The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Abstract

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including 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). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.

Keywords: Janus kinase inhibitor; biomarkers; fedratinib; myelofibrosis; ruxolitinib; safety; survival.

Figure 1

This is a forest plot of survival by patient subgroup in the COMFORT‐I trial. The red line represents the hazard ratio (HR) of the intent‐to‐treat (ITT) population, and the dashed line represents an HR of 1.0. The squares represent the HR and sample size for each subgroup, where the area of the square is proportional to the subgroup sample size. CI indicates confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IPSS, International Prognostic Scoring System; ITT, intention‐to‐treat; JAK, Janus‐associated kinase; PET‐MF, postessential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV‐MF, postpolycythemia vera myelofibrosis. Reproduced from: Verstovsek S, Mesa RA, Gotlib J, et al. The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo‐controlled, phase III study in patients with myelofibrosis. Br J Haematol. 2013;161:508‐516. © 2013 Wiley‐Blackwell.

Figure 2

A practical approach to therapy for patients with myelofibrosis (MF) is illustrated. AML indicates acute myeloid leukemia; IMiD, immunomodulatory drug; JAKi, Janus‐associated kinase inhibitor.