Janus kinase inhibitors for the treatment of myeloproliferative neoplasms.
BACKGROUND
Disordered signaling through the JAK/STAT pathway is a hallmark of myeloproliferative neoplasms (MPNs). Targeted therapies that inhibit and regulate this pathway are reasonable strategies for disease management. Only one JAK1/JAK2 inhibitor has gained FDA approval for treatment of myelofibrosis. Despite significant reductions in splenomegaly and disease-associated symptoms, additional agents are necessary to manage disease in those that do not respond.


METHODS
A review of the currently available literature and meeting abstracts for JAK inhibitors in myeloproliferative neoplasms identified studies aimed at improving outcomes and establishing alternative therapies in MPNs. Development of specific JAK inhibitors and ongoing trials involving ruxolitinib, CYT387, SAR302503, CEP701, SB 1518, XL-019, LY2784544, BMS-911453, NS-018, AZD1480 and INCB039110 are reviewed.


CONCLUSIONS
The identification of JAK2V617F mutation and its link to MPNs has revolutionized treatment options. Resultant research in targeting the JAK/STAT pathway led to the approval of ruxolitinib, a JAK1/JAK2 inhibitor with activity in MPNs. While ruxolitinib produces durable reductions in splenomegaly and improvement of symptoms, and prolongs survival, there is room for new and more specific agents to be developed. Minimizing toxicity and avoiding drug resistance are challenges that lie ahead. Combining agents with different mechanisms seems to be a rational strategy.
Mayo Clinic, Division of Hematology and Medical Oncology , Arizona , USA.
Allison
A
Rosenthal
Ruben A
RA
Mesa
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D053612:Janus Kinases
JAK2; Janus kinase; essential thrombocytosis; myelofibrosis; myeloproliferative neoplasm; polycythemia vera