J Berdeja1, F Palandri2, M R Baer3, D Quick4, J J Kiladjian5, G Martinelli2, A Verma6, O Hamid7, R Walgren7, C Pitou7, P L Li7, A T Gerds8. 1. Tennessee Oncology, 250 25th Ave N #412, Nashville, TN, 37203, USA. Electronic address: jberdeja@tnonc.com. 2. Institute of Hematology 'L. and A. Seràgnoli' S. Orsola-Malpighi Univeristy Hospital, Via Zamboni, 33, 40126, Bologna, Italy. 3. University of Maryland Greenebaum Comprehensive Cancer Center, 22S Greene Street, Baltimore, MD, 21201, USA. 4. Joe Arrington Cancer Research and Treatment Center, 4101 22nd Pl, Lubbock, TX, 79410, USA. 5. Hôpital Saint-Louis, AP-HP, INSERM CIC 1427, Université Paris Diderot, 1, Avenue Claude Vellefaux, 75010, Paris, France. 6. Albert Einstein College of Medicine, Montefiore Medical Center, 1300 Morris Park Avenue Chanin Building, Room 302B Bronx, NY, 10461, USA. 7. Eli Lilly and Company, Lilly Corporate Center Indianapolis, IN, 46285, USA. 8. Leukemia & Myeloid Disorders Program, Cleveland Clinic Taussig Cancer Insitute, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
Abstract
BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing. METHODS: A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug. FINDINGS: Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively. INTERPRETATIONS: LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a ≥50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score.
BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing. METHODS: A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug. FINDINGS: Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively. INTERPRETATIONS: LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a ≥50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score.
Authors: Yi Li; Lina Wei; Marie-Charlotte Meinsohn; Rana Suliman; Maeva Chauvin; Jim Berstler; Kate Hartland; Mark M Jensen; Natalie A Sicher; Nicholas Nagykery; Patricia K Donahoe; David Pepin Journal: Proc Natl Acad Sci U S A Date: 2022-04-05 Impact factor: 12.779
Authors: Angelina T Regua; Noah R Aguayo; Sara Abu Jalboush; Daniel L Doheny; Sara G Manore; Dongqin Zhu; Grace L Wong; Austin Arrigo; Calvin J Wagner; Yang Yu; Alexandra Thomas; Michael D Chan; Jimmy Ruiz; Guangxu Jin; Roy Strowd; Peiqing Sun; Jiayuh Lin; Hui-Wen Lo Journal: Cancers (Basel) Date: 2021-05-12 Impact factor: 6.639
Authors: Katrin Pansy; Barbara Uhl; Jelena Krstic; Marta Szmyra; Karoline Fechter; Ana Santiso; Lea Thüminger; Hildegard Greinix; Julia Kargl; Katharina Prochazka; Julia Feichtinger; Alexander Ja Deutsch Journal: Int J Mol Sci Date: 2021-12-10 Impact factor: 5.923