The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes
Two Janus kinase inhibitors (JAKi), ruxolitinib and, more recently, fedratinib, have been approved for treating intermediate-risk and high-risk myelofibrosis (MF). Clinical trials have shown that these drugs can improve spleen volume, alleviate disease symptoms, and enhance quality of life. However, these JAKi therapies are often discontinued due to adverse events or disease progression, and there is a lack of established overall survival benefits and clinical or molecular predictors of response for this patient group, which faces a high disease burden and limited treatment options. Notably, outcomes after discontinuing JAKi are generally poor, with survival times after ruxolitinib discontinuation ranging from 11 to 16 months in various studies.
To address this significant unmet need, several non-JAKi agents are being investigated in phase 3 clinical trials. These agents include pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). These trials are exploring the potential of these therapies both as monotherapies in JAKi-pretreated patients and in combination with ruxolitinib in first-line or salvage settings. The results from these studies are anticipated to shed light on whether non-JAKi treatments can alter the progression of MF.