{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:46:54Z","timestamp":1793641614109,"version":"4.5.1"},"reference-count":17,"publisher":"American Medical Association (AMA)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2025,1,1]]},"abstract":"\n Importance<\/jats:title>\n Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome\u2013positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome\u2013positive ALL resistant or intolerant to at least 2 TKIs.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome\u2013positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Pharmacokinetic profile of olverembatinib.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators\u2019 assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and\/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT04260022<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaoncol.2024.5157","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T11:00:37Z","timestamp":1732186837000},"page":"28","source":"Crossref","is-referenced-by-count":37,"title":["Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib"],"prefix":"10.1001","volume":"11","author":[{"given":"Elias","family":"Jabbour","sequence":"first","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian G.","family":"Oehler","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B.","family":"Koller","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation in the Division of Leukemia, City of Hope National Medical Center, Duarte, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer","family":"Jamy","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elza","family":"Lomaia","sequence":"additional","affiliation":[{"name":"Research Department of Immuno-Oncology, Almazov Medical Research Centre, St Petersburg, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony M.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Uspenskaya","sequence":"additional","affiliation":[{"name":"Leningrad Regional Clinical Hospital, St Petersburg, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Samarina","sequence":"additional","affiliation":[{"name":"Kirov Scientific Research Institute of Hematology and Blood Transfusion of the FMBA, Kirov, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipto","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge E.","family":"Cortes","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Augusta University, Augusta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Baer","sequence":"additional","affiliation":[{"name":"University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Zherebtsova","sequence":"additional","affiliation":[{"name":"S.P. Botkin City Clinical Hospital, Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasily","family":"Shuvaev","sequence":"additional","affiliation":[{"name":"A. Tsyb Medical Radiological Research Center, Obninsk, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Turkina","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Davydkin","sequence":"additional","affiliation":[{"name":"Samara State Medical University, Samara, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanshan","family":"Guo","sequence":"additional","affiliation":[{"name":"Guangzhou Healthquest Pharma Co Ltd, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Chen","sequence":"additional","affiliation":[{"name":"Ascentage Pharma (Suzhou) Co Ltd, Suzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommy","family":"Fu","sequence":"additional","affiliation":[{"name":"Ascentage 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