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. 1. Introduction Despite significant progress over the past several decades in understanding the biology of acute myeloid leukemia (AML) and despite important advances in treatment approaches, the majority of patients who develop acute myeloid leukemia will still die from their disease. A recent analysis by Southwest Oncology Group investigators of data from 1344 patients with newly diagnosed AML enrolled into SWOG studies between 1986 and 2009, excluding Acute Promyelocytic Leukemia, illustrated this point dramatically. In that study, overall survival at 4 years was only 49% for patients with favorable cytogenetics; overall survival was approximately 25% for those with intermediate-prognosis cytogenetics, and only 9% for those with unfavorable cytogenetics [1]. Among the most important advances made in recent decades in the treatment of AML was the recognition of the exquisite sensitivity of Acute Promyelocytic Leukemia (APL) to differentiation therapy using all-trans-retinoic acid (ATRA). This observation was, shortly thereafter, accompanied by the identification of the Retinoic Acid Receptor Alpha (RARA) gene as a partner in the balanced translocation that drives APL. The dual recognition of a novel mechanism of disease—in the case of APL, overexpression of RARA, a protein that participates in
References
[1]
B. C. Medeiros, M. Othus, M. Fang, D. Roulston, and F. R. Appelbaum, “Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience,” Blood, vol. 116, no. 13, pp. 2224–2228, 2010.
[2]
C. Miyaura, E. Abe, and T. Kuribayashi, “1α,25-dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells,” Biochemical and Biophysical Research Communications, vol. 102, no. 3, pp. 937–943, 1981.
[3]
M. Kim, L. Mirandola, A. Pandey, et al., “Application of vitamin D and derivatives in hematological malignancies,” Cancer Letters, vol. 319, no. 1, pp. 8–22, 2012.
[4]
S. Irino and T. Taoka, “Treatment of myelodysplastic syndrome and acute myelogenous leukemia with Vit. D3 [1α(OH)D3],” Japanese Journal of Cancer and Chemotherapy, vol. 15, no. 4, pp. 1183–1190, 1988.
[5]
T. Takahashi, S. Ichiba, Y. Okuno et al., “Therapeutic effectiveness of vitamin D3 in patients with myelodysplastic syndromes, leukemias and myeloproliferative disorders,” The Japanese Journal of Clinical Hematology, vol. 30, no. 1, pp. 1–10, 1989.
[6]
H. P. Koeffler, K. Hirji, and L. Itri, “1,25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells,” Cancer Treatment Reports, vol. 69, no. 12, pp. 1399–1407, 1985.
[7]
S. Nakayama, T. Ishikawa, H. Yabe, K. Nagai, S. Kasakura, and H. Uchino, “Successful treatment of a patient with acute myeloid leukemia with 1α(OH)D3,” Acta Haematologica Japonica, vol. 51, no. 6, pp. 1026–1030, 1988.
[8]
S. Motomura, H. Kanamori, A. Maruta, F. Kodama, and T. Ohkubo, “The effect of 1-hydroxyvitamin D3 for prolongation of leukemic transformation-free survival in myelodysplastic syndromes,” American Journal of Hematology, vol. 38, no. 1, pp. 67–68, 1991.
[9]
L. Mellibovsky, A. Díez, E. Pérez-Vila et al., “Vitamin D treatment in myelodysplastic syndromes,” British Journal of Haematology, vol. 100, no. 3, pp. 516–520, 1998.
[10]
G. J. Mufti, J. R. Stevens, and D. G. Oscier, “Myelodysplastic syndromes: a scoring system with prognostic significance,” British Journal of Haematology, vol. 59, no. 3, pp. 425–433, 1985.
[11]
Y. Yoshida, S. Oguma, H. Uchino, T. Maekawa, and T. Nomura, “A randomized study of alfacalcidol in the refractory myelodysplastic anaemias. A Japanese cooperative study,” International Journal of Clinical Pharmacology Research, vol. 13, no. 1, pp. 21–27, 1993.
[12]
A. Petrich, B. Kahl, H. Bailey, K. Kim, N. Turman, and M. Juckett, “Phase II study of doxercalciferol for the treatment of myelodysplastic syndrome,” Leukemia and Lymphoma, vol. 49, no. 1, pp. 57–61, 2008.
[13]
I. Blazsek, C. Farabos, M. Musset et al., “Retinoic acid in mono- or combined differentiation therapy of myelodysplasia and acute promyelocytic leukemia,” Biomedicine and Pharmacotherapy, vol. 45, no. 4-5, pp. 169–177, 1991.
[14]
T. Siitonen, T. Timonen, E. Juvonen et al., “Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes,” Haematologica, vol. 92, no. 8, pp. 1119–1122, 2007.
[15]
E. Hellstr？m, K. H. Robèrt, G. Gahrton et al., “Therapeutic effects of low-dose cytosine arabinoside, alpha-interferon, 1α-hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes,” European Journal of Haematology, vol. 40, no. 5, pp. 449–459, 1988.
[16]
E. Hellstr？m, K. H. Robèrt, J. Samuelsson et al., “Treatment of myelodysplastic syndromes with retinoic acid and 1α-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study,” European Journal of Haematology, vol. 45, no. 5, pp. 255–261, 1990.
[17]
L. De Rosa, A. Montuoro, and A. De Laurenzi, “Therapy of “high risk” myelodysplastic syndromes with an association of low-dose Ara-C, retinoic acid and 1,25-dihydroxyvitamin D3,” Biomedicine and Pharmacotherapy, vol. 46, no. 5-7, pp. 211–217, 1992.
[18]
D. Ferrero, B. Bruno, P. Pregno et al., “Combined differentiating therapy for myelodysplastic syndromes: a phase II study,” Leukemia Research, vol. 20, no. 10, pp. 867–876, 1996.
[19]
D. Ferrero, E. Campa, C. Dellacasa, S. Campana, C. Foli, and M. Boccadoro, “Differentiating agents + low-dose chemotherapy in the management of old/poor prognosis patients with acute myeloid leukemia or myelodysplastic syndrome,” Haematologica, vol. 89, no. 5, pp. 619–620, 2004.
[20]
C. A. Slapak, J. F. Desforges, T. Fogaren, and K. B. Miller, “Treatment of acute myeloid leukemia in the elderly with low-dose cytarabine, hydroxyurea, and calcitriol,” American Journal of Hematology, vol. 41, no. 3, pp. 178–183, 1992.
[21]
D. Ferrero, A. Darbesio, V. Giai et al., “Efficacy of a combination of human recombinant erythropoietin + 13-cis-retinoic acid and dihydroxylated vitamin D3 to improve moderate to severe anaemia in low/intermediate risk myelodysplastic syndromes,” British Journal of Haematology, vol. 144, no. 3, pp. 342–349, 2009.
[22]
N. Akiyama, K. Miyazawa, Y. Kanda et al., “Multicenter phase II trial of vitamin K2 monotherapy and vitamin K2 plus 1α-hydroxyvitamin D3 combination therapy for low-risk myelodysplastic syndromes,” Leukemia Research, vol. 34, no. 9, pp. 1151–1157, 2010.
[23]
B. D. Cheson, P. L. Greenberg, J. M. Bennett et al., “Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia,” Blood, vol. 108, no. 2, pp. 419–425, 2006.
[24]
G. P. Studzinski, X. Wang, Y. Ji et al., “The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway,” Journal of Steroid Biochemistry and Molecular Biology, vol. 97, no. 1-2, pp. 47–55, 2005.
[25]
R. Wieder, S. C. Novick, B. W. Hollis et al., “Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D 3 analogue, in a phase I study of patients with advanced malignancies,” Investigational New Drugs, vol. 21, no. 4, pp. 445–452, 2003.
