A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia

• Published in: Leukemia & lymphoma Vol. 59; no. 11; pp. 2595 - 2601
• Main 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.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.11.2018
• Subjects: Acute Disease; Aged; Aged, 80 and over; AML; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ATRA; dasatinib; Dasatinib - administration & dosage; Dasatinib - adverse effects; Dasatinib - pharmacokinetics; Drug Administration Schedule; Headache - chemically induced; Humans; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Long QT Syndrome - chemically induced; Middle Aged; pharmacodynamics; pharmacokinetics; phase I; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Treatment Outcome; Tretinoin - administration & dosage; Tretinoin - adverse effects; Tretinoin - pharmacokinetics; AML; pharmacokinetics; phase I; dasatinib; ATRA; pharmacodynamics
• ISSN: 1042-8194; 1029-2403; 1029-2403
• DOI: 10.1080/10428194.2018.1443330

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.