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

• Published in: Cancer 2022-07, Vol.128 (14), p.2717-2727
• Main Authors: Mascarenhas, John O., Verstovsek, Srdan
• Format: Article
• Language: English
• Subjects: Animals; biomarkers; Chromosome 2; Clinical trials; Enzyme inhibitors; fedratinib; Health services; Humans; Inhibitor drugs; Janus Kinase 2; Janus kinase inhibitor; Janus Kinase Inhibitors - therapeutic use; Kinases; Lymphoma; Mice; Myelofibrosis; Oncology; Patients; Phosphatidylinositol 3-Kinases; Primary Myelofibrosis - pathology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-bcl-2; Quality of Life; Review; ruxolitinib; safety; Signs and symptoms; Spleen; Survival; Targeted cancer therapy; Telomerase; Telomerase inhibitors
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.34222

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. Janus‐associated kinase inhibitor (JAKi) agents improved spleen volume and symptoms in patients who had myelofibrosis but were associated with high discontinuation rates, a lack of predictors of response, and poor outcomes after discontinuation. Non‐JAKi agents, in combination with or subsequent to JAK agents, were being actively explored in phase 3 clinical trials.