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Redner RL, Beumer JH, Kropf P, Agha M, Boyiadzis M, Dorritie K, Farah R, Hou JZ, Im A, Lim SH, Raptis A, Sehgal A, Christner SM, Normolle D, Johnson DE
A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia
Leuk Lymphoma (2018) 59:2595-2601.
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.
Publication Date: 2018-11-01.
PMCID: PMC6201295
Last updated on Monday, May 04, 2020