myeloproliferative_disorders.ppt

1. Myeloproliferative disorders

2. Introduction  Hemopoietic stem cell disorder  Clonal  Characterized by proliferation  Granulocytic  Erythroid  Megakaryocytic  Interrelationship between  Polycythaemia  Essential thrombocythaemia  myelofibrosis

3. Introduction / haemopoiesis

4. Introduction  Normal maturation (effective)  Increased number of  Red cells  Granulocytes  Platelets (Note: myeloproliferation in myelodysplastic syndrome is ineffective)  Frequent overlap of the clinical, laboratory & morphologic findings  Leucocytosis, thrombocytosis, increased megakaeryocytes, fibrosis & organomegaly blurs the boundaries  Hepatosplenomegaly  Sequestration of excess blood  Extramedullary haematopoiesis  Leukaemic infiltration

5. Rationale for classification  Classification is based on the lineage of the predominant proliferation  Level of marrow fibrosis  Clinical and laboratory data (FBP, BM, cytogenetic & molecular genetic)

6. Differential diagnosis Features distinguishing MPD from MDS, MDS/MPD & AML Disease cellularity BM % marrow blasts Maturation Morphology Haemato- poiesis Blood counts Large organs MPD Increase d Normal or < 10% Present Normal Effectiv e One or more myeloid increase d Common MDS Usually increased Normal or < 20% Present Abnorma l In- effective Low one or more cytopeni a Un- common MDS/ MPD Usually increased Normal or <20% Present Abnorma l Effective or ineffective Variable Common AML Usually increased Increase d >20% Minimal Dysplasia can be present In- effective Variable Un- common

7. Clonal evolution Clonal evolution & stepwise progression to fibrosis, marrow failure or acute blast phase

8. Incidence and epidemiology  Disease of adult  Peak incidence in 7th decade  6-9/100,000

9. Pathogenesis  Dysregulated proliferation  No specific genetic abnormality  CML (Ph chromosome t(9;22) BCR/ABL)  Growth-factor independent proliferation  PV, hypersensitiviy to IGF-1  Bone marrow fibrosis in all MPD  Fibrosis is secondary phenomena  Fibroblasts are not from malignant clone  TGF-β & Platelet like growth factor

10. Prognosis  Depends on the proper diagnosis and early treatment  Role of  IFN  BMT  Tyrosine kinase inhibitors

11. Myeloproliferative disorders  Clonal haematopoeitic disorders  Proliferation of one of myeloid lineages  Granulocytic  Erythroid  Megakaryocytic  Relatively normal maturation

12. Myeloproliferative disorders WHO Classification of CMPD  Ch Myeloid leukemia  Ch Neutrophillic leukemia  Ch Eosinophillic leukemia / Hyper Eo Synd  Polycythemia Vera  Essential Thrombocythemia  Myelofibrosis  CMPD unclassifiable

13. Myeloproliferative disorders MPD •PRV •ET •MF AML MDS •RA •RARS •RAEB I •RAEB II CMML CML

14. Myeloproliferative disorders  Ch Myeloid leukemia (BCR-ABL positive)  Polycythemia Vera  Essential Thrombocythemia  Myelofibrosis  Specific clincopathologic criteria for diagnosis and distinct diseases, have common features  Increased number of one or more myeloid cells  Hepatosplenomegaly  Hypercatabolism  Clonal marrow hyperplasia without dysplasia  Predisposition to evolve

15. Bone marrow stem cell Clonal abnormality Granulocyte precursors Red cell precursors Megakaryocytes Reactive fibrosis Essential thrombocytosis (ET) Polycythaemia rubra vera (PRV) Myelofibrosis AML Chronic myeloid leukemia 70% 10% 10% 30%

16. Epidemiology of CML  Median age range at presentation: 45 to 55 years  Incidence increases with age  12% - 30% of patients are >60 years old  At presentation  50% diagnosed by routine laboratory tests  85% diagnosed during chronic phase

17. Ionizing radiation Latent Period Atomic bomb survivors 11 years ( 2-25) Ankylosing spondylitis pts 3.6 years (1-6) No evidence of other genetic factors Chemical have not been associated with CML Incidence 1-1.5/100,000 population Male predominance Epidemiology of CML

18. Presentation Insidious onset Anorexia and weight loss Symptoms of anaemia Splenomegaly –may be massive Pt . maybe asymptomatic

19. The Philadelphia Chromosome 2 3 4 5 1 7 8 9 10 11 12 6 13 14 15 16 17 18 20 21 22 X Y 19

20. The Philadelphia Chromosome: t(9;22) Translocation bcr-abl Fusion protein with tyrosine kinase activity 22 bcr abl Ph 9 9+ Philadelphia chromosome

21. Clinical Course: Phases of CML Chronic phase Median 4–6 years stabilization Accelerated phase Median duration up to 1 year Blastic phase (blast crisis) Median survival 3–6 months Terminal phase Advanced phases

22. Treatment of Chronic Myeloid leukemia Arsenic Lissauer, 1865 Radiotherapy Pusey, 1902 Busulfan Galton, 1953 Hydroxyurea Fishbein et al, 1964 Autografting Buckner et al, 1974 Allogeneic BMT (SD) Doney et al, 1978 Interferon Talpaz et al, 1983 Allogeneic BMT (UD) Beatty et al, 1989 Donor Leukocytes Kolb et al, 1990 Imatinib Druker et al, 1998 Imatinib/Combination therapy O’Brien et al, 200……

23. CML Treatment •Chemotherapy to reduce WCC - Hydroxyurea •Interferon based treatment •Allogeneic bone marrow transplant •Molecular therapy - Imatinib

24. CML- CP survival post BMT (IBMTR 1994-1999) Years Probability %

25. Issues related to BMT • 70% long term cure rate • Donor Availability • Age of patient • Length/stage of disease • Treatment related mortality • Long term sequalae – infertility, cGVHD

26. The Ideal Target for Molecular Therapy  Present in the majority of patients with a specific disease  Determined to be the causative abnormality  Has unique activity that is - Required for disease induction - Dispensable for normal cellular function

27. Mechanism of Action of Imatinib Goldman JM. Lancet. 2000;355:1031-1032. Bcr-Abl ATP Substrate Imatinib Y = Tyrosine P = Phosphate Bcr-Abl Substrate P P P P

28. Imatinib compared with interferon and low dose Cytarabine for newly diagnosed chronic-phase Chronic Myeloid leukemia S.G. O’Brien et al New England Journal of Medicine Vol. 348 March 2003

29. Imatinib vs Interferon in newly diagnosed CP Chronic Myeloid leukemia (18 months) CHR 96% 67% MCR 83% 20% CCR 68% 7% Intolerance 0.7% 23% Progressive 1.5% 7% disease Imatinib 400mg Interferon and Ara-C

30. Evolution of treatment goals HR MCR CCR PCR - HU IFN Imatinib BMT

31. Issues related to Imatinib • Very few molecular responses (5-10%) • Resistance in some patients • Lack of response in some patients • Expensive • Long term toxicity/side effects unknown

32. CML Diagnosis Young with a well-matched donor Start Imatinib at 400mg/day Cosider for Allograft Allo SCT Poor response or Initial response Followed by Loss of response Add or substitute Other agents Allo-SCT Auto Good response maintained Continue Imatinib indefinitely

33. Polycythemia  True / Absolute  Primary Polycythemia  Secondary Polycythemia  Epo dependent  Hypoxia dependent  Hypoxia independent  Epo independent  Apparent / Relative  Reduction in plasma volume

34. POLYCYTHEMIA VERA  Chronic, clonal myeloproliferative disorder characterized by an absolute increase in number of RBCs  2-3 / 100000  Median age at presentation: 55-60  M/F: 0.8:1.2

35. POLYCYTHEMIA VERA JAK2 Mutation  JAK/STAT: cellular proliferation and cell survival  deficiency in mice at embryonic stage is lethal due to the absence of definitive erythropoiesis  Abnormal signaling in PV through JAK2 was first proposed in 2004  a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) in the majority of PV patients

36. Polycythaemia vera (Polycythaemia rubra vera)  Definition of polycythemia  Raised packed cell volume (PCV / HCT)  Male > 0.51 (50%)  Female > 0.48 (48%)  Classification  Absolute  Primary proliferative polycythaemia (polycythaemia vera)  Secondary polycythaemia  Idiopathic erythrocytosis  Apparent  Plasma volume or red cell mass changes

37. Polycythaemia vera (Polycythaemia rubra vera)  Polycythaemia vera is a clonal stem cell disorder characterised by increased red cell production  Abnormal clones behave autonomous  Same abnormal stem cell give rise to granulocytes and platelets  Disease phase  Proliferative phase  “Spent” post-polycythaemic phase  Rarely transformed into acute leukemia

38. Polycythaemia vera (Polycythaemia rubra vera)  Clinical features  Age  55-60 years  May occur in young adults and rare in childhood  Majority patients present due to vascular complications  Thrombosis (including portal and splenic vein)  DVT  Hypertension  Headache, poor vision and dizziness  Skin complications (pruritus, erythromelalgia)  Haemorrhage (GIT) due to platelet defect

39. Polycythaemia vera (Polycythaemia rubra vera)  Hepatosplenomegaly  Erythromelalgia  Increased skin temp  Burning sensation  Redness Liver 40% Spleen 70% Erythromelalgia

40. Polycythaemia vera (Polycythaemia rubra vera)  Laboratory features and morphology  Hb, PCV (HCT), and Red cell mass increased  Increased neutrophils and platelets  Normal NAP  Plasma urate high  Circulation erythroid precursors  Hypercellular bone marrow  Low serum erythropoietin Bone marrow in PV

41. Polycythaemia vera (Polycythaemia rubra vera)  Treatment  To decrease PVC (HCT)  Venesection  Chemotherapy  Treatment of complications

42. Clinical features  Plethora  Persistent leukocytosis  Persistent thrombocytosis  Microcytosis secondary to iron deficiency  Splenomegaly  Generalized pruritus (after bathing)  Unusual thrombosis (e.g., Budd-Chiari syndrome)  Erythromelalgia (acral dysesthesia and erythema)

43. Clinical features  Hypertention  Gout  Leukaemic transformation  Myelofibrosis

44. Diagnostic Criteria A1 Raised red cell mass A2 Normal O2 sats and EPO A3 Palpable spleen A4 No BCR-ABL fusion B1 Thrombocytosis >400 x 109/L B2 Neutrophilia >10 x 109/L B3 Radiological splenomegaly B4 Endogenous erythroid colonies A1+A2+either another A or two B establishes PV

45. Treatment  The mainstay of therapy in PV remains phlebotomy to keep the hematocrit below 45 percent in men and 42 percent in women  Additional hydroxyurea in high-risk pts for thrombosis (age over 70, prior thrombosis, platelet count >1,500,000/microL, presence of cardiovascular risk factors)  Aspirin (75-100 mg/d) if no CI  IFNa (3mu three times per week) in patients with refractory pruritus, pregnancy  Anagrelide (0.5 mg qds/d) is used mainly to manage thrombocytosis in patients refractory to other treatments.  Allopurinol

46. Causes of secondary polycythemia  ERYTHROPOIETIN (EPO)-MEDIATED  Hypoxia-Driven  Chronic lung disease  Right-to-left cardiopulmonary vascular shunts  High-altitude habitat  Chronic carbon monoxide exposure (e.g., smoking)  Hypoventilation syndromes including sleep apnea  Renal artery stenosis or an equivalent renal pathology  Hypoxia-Independent (Pathologic EPO Production)  Malignant tumors  Hepatocellular carcinoma  Renal cell cancer  Cerebellar hemangioblastoma  Nonmalignant conditions  Uterine leiomyomas  Renal cysts  Postrenal transplantation  Adrenal tumors

47. Causes of secondary polycythemia  EPO RECEPTOR–MEDIATED  Activating mutation of the erythropoietin receptor  DRUG-ASSOCIATED  EPO Doping  Treatment with Androgen Preparations

48. Secondary polycythaemia  Polycythaemia due to known causes  Compensatory increased in EPO  High altitude  Hulmonary diseases  Heart dzs eg- cyanotic heart disease  Abnormal hemoglobin- High affinity Hb  Heavy cigarette smoker  Inappropriate EPO production  Renal disease-carcinoma, hydronephrosis  Tumors-fibromyoma and liver carcinoma

49. Secondary polycythaemia  Arterial blood gas  Hb electrophoresis  Oxygen dissociation curve  EPO level  Ultrasound abdomen  Chest X ray  Total red cell volume(51Cr)  Total plasma volume(125 I- albumin)

50. Relative polycythaemia  Apparent polycythaemia or pseudopolycythaemia due to plasma volume contraction  Causes  Stress  Cigarette smoker or alcohol intake  Dehydration  Plasma loss- burn injury

51. Differentiation of PV, Secondary PV and Relative Erythrocytosis Features PV 2ndary PV Rel. Erythro organomegaly present absent absent O2 Sat Normal Dec. Normal RBC mass Inc Inc Normal EPO Dec Inc Normal WBC Inc Normal Normal

52. Essential Thrombocytosis  Clonal stem cell disorder characterized by marked thrombocytosis and abnormal platelet function  Plt count 600-2500 X 109/L  Abnormal plt aggregation studies

53. Essential Thrombocythaemia (ET)  Clonal MPD  Persistent elevation of Plt>600 x109/l  Poorly understood  Lack of positive diagnostic criteria  2.5 cases/100000  M:F 2:1  Median age at diagnosis: 60, however 20% cases <40yrs

54. Clinical Features  Vasomotor  Headache  Lightheadedness  Syncope  Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth)  Transient visual disturbances (eg, amaurosis fujax, scintillating scotomata, ocular migraine)  Thrombosis and Haemorrhage  Transformation

55. Investigations ET is a diagnosis of exclusion  Rule out other causes of elevated platelet count

56. Diagnostic criteria for ET  Platelet count >600 x 109/L for at least 2 months  Megakaryocytic hyperplasia on bone marrow aspiration and biopsy  No cause for reactive thrombocytosis  Absence of the Philadelphia chromosome  Normal red blood cell (RBC) mass or a HCT <0.48  Presence of stainable iron in a bone marrow aspiration  No evidence of myelofibrosis  No evidence of MDS

57. Therapy of ET based on the risk of thrombosis

58. Essential thrombocythaemia Primary thrombocytosis / idiopathic thrombocytosis  Clonal myeloproliferative disease of megakaryocytic lineage  Sustained thrombocytosis  Increase megakaeryocytes  Thrombotic or/and haemorrhage episodes  Positive criteria  Platelet count >600 x 109/L  Bone marrow biopsy; large and increased megas.

59. Essential thrombocythaemia Primary thrombocytosis / idiopathic thrombocytosis  Criteria of exclusion  No evidence of Polycythaemia vera  No evidence of CML  No evidence of myelofibrosis (CIMF)  No evidence of myelodysplastic syndrome  No evidence of reactive thrombocytosis  Bleeding  Trauma  Post operation  Chronic iron def  Malignancy  Chronic infection  Connective tissue disorders  Post splenectomy

60. Essential thrombocythaemia Primary thrombocytosis / idiopathic thrombocytosis  Clinical features  Haemorrhage  Microvascular occlusion  TIA, gangrene  Splenic or hepatic vein thrombosis  Hepatosplenomegaly

61. Essential thrombocythaemia Primary thrombocytosis / idiopathic thrombocytosis  Treatment  Anticoagulant  Chemotherapy  Role of aspirin  Disease course and prognosis  25 % develops myelofibrosis  Acute leukemia transformation  Death due to cardiovascular complication

62. Agnogenic Myeloid Metaplasia  Stem cell mutation causes hematopoietic abnormalities  Extramedullary hematopoiesis  BM fibrosis:uncontrolled production of fibroblasts from degenerating platelets result in dense thread-like scar tissue: dry BM tap  Differences from CML  LAP inc., Ph neg, nRBC, splenomegaly, tear drop cell

63. Myelofibrosis

64. Myelofibrosis  Myeloproliferative disorder (monoclonal stem cell disorder) in which increased marrow fibrosis is dominant feature  Rare  50-70 yrs  Clinical: fatigue, weakness, malaise, fever/night sweats, abdominal pain, anorexia/wt loss, nasuea/vomiting  May be primary or secondary (breast cancer, prostate cancer, Hodgkin's disease, non-Hodgkin's lymphoma, autoimmune diseases)  Hematopoietic stem cells grow out of control, producing both immature blood cells and excess fibrous tissue—replacing normal marrow

65. Myelofibrosis  Extramedullary hematopoeisis—hepatic and splenic enlargement, thoracic paravertebral masses  Bones  Uniform or heterogeneous increased density  Spine (“sandwich sign” or diffuse density), pelvis, skull, ribs, proximal femur/humerus  Cortical thickening in long bones  Decreased T1 and T2 marrow signal  Bone marrow bx needed to confirm dz  Progressive bone marrow failure = severe anemia / thrombocytopenia/leukopenia  risk of bleeding/infection  Slowly progressive dz leading to death  No available tx to effectively reverse progression; possible cure with bone marrow or stem cell transplantation (significant risks)

66. Myelofibrosis Chronic idiopathic myelofibrosis  Progressive fibrosis of the marrow & increase connective tissue element  Agnogenic myeloid metaplasia  Extramedullary erythropoiesis  Spleen  Liver  Abnormal megakaryocytes  Platelet derived growth factor (PDGF)  Platelet factor 4 (PF-4)

67. Myelofibrosis Chronic idiopathic myelofibrosis  Insidious onset in older people  Splenomegaly- massive  Hypermetabolic symptoms  Loss of weight, fever and night sweats Myelofibrosis Chronic idiopathic myelofibrosisc  Bleeding problems  Bone pain  Gout  Can transform to acute leukaemia in 10-20% of cases

68. Myelofibrosis Chronic idiopathic myelofibrosis  Anaemia  High WBC at presentation  Later leucopenia and thrombocytopenia  Leucoerythroblastic blood film  Tear drops red cells  Bone marrow aspiration- Failed due to fibrosis  Trephine biopsy- fibrotic hypercellular marrow  Increase in NAP score

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