Clinical Experience Using Vitamin D and Analogs in the Treatment of Myelodysplasia and Acute Myeloid Leukemia: A Review of the Literature

Abstract

Despite progress in understanding the biology of acute myeloid leukemia (AML), and despite advances in treatment, the majority of patients with AML die from the disease. The observation that Vitamin D can induce AML blast cells in vitro to differentiate along the monocytic lineage was made 30 years ago; however, it remains to translate this into a clinically meaningful strategy. This is a review of published clinical experience regarding the use of Vitamin D and its analogs, either alone or in combination with other agents, to treat AML. In many of these reports, investigators included patients with myelodysplasia (MDS) as well as AML patients in their treatment cohorts; therefore reports of Vitamin D and its analogs in treating MDS are included. This review documents heterogeneity in selection criteria for patients treated in these studies, the spectrum of Vitamin D analogs used in various studies, and the differing dosing strategies employed by investigators. Despite examples of occasional clinical efficacy, barriers remain to the successful application of Vitamin D in the treatment of MDS and AML. These include the lack of definition of a particularly sensitive target population, and the as yet unknown optimal choice of Vitamin D analog and dosing schedule.

Up-Regulation of the Vitamin D Pathway in Acute Myeloid Leukemia: A Novel Cause of Hypercalcemia

“…Considering these findings, it is plausible that the patient's leukemic clone co-opted the vitamin D pathway to enhance leukemic cell proliferation without impacting on differentiation. Whether utilising vitamin D or its derivatives in the treatment of AML (as previously reported [8]) may in actuality, enhance leukemia cell proliferation in some AML cases is pure conjecture, but our case highlights that the molecular heterogeneity of AML can now also be extended to vitamin D metabolism.…”

“…Indeed, previous experiments have demonstrated that vitamin D treatment can induce monocytic differentiation of leukemic precursors [7]. Predicated on these preclinical data and the success of all-trans-retinoic acid differentiation therapy for acute promyelocytic leukemia (APML), non-APML AML cases have also been treated with vitamin D and analogues, but with limited success [8]. In the aforementioned context, it is not obviously clear why up-regulation of the vitamin D pathway would be advantageous to this patient's leukemic blasts.…”

Vitamin D in cancer chemoprevention

“…Overexpression of p21 and HOXA10 facilitates the differentiation of U937 cells into monocytes/macrophages cell lineage (Kim et al, 2012;Rots et al, 1998). Therefore, the therapeutic strategies currently available in the clinical treatment of leukemias and MDS include agents that induce differentiation of hematopoietic precursors (Harrison & Bershadskiy, 2012;Kim et al, 2012;Nagpal et al, 2005;Shanafelt et al, 2011). The main hematologic responses were observed in patients with MDS treated with calcitriol and alfacalcidol (Kim et al, 2012;Mellibovsky et al, 1998).…”

Enhancement of arabinocytosine (AraC) toxicity to AML cells by a differentiation agent combination

“…However, recent clinical trials of vitamin D derivatives (VDDs) showed unremarkable results, suggesting that approaches to the application of this knowledge to the clinic are currently sub-optimal, as recently articulated [1]. In addition to the problems cited in that review, it is also difficult to obviate the hypercalcemic effect of VDDs, the principal cause of patient toxicity [2, 3]. Repeated attempts to synthesize and clinically test analogs of calcitriol, in which the hypercalcemic activity of the analog is dissociated from its differentiation-inducing activity, have as yet produced no tangible results [3, 4].…”

“…In addition to the problems cited in that review, it is also difficult to obviate the hypercalcemic effect of VDDs, the principal cause of patient toxicity [2, 3]. Repeated attempts to synthesize and clinically test analogs of calcitriol, in which the hypercalcemic activity of the analog is dissociated from its differentiation-inducing activity, have as yet produced no tangible results [3, 4]. An alternative approach to improve AML therapy is to combine VDDs, including calcitriol, with other compounds.…”