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

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/m2 ATRA daily, and three received 100?mg dasatinib plus 45?mg/m2 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/m2 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.

SUBMITTER: Redner RL

PROVIDER: S-EPMC6201295 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Redner Robert L RL Beumer Jan H JH Kropf Patricia P Agha Mounzer M Boyiadzis Michael M Dorritie Kathleen K Farah Rafic R Hou Jing-Zhao JZ Im Annie A Lim Seah H SH Raptis Anastasios A Sehgal Alison A Christner Susan M SM Normolle Daniel D Johnson Daniel E DE

Leukemia & lymphoma 20180404 11

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 ...[more]

PMID: 29616864

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Project description:A large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts.In this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 × 109/L.The study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells.Treatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy.

Dataset Information

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

Publications

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

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