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Novel Combination of Lithium and Tretinoin for Treatment-Resistant AML

By: Sarah Campen, PharmD
Posted: Monday, May 4, 2020

The novel combination of lithium, a glycogen synthase kinase-3 (GSK3) inhibitor, and tretinoin as a differentiation therapy appears to be safe and well tolerated in older, heavily pretreated patients with relapsed, refractory non-promyelocytic acute myeloid leukemia (AML). However, Masumi Ueda, MD, of the Fred Hutchinson Cancer Research Center and University of Washington, Seattle, and colleagues concluded that lithium achieved just modest GSK3 inhibition at clinically attainable serum concentrations, potentially limiting its clinical applicability in AML treatment. The findings of the phase I study were published in Frontiers in Oncology.

“More potent GSK3 inhibitors are likely necessary for greater clinical efficacy, and combinations of GSK3 inhibition with cytotoxic therapies may achieve greater clinical activity,” stated the authors.

The study included nine patients with relapsed leukemia after prior therapy. The median age of participants was 65. Oral lithium carbonate was initiated at 300 mg two to three times daily, and the dose was subsequently adjusted to meet the target serum concentration of 0.6 to 1.0 mmol/L. Tretinoin was given orally on days 1 to 7 and 15 to 21 of a 28-day cycle.

Disease stability, defined as no increase in circulating blasts for at least 4 weeks, was attained by four patients. All patients eventually had progressive disease, and the median survival was 106 days. Target serum lithium concentration was achieved in all patients and was associated with GSK3 inhibition in leukemic cells. The authors noted that the combination treatment appeared to target AML stem cells. In five patients, phenotypic changes associated with myeloid differentiation in the setting of GSK3 inhibition that correlated with serum lithium levels were observed.

“Differentiation therapy in patients with minimal residual disease or low leukemia burden following conventional chemotherapy warrants further investigation,” concluded the investigators.

Disclosure: The authors reported no conflicts of interest.



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