Janus Kinase Inhibitors for myeloproliferative neoplasms and

other hematologic malignancies

Grerk Sutamtewagul, M.D.Internal Medicine Resident, PGY-2

Myeloid malignancies

WHO Classification 20081. Acute myeloid leukemia (AML)2. Myelodysplastic syndrome (MDS)3. Myeloproliferative neoplasm (MPN)4. MDS/MPN5. PDGFR-rearranged or FGFR-rearranged myeloid and

lymphoid neoplasms associated with eosinophilia

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 leukemia6. Chronic eosinophilic leukemia (NOS)7. Systemic mastocytosis8. MPN unclassifiable

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.

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

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.

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.

Janus kinases (JAKs)

Biology of MPNs

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

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

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.

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

Functional consequence of JAK2V617F

Functional consequence of JAK2V617F

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

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

JAK inhibitors and selectivity