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Chronic Myeloproliferative Neoplasies (CMPN)

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Presentation on theme: "Chronic Myeloproliferative Neoplasies (CMPN)"— Presentation transcript:

1 Chronic Myeloproliferative Neoplasies (CMPN)

2 Myeloid Neoplasies WHO 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

3 Chronic Myeloproliferative Neoplasies (MPN)
Chronic myelocytic leukemia (CML) (Bcr-abl +) Chronic Neutrophylic Leukemia Polycythemia Vera Primary Myelofibrosis Essential Thrombocythemia Chronic Eosinophylic Leukemia Mastocytosis Unclassified types

4 Myeloproliferative Neoplasies
Systemic mastocytosis Polycythemia (rubra) vera Essential thrombocytemia Hypereosinophylic syndrome Chronic myeloid leukemia Chronic myelomonocytic leukemia Myelofibrosis with myeloid metaplasia

5 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

6 Polycythemia plasma Blood Cells (RBC) 6 6

7 1 2 3 a b Dehydration Hct: elevated Hct: b/a Normal True polycythemia

8 Polycythemia Relative Absolute/true Secondary Primary PRV Familial
Dehydration Gaisbock’s syndr (Nephropathy, Hypertension, Erythrocytosis) Stress polycythemia Absolute/true Secondary Primary PRV Familial

9 Erythropoetin Bone marrow Kidney Increased red cell production Hypoksia Anemia Oxygen transport capacity of the blood increases Increased Hb level

10 Increased red cell production
Erythropoetin Bone marrow Kidney Increased red cell production Causes of hypoksia other than anemia CO intoxication High altitude High O2 affinity Hb Methemoglobinemia Lung disease Respir. center dysfunction Sleep apnea Right to left shunts Erythrocytosis (Polycythemia)

11 Increased EPO levels without hypoxia Bone marrow
High EPO due to Renal disease Renal cysts Hydronephrosis R.Artery stenosis Renal transplantation Focal glomerulonephritis Bartter’s syndrome Inappropriate EPO production EPO production by Tumors Hypernephroma Hepatoma Cerebellar hemangioblastoma Adrenal adenoma Pheocromocytoma Meningioma Uterine fibromyoma Androgen therapy EPO administration Other Congenital /familial erythrocytosis Eg: EPO receptor hypersensitivity Increased red cell production Erythrocytosis (Polycythemia)

12 Overproduction of RBCs
Stem cell disease Bone marrow Overproduction of RBCs + WBCs+ Platelets Polycythemia vera

13 PV (PRV) First described by Vaquez in 1892 Epidemiology:
Incidence:2/ 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

14 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 !!!!!!!!!!!!!

15 PRV: Etiology-Pathophysiology
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.

16 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

17 JAK2 mutation (Chr 9p): 97 % of cases !!!!!!!
Campbell P and Green A. N Engl J Med 2006;355: JAK2 mutation (Chr 9p): 97 % of cases !!!!!!! EPO unrelated signal EPO related signal

18 PRV: Clinical features
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

19 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

20 Blood counts of a PV case

21 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 .

22 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

23 Leukocyte alkaline phosphatase level increases JAK2 (+)
Serum levels of LDH Uric acid Vit B12 or B12 binding capacity may increase and 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

24 Diagnosis Exclude other causes of polycythemia
Search for the criteria for the diagnosis of PRV

25 PV 2008 WHO Diagnostic Criteria
2 major and 1 minör or First major and 2 minor criteria are needed for diagnosis Major criteria 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) 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 25

26 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

27 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

28 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

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

30 PV: Treatment Risk group Treatment
High risk patients: Thrombosis history+ Age > 60 Platelets > /mm3 Intermediate risk Without high/low risk features Low risk: Age < 40 Without any risk factor Venesection Low dose aspirin + Hydroksyurea (anegrelide or interpheron) Low dose aspirin + Venesection Myelosupressive 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,p

31 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

32 Essential Thrombocytemia(ET)
First described by Epstein and Goedel in 1934 as “haemorrhagic thrombocytemia” In Dameshek defined it as a MPD

33 Essential Thrombocytemia (ET)
1-2/ 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 %

34 ET: Clinical Some patients may be asymptomatic Vasomotor symptoms:
Visual disturbances Lightheadedness Headaches Palpitations Atypical chest pain Erythromelalgia Livedo reticularis Acral paresthesias

35 ET: Clinical Thrombosis: Bleeding: Splenomegaly : 20-25%
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%

36 Diagnosis of ET: WHO 2008 4 criteria must be present
Thrombocytosis > 450 x 10^9/L More than two months on more than two occasions Megakaryocytic proliferation without granulocytic and erythroid proliferation Without diagnostic criteria of CML,PV,IMF,MDS and other CMPN JAK2V617F (50%) or cMPL mutation (MPLW515L and MPLW515K) + or no evidence of reactive thrombocytosis 36

37 Diagnosis of ET: WHO 2008 (2) 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 37

38 Prognosis Myelofibrosis: (spent phase) Acute leukemia:
Mortality: mostly because of thrombosis or bleeding

39 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 > /mm3 Thrombopheresis Rapid reduction of very high plt counts

40 ET: Treatment Risk group Treatment
High risk patients: Thrombosis history+ Age > 60 Platelets > /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,p

41 Causes of myelofibrosis
Idiopathic myelofibrosis and PRV ,ET, CML, MDS Lymphoma,M Myeloma A.Leukemia (ANLL-M7,ALL) Hairy cell leukemia Metastatic carcinoma Infection :eg: Tbc,Fungal inf. SLE,Systemic sclerosis Systemic Mastocytosis Hypovit. D , renal osteodystrophy Hypoparathyroidism,Hyperparathyroidism etc

42 Myelofibrosis with myeloid metaplasia (Idiopathic myelofibrosis)
Etiology : Unknown (radiation ? other?) Epidemiology: 0.4 – 1.3 / year Age: Median (wide age distribution) Survival: median:3-5 years

43 (Idiopathic Myelofibrosis)
(Myelofibrosis with Myeloid Metaplasia) bone

44 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)

45 IMF:Clinical 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

46 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.)


48 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

49 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

50 Complications Prognosis Transformation to acute leukemia Gout
Infections Termination to a stage of deep marrow failure Prognosis Death due to Infection ANLL (20% in first ten years)

51 IMF: Treatment Transfusions when indicated Androgens
Corticosteroids & other Myelosupressive treatment Hydroxyurea Other Splenectomy Splenic irradiation? Stem Cell Transplantation : The only treatment with cure potential Can be performed in a limited number of patients

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