{"title":"阿扎胞苷联合奎沙替尼治疗 FLT3 或 CBL 突变 MDS 和 MDS/MPN 患者的 1 期研究","authors":"Guillermo Montalban-Bravo , Elias Jabbour , Kelly Chien , Danielle Hammond , Nicholas Short , Farhad Ravandi , Marina Konopleva , Gautam Borthakur , Naval Daver , Rashmi Kanagal-Shammana , Sanam Loghavi , Wei Qiao , Xuelin Huang , Heather Schneider , Meghan Meyer , Hagop Kantarjian , Guillermo Garcia-Manero","doi":"10.1016/j.leukres.2024.107518","DOIUrl":null,"url":null,"abstract":"<div><p>We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with <em>FLT3</em> or <em>CBL</em> mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had <em>FLT3</em> mutations and 5 (42 %) had <em>CBL</em> mutations. The maximum tolerated dose was not reached. Most common grade 3–4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0–38.4 months) and 17.5 months (95 % CI NC-NC), respectively. <em>FLT3</em> mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in <em>FLT3</em>-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"142 ","pages":"Article 107518"},"PeriodicalIF":2.1000,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Phase 1 study of azacitidine in combination with quizartinib in patients with FLT3 or CBL mutated MDS and MDS/MPN\",\"authors\":\"Guillermo Montalban-Bravo , Elias Jabbour , Kelly Chien , Danielle Hammond , Nicholas Short , Farhad Ravandi , Marina Konopleva , Gautam Borthakur , Naval Daver , Rashmi Kanagal-Shammana , Sanam Loghavi , Wei Qiao , Xuelin Huang , Heather Schneider , Meghan Meyer , Hagop Kantarjian , Guillermo Garcia-Manero\",\"doi\":\"10.1016/j.leukres.2024.107518\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with <em>FLT3</em> or <em>CBL</em> mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had <em>FLT3</em> mutations and 5 (42 %) had <em>CBL</em> mutations. The maximum tolerated dose was not reached. Most common grade 3–4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0–38.4 months) and 17.5 months (95 % CI NC-NC), respectively. <em>FLT3</em> mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in <em>FLT3</em>-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.</p></div>\",\"PeriodicalId\":18051,\"journal\":{\"name\":\"Leukemia research\",\"volume\":\"142 \",\"pages\":\"Article 107518\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2024-05-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0145212624000845\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0145212624000845","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
我们开展了一项1期研究,评估了奎沙替尼与阿扎胞苷联用治疗HMA无效或复发/难治性MDS或FLT3或CBL突变的MDS/MPN的3种剂量水平(30毫克、40毫克或60毫克)。共有12名患者(HMA新药:9人,HMA失败:3人)入组;7名(58%)患者存在FLT3突变,5名(42%)患者存在CBL突变。未达到最大耐受剂量。最常见的3-4级治疗突发不良事件为血小板减少(5例,42%)、贫血(4例,33%)、肺部感染(2例,17%)、皮肤感染(2例,17%)、低钠血症(2例,17%)和败血症(2例,17%)。总反应率为83%,无复发中位生存期和总生存期分别为15.1个月(95% CI 0.0-38.4个月)和17.5个月(95% CI NC-NC)。57%(n=4)的患者清除了FLT3突变。这些数据表明喹沙替尼是安全的,而且在FLT3突变的MDS和MDS/MPN中显示出令人鼓舞的活性。该研究已在 Clinicaltrials.gov 登记为 NCT04493138。
Phase 1 study of azacitidine in combination with quizartinib in patients with FLT3 or CBL mutated MDS and MDS/MPN
We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3–4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0–38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.
期刊介绍:
Leukemia Research an international journal which brings comprehensive and current information to all health care professionals involved in basic and applied clinical research in hematological malignancies. The editors encourage the submission of articles relevant to hematological malignancies. The Journal scope includes reporting studies of cellular and molecular biology, genetics, immunology, epidemiology, clinical evaluation, and therapy of these diseases.