Janus kinase inhibitors after ruxolitinib failure in myelofibrosis: A systematic review and pooled analysis of phase 3 efficacy and integrated safety across clinical trials and real-world evidence.
Key claim: After ruxolitinib failure in myelofibrosis, fedratinib, momelotinib, and pacritinib each have distinct spleen, symptom, and safety profiles that can guide second-line JAK inhibitor choice by clinical phenotype and prior adverse events.
Abstract
Ruxolitinib remains first-line standard of care for symptomatic myelofibrosis, but resistance/intolerance develops in most patients. Three Janus kinase inhibitors (JAKis) have entered the post-ruxolitinib space via distinct pivotal trials. We systematically searched prospective trials evaluating JAKi in refractory adults with myelofibrosis. Efficacy was assessed across phase 3 trials, with safety integrating phase 2 and real-world data. Pooled ≥35% spleen volume reduction at week 24 was 32.7% (95% confidence intervals 27.3-38.6) for fedratinib, 15.8% (11.7-21.0) for momelotinib and 21.6% (13.8-32.3) for pacritinib 200 mg bis in die; pooled ≥50% Total Symptom Score reduction rates were 32.8% (27.4-38.7), 25.3% (20.2-31.3) and 32.4% (22.9-43.7) respectively. Across safety datasets (n = 1004 trial; n = 790 real-world), fedratinib showed the highest grade ≥3 anaemia (34.3%) and any-grade diarrhoea (56.6%), whereas momelotinib the lowest (8.0%). Pacritinib carried the greatest risk of grade ≥3 bleeding (11.2%). Discontinuation due to adverse events was comparable across agents (~16%-17%). Real-world evidence from five momelotinib cohorts (n = 580) identified nephrotoxicity (glomerular filtration rate decline 17%-29%) and peripheral neuropathy (4%-20%) as monitoring targets. Despite limitations from differing study designs, each post-ruxolitinib JAKi shows a distinct efficacy/safety fingerprint mapping onto a phenotype, guiding second-line choice by clinical factors and prior adverse events.
Why this matters
Ruxolitinib failure is a defining inflection point in the natural history of PMF (and post-PV/post-ET MF), and until now comparative guidance across the three approved second-line JAK inhibitors has been indirect. This pooled phase-3 + real-world synthesis gives clinicians phenotype-matched fingerprints — pacritinib for severe thrombocytopenia, momelotinib for anemia/transfusion dependence, fedratinib for preserved counts — that operationalize sequencing decisions in the highest-mortality MPN subtype and anchor the comparator landscape for emerging JAKi-refractory agents (AJ1-11095, flonoltinib, selinexor, imetelstat).