Redner Robert L, Beumer Jan H, Kropf Patricia, Agha Mounzer, Boyiadzis Michael, Dorritie Kathleen, Farah Rafic, Hou Jing-Zhao, Im Annie, Lim Seah H, Raptis Anastasios, Sehgal Alison, Christner Susan M, Normolle Daniel, Johnson Daniel E
a Cancer Therapeutics Program, UPMC Hillman Cancer Center , Pittsburgh , PA , USA.
b Division of Hematology-Oncology, Department of Medicine , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
Leuk Lymphoma. 2018 Nov;59(11):2595-2601. doi: 10.1080/10428194.2018.1443330. Epub 2018 Apr 4.
Src family kinases (SFKs) are hyperactivated in acute myeloid leukemia (AML). SFKs impede the retinoic acid receptor, and SFK inhibitors enhance all-trans retinoic acid (ATRA)-mediated cellular differentiation in AML cell lines and primary blasts. To translate these findings into the clinic, we undertook a phase-I dose-escalation study of the combination of the SFK inhibitor dasatinib and ATRA in patients with high-risk myeloid neoplasms. Nine subjects were enrolled: six received 70 mg dasatinib plus 45 mg/m ATRA daily, and three received 100 mg dasatinib plus 45 mg/m ATRA daily for 28 days. Headache and QTc prolongations were the only two grade 3 adverse events observed. No significant clinical responses were observed. We conclude that the combination of 70 mg dasatinib and 45 mg/m ATRA daily is safe with acceptable toxicity. Our results provide the safety profile for further investigations into the clinical efficacy of this combination therapy in myeloid malignancies.
Src家族激酶（SFKs）在急性髓系白血病（AML）中高度活化。SFKs会阻碍视黄酸受体，而SFK抑制剂可增强全反式维甲酸（ATRA）介导的AML细胞系和原代母细胞的细胞分化。为了将这些研究结果应用于临床，我们对高危髓系肿瘤患者进行了一项关于SFK抑制剂达沙替尼与ATRA联合用药的I期剂量递增研究。招募了9名受试者：6名受试者每天接受70毫克达沙替尼加45毫克/平方米ATRA，3名受试者每天接受100毫克达沙替尼加45毫克/平方米ATRA，持续28天。观察到的仅有的两个3级不良事件是头痛和QTc延长。未观察到显著的临床反应。我们得出结论，每天70毫克达沙替尼与45毫克/平方米ATRA联合用药是安全的，毒性可接受。我们的结果为进一步研究这种联合疗法在髓系恶性肿瘤中的临床疗效提供了安全性概况。
