Making a case for disease-modifying agents in myelofibrosis

Abstract

JAK inhibitors are currently the cornerstone of non-transplantation treatment strategies in intermediate and high-risk myelofibrosis. 1 National Comprehensive Cancer NetworkNCCN clinical practice guidelines in oncology — myeloproliferative neoplasms, version 2. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdfDate: 2022 Date accessed: May 9, 2022 Google Scholar Ruxolitinib, the first approved JAK inhibitor in this setting, rapidly reduces splenomegaly and controls symptoms in a substantial proportion of patients, 2 Harrison C Kiladjian J-J Al-Ali HK et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366: 787-798 Crossref PubMed Scopus (1280) Google Scholar , 3 Verstovsek S Mesa RA Gotlib J et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012; 366: 799-807 Crossref PubMed Scopus (1407) Google Scholar alongside conferring a survival benefit that seems to occur in the absence of a consistent disease-modifying ability. 4 Harrison CN Vannucchi AM Kiladjian JJ et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016; 30: 1701-1707 Crossref PubMed Scopus (284) Google Scholar However, high discontinuation rates by the third year of treatment and dismal outcomes of patients after stopping ruxolitinib 5 Newberry KJ Patel K Masarova L et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017; 130: 1125-1131 Crossref PubMed Scopus (135) Google Scholar underline the need for effective second-line treatments and, ideally, for improved front-line options. Fedratinib and pacritinib, two JAK inhibitors recently approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis regardless of previous JAK inhibitor exposure, will probably only partially fill the second-line therapeutic gap. 6 Harrison CN Schaap N Vannucchi AM et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017; 4: e317-e324 Summary Full Text Full Text PDF PubMed Scopus (168) Google Scholar , 7 Mascarenhas J Hoffman R Talpaz M et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018; 4: 652-659 Crossref PubMed Scopus (140) Google Scholar Multiple molecules are currently being tested, either alone or in combination, in patients with previous exposure to JAK inhibitors, and some of these experimental drugs are in more advanced phases of development. The appendix describes selected (ie, non-JAK inhibitor monotherapy), ongoing second-line phase 3 trials in patients with myelofibrosis, and highlights the heterogeneity of inclusion criteria with respect to previous JAK inhibitor exposure, deriving from the absence of both reliable predictive biomarkers and of well-defined response criteria to JAK inhibitors associated with clinically relevant endpoints. The recent “Response to Ruxolitinib After 6 Months” model 8 Maffioli M Mora B Ball S et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022; 6: 1855-1864 Crossref PubMed Scopus (8) Google Scholar identifies predictors of survival after 6 months of ruxolitinib treatment, including spleen length reduction, red blood cell transfusion requirement, and ruxolitinib dose intensity, and will hopefully facilitate the harmonisation of second-line trial inclusion criteria. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 studyThese biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy. Full-Text PDF