ReviewApplication of vitamin D and vitamin D analogs in acute myelogenous leukemia

- 1,25-D3 and VDAs can differentiate AML cells potently in vitro and in vivo.
- Early clinical trials of 1,25-D3 and VDAs resulted in mixed outcomes.
- Clinical application of 1,25-D3 and VDAs is limited by systemic hypercalcemia.
- 1,25-D3 can potentially play a role in AML epigenetic regulation and prognosis.
- Combination treatment of VDAs with HDAC inhibitors or hypomethylating agents is a possibility.

Acute myeloid leukemia (AML) is characterized by the accumulation of malignant, transformed immature hematopoietic myeloid precursors that have lost their ability to differentiate and proliferate normally. Current treatment for AML requires intensive cytotoxic chemotherapy and results in significant morbidity and mortality, especially in older patients. Effective and better-tolerated treatment is urgently needed. Studies have shown that 1α,25-dihydroxyvitamin D3 (1,25-D3, active VD3) or vitamin D analogs (VDAs) can potently differentiate AML cells in vitro and ex vivo, which led to early clinical trials in AML and myelodysplastic syndrome patients. However, one major limiting factor in the clinical application of active VD3 or VDAs is the supraphysiologic dose required, which results in systemic hypercalcemia. Several important questions (i.e., dosage, method of delivery, metabolism of 1,25-D3 in situ, systemic hypercalcemia, and mechanisms of action of combination treatment) have to be addressed before vitamin D treatment can be applied to the clinical setting. This review focuses on 1,25-D3's mechanism of action in AML, preclinical data, and clinical trial outcomes, with an emphasis on major roadblocks to successful trials and suggestions for future directions.