Janus kinase inhibitors


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Janus kinase inhibitors

  1. 1. Janus Kinase Inhibitors for myeloproliferativeneoplasms and other hematologic malignancies Grerk Sutamtewagul, M.D. Internal Medicine Resident, PGY-2
  2. 2. Myeloid malignancies WHO Classification 2008 1. Acute myeloid leukemia (AML) 2. Myelodysplastic syndrome (MDS) 3. Myeloproliferative neoplasm (MPN) 4. MDS/MPN 5. PDGFR-rearranged or FGFR-rearranged myeloid and lymphoid neoplasms associated with eosinophilia
  3. 3. Myeloproliferative neoplasms • Distinguished from MDS, MDS/MPN by the absence of dyserythropoiesis, dysgranulopoiesis and monocytosis • 8 different entities 1. Chronic myeloid leukemia (BCR-ABL1-positive) 2. Polycythemia vera (PV) 3. Essential thrombocytopenia (ET) 4. Primary myelofibrosis (PMF) 5. Chronic neutrophilic leukemia 6. Chronic eosinophilic leukemia (NOS) 7. Systemic mastocytosis 8. MPN unclassifiable
  4. 4. Myeloproliferative neoplasms • Polycythemia vera • Increased red cell mass, low serum EPO • Trilineage proliferation and megakaryocyte pleomorphism in bone marrow • Essential thrombocytosis • High platelet counts, increased megakaryocyte mass • Primary myelofibrosis • Anemia, splenomegaly, leukoerythroblastosis, constitutional symptoms • Marked collagen and reticulin bone marrow fibrosis • Both 3 disorders can progress to AML and have tendency to develop thrombotic and hemorrhagic complications.
  5. 5. Standard therapy • Polycythemia vera • Low risk PV – phlebotomy to keep Hct < 45% (M) or < 42% (F) • High risk PV – Aspirin (improves microvascular complications: ocular migraine and erythromelalgia) • Hydroxyurea failed to prolong survival, prevent thrombotic event or progression to myelofibrosis but reduced TIA. • Essential thrombocytosis • Low risk ET – not require therapy • High risk ET – Hydroxyurea (cytoreductive agent, reduce thrombotic events) • Anagrelide (platelet lowering agent) was associated with increased arterial thrombosis, serious hemorrhage and transformation to myelofibrosis. • Aspirin for intermediate to high risk ET
  6. 6. Standard therapy • Primary myelofibrosis • Supportive treatment • Cytopenia: corticosteroids, danazol or erythropoietic stimulating agents • Splenomegaly: Hydroxyurea, spleen irradiation, splenectomy • Combination of lenalidomide and prednisone • Median survival 3-5 years • Curative option is allogeneic stem cell transplant.
  7. 7. Janus kinases (JAKs) • JAK family: JAK1, JAK2, JAK3, TYK2 • Associate with intracellular tails of cytokine receptors • Activate members of the signal transducer and activator of transcription (STAT) family of transcription factors  bind specific gene promotors that regulate proliferation and differentiation.
  8. 8. Janus kinases (JAKs)
  9. 9. Biology of MPNs
  10. 10. JAK2 • JAK2 is a tyrosine kinase engaging with multiple cytokine receptors: Erythropoietin receptor (EPOR), Thombopoietin receptor (TPOR also known as MPL), G-CSFR, GM-CSFR, IL-3R • Recurrent acquired somatic mutation Valine-to-Phenylalanine substitution at codon 617 of pseudokinase domain of JAK2 (JAK2V617F) • > 95% in PV • 32-57% in ET • 35-50% in PMF
  11. 11. JAK2 • PV • Homozygous (uniparental disomy) JAK2V617F as a consequence of mitotic recombination and duplication of JAK2V617F allele • JAK2V617F-negative PV have gain-of-function mutation at exon 12 of JAK2 and may cause similar structural change that result in JAK2 activation. • ET • JAK2 wild type or JAK2V617F heterozygous
  12. 12. Functional consequence of JAK2V617F • JAK2V617F mutation maps to the JH2 domain of JAK2. • JH2 domain has significant homology to JH1 but lacks catalytic activity, is believed to involve in autoinhibition of JAK2 activity. • Mutant JAK2V617F is constitutively activated, independent of (and also hypersensitive to) its ligand, e.g. EPO.
  13. 13. Functional consequence of JAK2V617F • Several signaling pathways are activated (canonical): • STAT3 and STAT5  dimerization and translocation to nucleus • Mitogen-activated protein kinase (MAPK) • Extracellular signal-regulated kinase (ERK) • Phosphoinositide 3-kinase (PI3K)-AKT pathway • Non-canonical pathway • Phosphorylation of histone H3 at tyrosine 41 • High mutant to wild-type JAK2 ratio  PV-like phenotype • Low mutant to wild-type JAK2 ratio  ET-like phenotype
  14. 14. Functional consequence of JAK2V617F
  15. 15. Functional consequence of JAK2V617F
  16. 16. JAK inhibitors • JAK inhibitors available now has different selectivity for the four members of JAK family of kinases. • Now there is no specific JAK2V617F inhibitor available due to lack of definite crystal structure of both wild type and mutated JAK2. • Ruxolitinib (INCB018424) • Potent inhibitor of JAK1 and JAK2 (wild type and mutated) • Moderate TYK2 inhibitor but no activity against JAK3 • Promising effect in Phase III clinical trial for PMF, secondary MF
  17. 17. JAK inhibitors • TG101348 • Inhibit JAK2 and JAK2V617F with higher selectivity • Good result in Phase II clinical trial • Lestaurtinib (also known as CEP-701) • Multikinase inhibitor, inhibit both JAK2 and JAK2V617F • Good result in Phase II study • XL019 • High selectivity against JAK2 compare to other JAKs • Good result in Phase I/II study but unacceptable neurological side effect • SB1518 • high selectivity against JAK2 and JAK2V617F compared with JAK1 or JAK3 • Has been shown to be active against Leukemia, lymphoma
  18. 18. JAK inhibitors and selectivity