MYELOPROLIFERATIVE DISORDERS EVOLVING CONCEPTS
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Transcript of MYELOPROLIFERATIVE DISORDERS EVOLVING CONCEPTS
MYELOPROLIFERATIVE DISORDERS EVOLVING CONCEPTS
ANTONIO PARREIRAIPOFG - LISBOA
MPD- PV
- ET
- MF
MDS- RA
- RARS
- RAEB – I
- RAEB - II
CMML
CML
AML
Neoplastic Myeloid disorders
1950
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
• Red cells - Polycythemia Rubra Vera – PV
• White cells - Chronic Myeloid Leukemia – CML
• Platelets- Essential Thrombocytemia – ET
• Stroma - Idiopathic Myelofibrosis - IM
Myeloproliferative disorders - MPD
Chronic Myeloid Leukemia15-20% of adult leukemia (1.6/100000)
Increased WBC
Nowell & Ungeford. J Nat Cancer Inst, 1960
David Hungeford
1973. Rowley J. Nature. 1973 Jun 1;243(5405):290-3.
CML was the first human malignancy shown to be ‘due’ to acquisition CML was the first human malignancy shown to be ‘due’ to acquisition
of a fusion protein with activated tyrosine kinase activityof a fusion protein with activated tyrosine kinase activity
ALTERED ADHESION
APTOPTOSIS INHIBITION
MITOGENIC ACTIVATION -
PROLIFERATION
“Blast” crisis(acute leukemia – AML, ALL)
Diag 1 2 3 4 5
Chronic phase
Acceleratedphase
Death
Chronic Myeloid Leukemia – clinical evolution
years
Clonal evolution
Ren R. NATURE REVIEWS | CANCER VOLUME 5 | MARCH 2005
1960 1973 1986 1996 2001
t(9;22)# Ph
Imatinib in vitro
Imatinib therapy
Clinical examination and morphology
Cytogenetics
PCR/interphase cytogenetics
Bcr-Abl
Morphology Molecular lesion Pathophysiology Rational treatment
50 years
New TK inhibitors
46,XY,t(9;22)(q34;q11)
IRIS Trial Results: Cumulative Best Responseat 12 and 60 Months
Adapted from: Druker B et al. ASCO 2006. Abstract 6506.
% r
esp
on
din
g
Months since randomisation to imatinib
57 y ♀ pt, Ph+ CML in chronic phase
BCR-ABL Real-time quantitative PCR follow-up
0,001
0,01
0,1
1
10
100
0 6 18 24 26 29 38 41 45 48 50
Months from diagnosis
% B
CR
-AB
L t
ran
scri
pts
GLIVEC 400 mg
GLIVEC 600 mg
E255V DASATINIB 140 mg/day
IPOFG 2006
Adapted from Campbell and Green, NEJM, 2006;355,2452
Historical perspective of Ph-negative Myeloproliferative Disorders
1892- 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.
Campbell P and Green A. N Engl J Med 2006;355:2452-2466
Laboratory Features of Polycythemia Vera, Essential Thrombocythemia, and Idiopathic Myelofibrosis
Polycythemia
● True / Absolute– Primary Polycythemia– Secondary polycythemia
● Epo dependent– Hypoxia dependent– Hypoxia independent
● Epo independent– Apparent / Relative
● Reduction in plasma volume
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
Polycythemia Rubra Vera - PV
● 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
Diag criteria
Essential Thrombocythemia - ET
Clonal MPD
Platelets persistently > 600
Lack of positive diagn criteria
2.5 / 100.000
M/F: 2:1
Median age diagn: 60
Transformation
Headache, lightheadness
Syncope
Erythromelalgia (burning hands and feet wih erythema)
Transient visual disturbancies
Thrombosis and haemorrhage
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
JAK2 V617F MUTATION
•The mutation leads to the constitutive activation of the JAK2 tyrosine kinase
• JAK2 protein is a cytoplasmic tyrosine kinase
AAT TAT GGA GTA TGT GTC TGT GGA GAC GAG
wild type
mutant
617 codon
valine
phenylalanine
AAT TAT GGA GTA TGT TTC TGT GGA GAC GAG
•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).
• 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).
Campbell P and Green A. N Engl J Med 2006;355:2452-2466
Campbell P and Green A. N Engl J Med 2006;355:2452-2466
Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation
Kralovics R et al. N Engl J Med 2005;352:1779-1790
Possible Roles of the JAK2 V617F Mutation in Myeloproliferative Diseases
Incidence of JAK2 V617F mutation in MPD
Polycythemia Vera 90 - 95% 25 - 30%
Essential Thrombocytemia 35 – 50% 1 – 3 %
Idiopathic Myelofibrosis 50 – 60% 10 – 29%
JAK2 homozygosityJAK2 mutation
Ross and Wernig, Hematology 2006
Campbell P and Green A. N Engl J Med 2006;355:2452-2466
Classification of the Myeloproliferative Disorders on the Basis of Molecular Pathogenetic Characteristics
JAK2 exon 12 mutations
Scott et al, 2007
Diagnostic algorithm for suspected PV in routin clinical practice – Tefferi, ASH 2006
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