1. Janus Kinase Inhibitors for
myeloproliferativeneoplasms and
other hematologic malignancies
Grerk Sutamtewagul, M.D.
Internal Medicine Resident, PGY-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. 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. 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. 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. 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. 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.
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. 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. 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. 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
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. 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
