disorders: It All Makes Sense.ASH Education Book 2005,p 533-537

IMF: Diagnosis• Typical blood findings• Splenomegaly• Bone marrow

– Dry tap aspirate– Bone marrow fibrosis and megakaryocytic

diysplasia (biopsy finding)• JAK2 ( about 50%)• Other causes excluded

Complications• Transformation to acute leukemia• Gout• Infections• Termination to a stage of deep marrow

failurePrognosis• Death due to

– Infection– ANLL (20% in first ten years)

IMF: Treatment• Transfusions when indicated• Androgens• Corticosteroids & other

Myelosupressive treatment• HydroxyureaOther• Splenectomy• Splenic irradiation?Stem Cell Transplantation :

– The only treatment with cure potential– Can be performed in a limited number of

patients