Presentation is loading. Please wait.

Presentation is loading. Please wait.

Chronic Myeloproliferative Neoplasies (CMPN). Myeloid Neoplasies WHO Classification Myeloproliferative neoplasies (MPN) Myelodysplastic syndromes (MDS)

Similar presentations


Presentation on theme: "Chronic Myeloproliferative Neoplasies (CMPN). Myeloid Neoplasies WHO Classification Myeloproliferative neoplasies (MPN) Myelodysplastic syndromes (MDS)"— 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 myelocytic leukemia (CML) (Bcr-abl +) Chronic Neutrophylic Leukemia Polycythemia Vera Primary Myelofibrosis Essential Thrombocythemia Chronic Eosinophylic Leukemia Mastocytosis Unclassified types Chronic Myeloproliferative Neoplasies (MPN)

4 Systemic mastocytosis Polycythemia (rubra) vera Essential thrombocytemia Hypereosinophylic syndrome Myeloproliferative Neoplasies 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 Cells (RBC) plasma Blood 6

7 Hct: b/a Normal Dehydration Hct: elevated 123 True polycythemia a b

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

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

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

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

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

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

18 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

19 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

20 Blood counts of a PV case

21 Disease presentation: Some cases have isolated erythrocytosisSome cases have isolated erythrocytosis Some may have trilinegae hyperplasiaSome 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.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 increaseHct > 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 HctIron deficiency or hypersplenism may cause an underestimation of red cell mass due to a decreased Hct

23 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 –Major criteria 1.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

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” ( 32 P) –Anegrelide (only to supress platelet production)

30 PV: Treatment Risk groupTreatment 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 First described by Epstein and Goedel in 1934 as “haemorrhagic thrombocytemia” In 1951 Dameshek defined it as a MPD Essential Thrombocytemia(ET)

33 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: – –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 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 CMPN 4.JAK2V617F (50%) or cMPL mutation (MPLW515L and MPLW515K) + or no evidence of reactive thrombocytosis

37 –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)

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 > /mm 3 Thrombopheresis –Rapid reduction of very high plt counts

40 ET: Treatment Risk groupTreatment High risk patients: –Thrombosis history+ –Age > 60 –Platelets > /mm3 Intermediate risk –Age: –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 Etiology : Unknown (radiation ? other?) Epidemiology: 0.4 – 1.3 / year Age: Median (wide age distribution) Survival: median:3-5 years Myelofibrosis with myeloid metaplasia (Idiopathic myelofibrosis)

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 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

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.)

47

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 Transformation to acute leukemiaTransformation to acute leukemia GoutGout InfectionsInfections Termination to a stage of deep marrow failureTermination 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


Download ppt "Chronic Myeloproliferative Neoplasies (CMPN). Myeloid Neoplasies WHO Classification Myeloproliferative neoplasies (MPN) Myelodysplastic syndromes (MDS)"

Similar presentations


Ads by Google