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MYELOPROLIFERATIVE DISORDERS EVOLVING CONCEPTS

MYELOPROLIFERATIVE DISORDERS EVOLVING CONCEPTS. ANTONIO PARREIRA IPOFG - LISBOA. Neoplastic Myeloid disorders. MPD - PV - ET - MF. AML. CML. CMML. MDS - RA - RARS - RAEB – I - RAEB - II. 1950. Myeloproliferative disorders - MPD.

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MYELOPROLIFERATIVE DISORDERS EVOLVING CONCEPTS

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  1. MYELOPROLIFERATIVE DISORDERS EVOLVING CONCEPTS ANTONIO PARREIRA IPOFG - LISBOA

  2. Neoplastic Myeloid disorders MPD - PV - ET - MF AML CML CMML MDS - RA - RARS - RAEB – I - RAEB - II

  3. 1950

  4. Myeloproliferative disorders - MPD • Neoplastic (clonal) disorders of hematopoietic stem cells • Dysregulated proliferation of one / several cell lineages • Thrombotic and hemorrhagic complications • Fibrosis is frequent • Progression to AML may occur

  5. Red cells - Polycythemia Rubra Vera – PV White cells - Chronic Myeloid Leukemia – CML Platelets - Essential Thrombocytemia – ET Stroma - Idiopathic Myelofibrosis - IM Myeloproliferative disorders - MPD

  6. Chronic Myeloid Leukemia 15-20% of adult leukemia (1.6/100000) Increased WBC

  7. Nowell & Ungeford. J Nat Cancer Inst, 1960 David Hungeford

  8. 1973. Rowley J. Nature. 1973 Jun 1;243(5405):290-3. CML was the first human malignancy shown to be ‘due’ to acquisition of a fusion protein with activated tyrosine kinase activity

  9. ALTERED ADHESION MITOGENIC ACTIVATION - PROLIFERATION APTOPTOSIS INHIBITION

  10. Chronic Myeloid Leukemia – clinical evolution “Blast” crisis (acute leukemia – AML, ALL) Death Accelerated phase Chronic phase Clonal evolution Diag 1 2 3 4 5 years

  11. Ren R. NATURE REVIEWS | CANCER VOLUME 5 | MARCH 2005

  12. t(9;22) # Ph 50 years Morphology Molecular lesion Pathophysiology Rational treatment Bcr-Abl Imatinib in vitro Imatinib therapy New TK inhibitors 1960 1973 1986 1996 2001 Clinical examination and morphology Cytogenetics PCR/interphase cytogenetics 46,XY,t(9;22)(q34;q11)

  13. 57 y ♀ pt, Ph+ CML in chronic phase BCR-ABL Real-time quantitative PCR follow-up GLIVEC 400 mg DASATINIB 140 mg/day E255V GLIVEC 600 mg IPOFG 2006

  14. Historical perspective of Ph-negative Myeloproliferative Disorders • - First description of PV • 1951 – PV, ET, IM linked as related disorders • 1974 - Identification of EPO-independent erythroid colonies • 1976 – Stem-cell origin of PV • 1983-2003 – Dysregulated tyrosine kinases described in CML, CMML, Chronic eosinophilic leukemia and mastocytosis • 2002 – Mitotic recombination of chromosome 9p as common lesion in PV • 2001-2004 – EPO independent growth in PV dependent on JAK-STAT signaling • 2005 – Description of JAK2 V617F mutation. Adapted from Campbell and Green, NEJM, 2006;355,2452

  15. Laboratory Features of Polycythemia Vera, Essential Thrombocythemia, and Idiopathic Myelofibrosis Campbell P and Green A. N Engl J Med 2006;355:2452-2466

  16. Polycythemia • True / Absolute • Primary Polycythemia • Secondary polycythemia • Epo dependent • Hypoxia dependent • Hypoxia independent • Epo independent • Apparent / Relative • Reduction in plasma volume

  17. Polycythemia Rubra Vera - PV Diag criteria Absolute increase in RBCs, leukocytosis, trhombocytosis • 2-3 / 100.000 • Median age of presentation – 55-70; M/F: 1.2 • Plethora, generalized pruritus, unusual thrombosis, gout • Splenomegaly • A1 – raised red cell mass • A2 - Normal O2 sat and low EPO • A3 – palpable spleen • A4 – No BCR-ABL fusion • B1 – Thrombocytosis > 400 • B2 – Neutrophilia > 10 • B3 – Radiological splenomegaly • B4 – Endogenous erythroid colonies • A1+A2+ either one A or two B

  18. Essential Thrombocythemia - ET Headache, lightheadness Syncope Erythromelalgia (burning hands and feet wih erythema) Transient visual disturbancies Thrombosis and haemorrhage Clonal MPD Platelets persistently > 600 Lack of positive diagn criteria 2.5 / 100.000 M/F: 2:1 Median age diagn: 60 Transformation

  19. Idiopathic myelofibrosis - IM Normocytic anemia, poikilocytosis • Low WBC / Platelets • Hepatosplenomegaly • Extramedulllary hematopoesis • BM fibrosis • Rare, M/F: 2:1 • Median age diagn: 60 • Transformation agnogenic myeloid metaplasia or myelofibrosis with myeloid metaplasia

  20. wild type 617 codon AAT TAT GGA GTA TGT GTC TGT GGA GAC GAG valine mutant AAT TAT GGA GTA TGT TTC TGT GGA GAC GAG phenylalanine JAK2 V617F MUTATION • JAK2 protein is a cytoplasmic tyrosine kinase • A single point mutation (G T) in the JH2 pseudokinase domain of the JAK2 gene • results in a valine to phenylalanine substitution at amino acid 617 (V617F). • The mutation leads to the constitutive activation of the JAK2 tyrosine kinase • Two independent studies in 2005 demonstrated that a significant proportion of patients with PV, ET and IM have acquired this somatic mutation (Baxter et al, Lancet 2005, Levine et al, Cancer Cell 2005).

  21. Campbell P and Green A. N Engl J Med 2006;355:2452-2466

  22. Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation Campbell P and Green A. N Engl J Med 2006;355:2452-2466

  23. Possible Roles of the JAK2 V617F Mutation in Myeloproliferative Diseases Kralovics R et al. N Engl J Med 2005;352:1779-1790

  24. Incidence of JAK2 V617F mutation in MPD Ross and Wernig, Hematology 2006 JAK2 mutation JAK2 homozygosity Polycythemia Vera 90 - 95% 25 - 30% Essential Thrombocytemia 35 – 50% 1 – 3 % Idiopathic Myelofibrosis 50 – 60% 10 – 29%

  25. Classification of the Myeloproliferative Disorders on the Basis of Molecular Pathogenetic Characteristics JAK2 exon 12 mutations Scott et al, 2007 Campbell P and Green A. N Engl J Med 2006;355:2452-2466

  26. Diagnostic algorithm for suspected PV in routin clinical practice – Tefferi, ASH 2006

  27. Diagnostic criteria of MPD JAK2 V617F + (proposed by Campbell and Green, 2006) JAK2+ Polycythemia (Diagn if both criteria) A1 High hematocrit (>52% M; >48% F) or increased red cell mass (>25% predicted value) A2 Mutation in JAK2 JAK2+ Thrombocytemia (Diagn if both criteria) A1 Platelet count > 450x10e9/L A2 Mutation in JAK2 A3 No other myeloid cancer, especially JAK2 PV, IM or MDS JAK2+ Myelofibrosis Diagn if A1 and A2 and any two of B criteria) A1 Reticulin grade 3 or higher A2 Mutation in JAK2 B1 Palpable spenomegaly B2 Otherwise unexplained anemia B3 Teardrop cells on peripheral blood smear B4 Leucoerythroblastic blood film B5 Systemic symptoms B6 Histological evidence of extramedullary hematopoiesis

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