Targeting myeloproliferative neoplasms with JAK inhibitors.
OBJECTIVE
The discovery of JAK2V617F and other JAK-STAT-activating mutations in BCR-ABL1-negative myeloproliferative neoplasms (MPN) has led to the development of small-molecule ATP-mimetics that inhibit wild-type and mutant JAK. Here, we review the current experience with JAK inhibitors used for the treatment of myelofibrosis and polycythemia vera/essential thrombocythemia.


RESULTS
Consistent with the clonal complexity of MPN, JAK inhibitors have not thus far shown disease-modifying activity; treatment with these agents has however shown clinically meaningful benefits, particularly decreased splenomegaly and improvement in constitutional symptoms, in myelofibrosis patients. Although these benefits accrue with both JAK-2 (TG101348) and JAK-1/2 (INCB018424, CYT387) inhibitors, the mode of action (predominant anticlonal versus anticytokine activity) may be different between the two groups. It is possible that an optimal balance between JAK-1-inhibitory and JAK-2-inhibitory activities may broaden the therapeutic activity (i.e. anemia improvement), as has been preliminarily seen (CYT387).


CONCLUSIONS
Although JAK inhibitors have important benefits in myelofibrosis therapy, their role in polycythemia vera/essential thrombocythemia treatment is still being defined. The optimal dosing strategy and feasibility for combination with other therapeutic agents remains to be established. Another challenge is the identification of robust primary end-points that will support labeling claims for JAK inhibitors for the aforementioned indications.
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. Pardanani.animesh@mayo.edu
Animesh
A
Pardanani
Ayalew
A
Tefferi
D001549:Benzamides / Q000627:therapeutic use; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics; D009570:Nitriles; D011087:Polycythemia Vera / Q000188:drug therapy; D055728:Primary Myelofibrosis / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D013920:Thrombocythemia, Essential / Q000188:drug therapy; D000096926:Benzenesulfonamides
D001549:Benzamides; D053614:Janus Kinase 2; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; C540383:ruxolitinib; C507924:JAK2 protein, human