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CML

William Dameshek, 1900-1969 BJH 111 (4), 1023-1034, 2000 . 1951. Classic Myeloproliferative disorders. CML. MF. ET. PV. Chronic myeloid disorders. Non-classic myeloproliferative disorders. Myelodysplastic syndrome. Classic myeloproliferative disorders. CMML JMML CNL CEL

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CML

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  1. William Dameshek, 1900-1969 BJH111 (4), 1023-1034, 2000 1951 Classic Myeloproliferative disorders CML MF ET PV

  2. Chronic myeloid disorders Non-classic myeloproliferative disorders Myelodysplastic syndrome Classic myeloproliferative disorders CMML JMML CNL CEL CBL HES SM UMPD BCR-ABL(-) BCR-ABL(+) CML MF ET PV

  3. Chronic Myeloid disorders PDGFRA/B mutations BCR-ABL FGFR1 mutations JAK2V617F KIT mutations JAK2 exon 12 mutations Ras pathway mutations MPLW515L/K Atypical myeloproliferative disorders Myelodysplastic syndrome Classic myeloproliferative disorders CMML JMML CNL CEL CBL HES SM UMPD BCR-ABL(-) BCR-ABL(+) CML MF ET PV

  4. JAK2V617F: Pathogenetic Observations • Causes PV-like disease in mice • Erythrocytosis, granulocytosis, but not thrombocytosis • Bone marrow and spleen trilineage hyperplasia, fibrosis, and EMH • EEC formation, Epo hypersensitivity, STAT5 activation • Transforms cell lines • Growth factor independence of factor dependent cell lines • Epo hypersensitivity • Induces constitutive JAK-STAT activation • JAK2 phosphorylation • STAT5 and STAT3 phosphorylation • Appears to be myeloid lineage-specific but affects primitive stem cells and NK cells might be involved • Not all clonal cells in human MPD necessarily carry the JAK2V617F allele

  5. JAK2V617F: Clinical Observations • Not seen in healthy persons, non-myeloid tissue from affected patients, or MPD patient relatives • Not seen in reactive myeloproliferation, solid tumor, or lymphoid malignancies • Affects a spectrum of molecularly undefined myeloid disorders; mutational frequency is… • 100% in PV • 50% in either ET or MMM • 20% in atypical MPD • < 5% in MDS or AML • Does not affect either survival or leukemic transformation • Controversial if it affects thrombosis risk • Associated with higher hemoglobin, WBC, and age

  6. Initial clonogenic event ? ? Unidentified mutation JAK2V617F Unidentified mutation Germline genetic variation Other interacting mutations PV MF ET Tefferi and Gilliland Cell Cycle, in press

  7. [671] A Phase-II-Study To Evaluate Efficacy and Safety of Imatinib in Eosinophilia-Associated Myeloproliferative Disorders and Idiopathic Hypereosinophilic Syndrome. Session Type: Oral Session • Background • Imatinib at low doses (100 mg/day) produces clinical and molecular responses in FIP1L1-PDGFRA-associated chronic eosinophilic leukemia and/or systemic mastocytosis • Methods • 35 total patients; 17 with FIP1L1-PDGFRA, 4 with PDGFRB-rearrangement, and 14 with HES • Median drug exposure 7 months (range 1-22) • Results • FIP1L-PDGFRA…CHR in 1 or 3 months was 59% and 100%; CMR in 3 or 6 months in 27% and 83%; • PDGFRB (400 mg/day)…median time to CHR 1.4 months (range 0.5-2) • HES…21% sustained hematologic PR/CR • Conclusion • Confirms activity in the presence of molecular targets and inefficacy in HES

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