Vitamin D is a steroid-like hormone which acts by binding to vitamin D receptor (VDR). It plays a main role in the calcium homeostasis and metabolism. In addition, vitamin D display other important effects called “non-classical actions.” Among them, vitamin D regulates immune cells function and hematopoietic cells differentiation and proliferation. Based on these effects, it is currently being evaluated for the treatment of hematologic malignancies. In addition, vitamin D levels have been correlated with patients’ outcome after allogeneic stem cell transplantation, where it might regulate immune response and, accordingly, might influence the risk of graft-versus-host disease. Here, we present recent advances regarding its clinical applications both in the treatment of hematologic malignancies and in the transplant setting.

https://www.mdpi.com/1422-0067/19/9/2663/pdf

Vitamin D: Effect on Haematopoiesis and Immune System and Clinical Applications

Steroids including prednisone or dexamethasone, have clear efficiency in therapy of acute lymphoblastic leukemia. All trans retinoic acid (seco-steroid) has revolutionized our therapy of acute promyelocytic leukemia. Efficacy is based on its binding to the aberrant PML-RARa and reversing the inhibition of the leukemic fusion protein. In other malignant disorders including myelodysplastic syndrome (MDS), which does not have the abnormal fusion protein, retinoids have only moderate efficacy. Another seco-steroid, the active vitamin D3 (1,25 dihydroxy-vitamin-D3, [1,25(OH)2D3]) has the ability to terminally differentiate several myeloid leukemia cell lines and has the anti-proliferative activity against selected additional hematopoietic cell lines and fresh leukemic cells. The 1,25(OH)2D3 also has the ability to inhibit the growth of solid tumor cell lines. How 1,25(OH)2D3 mediates these effects is unclear. The ligand binds to its receptor, and this complex binds to a myriad of genes that can control growth and differentiation, some of these genes include: increased expression of p21, p27, Rb, PTEN, p53 and decreased levels of cyclin D1, Cdk-2, Bcl-2, c-myc. Nevertheless, 1,25(OH)2D3 has had less than spectacular results when used as a therapy for MDS (Table I). The amount of 1,25(OH)2D3 that can be given is limited by development of hypercalcemia. This led to the synthesis of vitamin D analogs that have increased anti-proliferative activities with markedly decreased calcemic activity. Paricalcitol (Zemplar) and doxercalciferol (Hectorol) are examples of these analogs. They often have short half-lives and may also alter the vitamin D receptor to enhance its transcriptional activity. Sadly, these analogs also have only minimal activity against MDS including the excellent trial by

Vitamin D compounds and myelodysplastic syndrome

Publisher Summary
Hematopoiesis is the process that leads to the regulated formation of the highly specialized circulating blood cells from pluripotent hematopoietic stem cells (HSCs) in the bone marrow. This chapter focuses on the interaction of 1,25(OH)2D3 with the normal and the malignant hematopoietic system, especially examining the ability of this secosteroid to induce differentiation and inhibit proliferation of normal and leukemic myeloid cells. It also discusses the development and testing in vitro and in vivo of vitamin D analogs. The secosteroid hormone 1,25(OH)2D3 has a role in normal hematopoiesis, enhancing the activity of monocyte–macrophage differentiation. It also has anti-proliferative and pro-differentiation effects against various myeloid leukemia cell lines by both genomic and nongenomic pathways. Nevertheless, hematopoiesis in vitamin D3 receptor deletional mice is fairly normal, suggesting the vitamin D3 pathway has an adjunctive role in blood formation in mammals. Although these compounds, used either alone or combined with other agents, have preclinical activity, their efficacy in clinical trials has thus far appeared to be limited.

Chapter 88 – Hematological Malignancy

The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has multiple anticancer activities including growth arrest, induction of apoptosis, and differentiation. Here, the actions of vitamin D compounds are addressed from normal to malignant hematopoietic cells. The effects are driven by binding of vitamin D to vitamin D receptor in either genomic and/or nongenomic fashions. However, its application as a therapeutic agent is limited by its side effect, hypercalcemia. 1,25(OH)2D3 analogs have been synthesized to obtain antitumor activity with less calcemic toxicity. Limited clinical studies using vitamin D compounds have had only minor clinical success for patients with leukemia or myelodysplasia syndrome. Nevertheless, preclinical studies suggest that the combination of vitamin D compounds with other agents can have additive or synergistic anticancer activities, renewing hope for future clinical studies.

Vitamin D and Hematologic Malignancies

Vitamin D is a steroid hormone with a broad range of biological effects ranging from the classical role as a mediator of calcium and phosphate balance to cellular differentiation and immune modulation. These effects impact normal and dysfunctional hematopoietic and immune function, which may allow an avenue for improved treatment and support of patients suffering from hematologic disorders. In this review, we will summarize the role of vitamin D in normal hematopoiesis, discuss ways in which vitamin D may improve outcomes, and discuss a potential role of vitamin D for treating hematologic disorders and modulating the immune system to improve the outcome of allogeneic stem cell transplant.

https://www.mdpi.com/2072-6643/5/6/2206/pdf

The Role of Vitamin D in Hematologic Disease and Stem Cell Transplantation

Treatment of low-risk myelodysplastic syndromes with high-dose daily oral cholecalciferol (2000–4000 IU vitamin D 3 )

Treatment of low-risk myelodysplastic syndromes with high-dose daily oral cholecalciferol (2000–4000 IU vitamin D 3 )

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Treatment of low-risk myelodysplastic syndromes with high-dose daily oral cholecalciferol (2000–4000 IU vitamin D 3 )