S86 EXABS-193-MPN Choosing and Properly Using a JAK Inhibitor in Myelofibrosis Colin A Vale, MD1, and Anthony M Hunter, MD1,* 1Winship Cancer Institute of Emory University, 1365 Clifton Rd, Atlanta, GA, 30322, USA *Corresponding author: anthony.michael.hunter@emory.edu Keywords Myeloproliferative neoplasm, ruxolitinib, pacritinib, fedratinib, momelotinib Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, and secretion of inflammatory cytokines. These features produce a clinical phenotype that variably includes hepatosplenomegaly, constitutional symptoms, cytopenias, and risk of transformation to acute myeloid leukemia. Activation of JAK-STAT signaling is the hallmark biologic feature of the disease, generally resulting from the presence of one of three “driver” mutations; namely JAK2, CALR, or MPL. The pivotal role of this pathway in disease pathogenesis makes it a key therapeutic target, and the development of Janus kinase inhibitors (JAKi) has indeed been a seminal advancement in MF therapy. Treatment selection in MF is impacted by multiple patient-specific and disease-specific factors, including presenting features and risk stratification, the latter incorporating both genetic information and clinical risk factors.1 Herein, we will review data regarding JAKi therapies in MF and describe strategies to ensure optimal utilization. Ruxolitinib, a JAK 1/2 inhibitor, was approved in 2011 by the U.S. Food and Drug Administration (FDA) based on results of the phase 3 COMFORT-1 and COMFORT-2 studies and remains a cornerstone of therapy. Both studies evaluated patients with intermediate-2 or high-risk MF and palpable splenomegaly, comparing ruxolitinib to placebo (COMFORT-1)2 or best available therapy (COMFORT-2).3 The key primary endpoint of reduction in spleen volume of ≥35% was achieved in both studies; 41.9% at 24 weeks in COMFORT-1 and 28% at week 48 in COMFORT-2. Symptom reductions were also seen, including 45.9% of ruxolitinib-treated patients achieving a ≥50% reduction in COMFORT-1. An overall survival (OS) benefit has also been reported in a pooled analysis of the COMFORT-1 and COMFORT-2 trials.4 Multiple real-world studies have also documented this benefit, including The European Registry for Myeloproliferative Neoplasms: Toward a Better Understanding of Epidemiology, Survival, and Treatment, which prospectively enrolled patients with MF. This study described an OS benefit by both multivariate and propensity score matching analysis in patients treated with ruxolitinib compared to hydroxyurea.5 Beyond the high-risk patients treated in the COMFORT studies, the JUMP study included patients with Intermediate-1 risk MF and similarly demonstrated clinical benefit in this lower risk group.6 While these studies established the ability of ruxolitinib to improve splenomegaly and symptom burden and prolong survival, anemia and thrombocytopenia can be challenging, particularly in patients with pre-existing cytopenias. Approximately one-third of patients had a dose modification or interruption during the first six months of therapy according to an analysis of ruxolitinib dosing patterns in the real-world setting.7 These dose adjustments were commonly due to cytopenias. Duration of therapy in the real-world setting is generally less than 2 years, with poor outcomes observed following treatment discontinuation. However, recent studies evaluating novel dosing strategies in cytopenic patients have demonstrated that delaying or withholding ruxolitinib due to co-existent or treatmentemergent anemia is typically unnecessary.8 Despite limitations, ruxolitinib remains a mainstay in MF therapy, including as a backbone for emerging combination approaches. The second JAKi to be FDA-approved, fedratinib is a selective JAK2 inhibitor. It was evaluated in higher-risk JAKi-naïve patients in the phase III JAKARTA trial, demonstrating improvements in splenomegaly (36%) and symptom burden (36%),9 which is similar to results seen with ruxolitinib. Importantly, the phase 2 JAKARTA210 study illustrated activity in the post-ruxolitinib setting with spleen response in 30% of patients stringently defined as resistant or intolerant to ruxolitinib, a population previously lacking effective therapies. Cytopenias are observed with this agent and gastrointestinal toxicity contributed to dose reductions or interruptions in more than 20% of patients, with diarrhea a particular challenge in clinical practice often requiring supportive therapy. Further, cases of encephalopathy were observed leading to a black-box warning. Thiamine levels should be checked at baseline and periodically, and repleted if low to minimize risk. The most recently FDA-approved agent in the JAKi toolbox, pacritinib is an inhibitor of JAK2 as well as IRAK1 and FMS-like tyrosine kinase 3 (FLT3). Importantly, pacritinib has demonstrated safety in MF patients with thrombocytopenia and has been approved specifically for patients with a platelet count of <50, expanding the potential benefit of JAKi to a group that was previously ineligible. Efficacy was illustrated in the PERSIST-1 and 2 studies. PERSIST-211 specifically enrolled patients with a platelet count of <100, and improvements in spleen response and symptom
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