A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia. Issue 11 (2nd November 2018)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Leukemia & lymphoma. Volume 59:Issue 11(2018)
• Page Start: 2595
• Page End: 2601
• Publication Date: 2018-11-02
• Subjects: ATRA -- dasatinib -- phase I -- pharmacokinetics -- pharmacodynamics -- AML; Leukemia -- Periodicals; Lymphomas -- Periodicals; 616.99419
• DOI: 10.1080/10428194.2018.1443330
• Languages: English
• ISSNs: 1042-8194

Abstract

Abstract: 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 2 ATRA daily, and three received 100 mg dasatinib plus 45 mg/m 2 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 2 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.