The role of JAK2 inhibitors in MPN seven years after approval

Francesco Passamonti and Margherita Maffioli


Myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera (PV) and primary myelofibrosis (PMF). Phenotype-driver mutations of JAK2, CALR and MPL genes are present in MPNs and can be variably combined with additional mutations. Driver mutations entail a constitutive activation of the JAK2/STAT pathway, the key signaling cascade in MPNs. Among JAK2 inhibitors (JAKis), ruxolitinib (RUX) has been approved for the treatment of intermediate and high risk myelofibrosis (MF) and of PV inadequately controlled by or intolerant of hydroxyurea. Other JAKis, such as fedratinib, pacritinib proved to be useful in MF. The primary endpoints in MF trials were spleen volume response (SVR) and symptom response, whereas in PV trials they were hematocrit control with/without spleen response. In advanced MF, RUX achieved a SVR of more than 35% in around 60% of patients and is long lasting, establishing a new benchmark for MF treatment. RUX efficacy in early MF is also remarkable and toxicity is mild. In PV, hematocrit control was achieved with RUX in approximately 60% of the cases and SVR in 40%. Symptom relief was evident in both conditions. In the long term however, many MF patients lose their SVR. Indeed, the definition of RUX-failure and the design of new trials in this setting are unmet needs. Decrease of hemoglobin/platelet levels and increased infection rates are the most common side effects of RUX, and non-melanoma skin tumors need to be monitored while on treatment. In conclusion, the introduction of JAKis raises the bar of treatment goals in MF and PV.

  • Submitted January 11, 2018.
  • Accepted April 7, 2018.