|Year : 2014 | Volume
| Issue : 2 | Page : 47-51
Serum 25-hydroxyvitamin D levels in relation to disease status and prognosis in acute myeloid leukemia
Tahani A Elkerdany1, Doaa G Eissa1, Mohamed M Moussa2
1 Department of Clinical Pathology, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine and Hematology, Ain Shams University, Cairo, Egypt
|Date of Submission||16-Nov-2013|
|Date of Acceptance||23-Jan-2014|
|Date of Web Publication||30-Aug-2014|
Doaa G Eissa
20 Nagaty Sarag Street, 8th district, Nasr city, Cairo 11471
Source of Support: None, Conflict of Interest: None
Background Low vitamin D levels are linked to higher incidence of cancer. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for acute leukemia.
Aim of the work To evaluate the relationship between serum 25-hydroxyvitamin D (25[OH]D) levels and disease status in acute myeloid leukemia (AML) and correlate these levels with prognostic markers of the disease.
Materials and Methods Sixty AML patients, 32 newly diagnosed, 15 in relapse, and 13 in complete remission, as well as 30 healthy control individuals were studied using enzyme-linked immunosorbent assay for the measurement of serum 25[OH]D.
Results There was a significantly lower white blood cell count, hemoglobin level, platelet count, and serum vitamin D level among AML patients compared with the control group. Vitamin D-insufficient patients showed lower hemoglobin levels and platelet counts, together with a higher lactate dehydrogenase level, higher percentage of peripheral blood blasts infiltration, and higher percentage of bone marrow blasts' infiltration compared with vitamin D-sufficient patients. Vitamin D levels showed a significantly higher median value among patients who had favorable cytogenetics and a higher median value among those who showed complete remission than those newly diagnosed or in relapse. Survival curve analysis showed shorter overall survival of vitamin D-insufficient patients compared with vitamin D-sufficient patients.
Conclusion and Recommendations Vitamin D level is related to the active stage of the disease and therefore aggressiveness of the disease. It can be used as a prognostic tool for survival in AML patients. It is recommended that further evaluation be carried out on a large number of patients with a longer follow-up period and that it is incorporated into the routine evaluation of all AML patients. Additional studies are needed to determine the exact role of vitamin D in acute leukemia and whether it could be used as a therapeutic or a preventive approach.
Keywords: acute myeloid leukemia, prognosis, vitamin D
|How to cite this article:|
Elkerdany TA, Eissa DG, Moussa MM. Serum 25-hydroxyvitamin D levels in relation to disease status and prognosis in acute myeloid leukemia
. Egypt J Haematol 2014;39:47-51
|How to cite this URL:|
Elkerdany TA, Eissa DG, Moussa MM. Serum 25-hydroxyvitamin D levels in relation to disease status and prognosis in acute myeloid leukemia
. Egypt J Haematol [serial online] 2014 [cited 2018 Jul 20];39:47-51. Available from: http://www.ehj.eg.net/text.asp?2014/39/2/47/139757
| Introduction|| |
Vitamin D is a steroid hormone produced in the skin, acts through a nuclear transcription factor to regulate many aspects of cellular growth and differentiation, and exerts its action through specific intracellular receptors, which are found in normal as well as cancer cells. Serum levels of 25-hydroxyvitamin D (25[OH]D) reflect whole-body vitamin D stores and are used to assess individual vitamin D adequacy or insufficiency  .
Vitamin D plays a central role in maintaining serum calcium and skeletal homeostasis as well as multiple other cellular effects including regulation of differentiation, proliferation, apoptosis, metastatic potential, and angiogenesis  . Observational studies have indicated that inadequate 25(OH)D levels are a risk factor for certain types of cancer  .
In several pathologies, a level of 25(OH)D higher than 20 ng/ml at the time of diagnosis and during cancer treatment may improve the prognosis  . Both prospective and retrospective studies have indicated that levels of 25(OH)D below 20 ng/ml are associated with an increased risk of solid tumors, along with higher mortality from these cancers  .
Despite growing evidence for a relationship between vitamin D levels and the risk of solid tumor, far less is known about the relationship between vitamin D and the risk of hematologic malignancy. In this study, we investigated the relationship between vitamin D level and acute myeloid leukemia (AML) and correlated these levels with disease status and prognostic markers of the disease.
| Patients and methods|| |
This study was carried out on 60 AML patients, 32 newly diagnosed, 15 in relapse, and 13 in complete remission. They were attending the Hematology Oncology Clinic of Ain Shams University Hospital during the period from September 2011 to March 2013. Follow-up of all patients was done through the period of this study. Thirty healthy volunteers were recruited as a control group. Data for clinical and laboratory assessment were collected from the medical records of the patients. Formal consent was obtained from all the individuals studied and the study protocol was approved by the Ain Shams medical research ethical committee. All patients were subjected to laboratory investigations including complete blood count and examination of Leishman-stained peripheral blood film smears. Bone marrow examination was carried out with morphological assessment of bone marrow blast cell percentage. Routine immunophenotyping together with the routine panel of cytogenetics for adult AML patients was performed on bone marrow or peripheral blood samples to detect patients with favorable cytogenetics [t(8;21), t(15;17), Inv(16)] from those with unfavorable cytogenetics [11q23 rearrangements, −7, t(9;22)]. Measurement of 25-hydroxy vitamin D was performed on serum samples collected from both the patient and the control group using an enzyme-linked immunosorbent assay.
Serum 25(OH) vitamin D measurement
Two millilitres of peripheral venous blood were drawn from each patient and control into plain vacutainer tubes for serum 25(OH)D analyses. For each patient, the 25(OH) D was measured once: either at the time of diagnosis or during the evolution of the disease. Serum samples were separated and circulating 25(OH)D levels were measured using a radioimmunoassay Kit (Immunodiagnostik; Bensheim and Biomedica, Vienna, Austria). Vitamin D deficiency was defined as a 25(OH)D level of less than 20 ng/ml (seriously deficient). A level of 21-30 ng/ml was considered to indicate a relative insufficiency and a level of 30 ng/ml or more was considered to indicate sufficient vitamin D (adequately supplied)  .
Statistical analysis was carried out using the statistical package for social science software package, version 20.0, (IBM Corporation, Chicago, USA), using a Windows 7 operating system. Data were expressed as median and percentiles for quantitative nonparametric measures. Comparison of quantitative data was carried out using the Mann-Whitney test. The relationship between 25(OH)D levels and quantitative data was studied using the Spearman rank correlation test. Survival analysis was carried out according to Kaplan-Meier survival curve and analysis. P values less than 0.05 and 0.01 were considered statistically significant and highly significant, respectively.
| Results|| |
The patient group included 60 patients aged between 22 and 76 years, mean 45.9 ± 15.8 years, whereas the control group included 30 healthy volunteers whose ages ranged from 25 to 75 years, mean 39.7 ± 13.9 years. Comparison between both groups showed a highly statistically significant lower hemoglobin level, platelet count, and serum vitamin D level among AML patients (P = 0.001, 0.001, and 0.001, respectively). However, a significantly higher lactate dehydrogenase (LDH) level was detected in AML patients (P = 0.001).
Comparison between vitamin D-insufficient and vitamin D-sufficient patients
According to vitamin D sufficiency, all patients were grouped into two groups: vitamin D sufficient (>20 ng/ml) and vitamin D insufficient (≤20 ng/ml). A statistically significant lower hemoglobin level and platelet count was observed in vitamin D-insufficient patients compared with vitamin D-sufficient patients (P = 0.01 and 0.003, respectively). However, a statistically significant higher LDH level, percentage of peripheral blood blasts infiltration, and percentage of bone marrow blasts infiltration was detected in vitamin D-insufficient patients compared with vitamin D-sufficient patients (P = 0.013 and P = 0.002, and P = 0.002, respectively). No statistically significant difference was detected between both groups in age, BMI, and white blood cells count (P = 0.437 and P = 0.82, and P = 0.666, respectively) [Table 1].
|Table 1: Comparison between vitamin D-sufficient patients and vitamin D-insufficient patients|
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Vitamin D in relation to AML patients
The relation between vitamin D level and each of the demographic and clinical data of AML patients showed no significant difference for all parameters including age, sex, BMI, hepatomegaly, splenomegaly, and lymphadenopathy (P > 0.05). However, the relation between vitamin D and cytogenetic analysis showed a significantly higher median value of vitamin D among patients who had favorable cytogenetics (P = 0.001). Also, vitamin D showed a higher median value among patients who showed complete remission than those newly diagnosed or in relapse; this difference was statistically highly significant (P = 0.001) [Table 2].
|Table 2: Relation between vitamin D level and demographic data of the AML patients studied together with clinical data|
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In terms of laboratory data, vitamin D level showed a highly significant positive correlation with platelet count (P = 0.007) and a highly significant negative correlation with percentage of peripheral blood blasts' infiltration and percentage of bone marrow blasts' infiltration (P = 0.001). In addition, a significant negative correlation with serum LDH level was detected (P = 0.033). There was no correlation between vitamin D and the other laboratory parameters such as white blood cell count and hemoglobin level (P = 0.634 and 0.062, respectively) [Table 3].
|Table 3: Vitamin D level in correlation to laboratory data of the AML patients studied|
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Impact of vitamin D sufficiency on patients' survival
Kaplan-Meier analysis for estimation of overall survival time according to vitamin D sufficiency showed that vitamin D-insufficient patients had significantly shorter overall survival compared with vitamin D-sufficient patients (P < 0.001) [Figure 1].
|Figure 1: Kaplan– Meier curve showing vitamin D-sufficient and vitamin D-insufficient patients.|
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| Discussion|| |
Vitamin D and its analogs, collectively called deltanoids, have been investigated as noncytotoxic treatment options in differentiation therapy for AML, perhaps more extensively than any other hematological malignancy  . Along with the role of 1,25(OH)D in the activation of transcription of target genes and various signaling pathways, other effects of 1,25(OH)D on myeloid leukemia cells have been discovered that may account for its antiproliferative effects  .
Several reports now suggest that low serum 25(OH)D levels may be associated with increased incidence of colorectal, breast, and other cancers  . In addition to the risk of developing malignancy, recent data suggest that low 25(OH)D levels at diagnosis may be associated with poorer prognosis in colorectal, breast, melanoma, and lung cancer, although these data have not yet been replicated in independent cohorts , .
In this study, we observed a statistically significant lower vitamin D level among AML patients compared with healthy controls. Similarly, Bobilev et al.  reported low concentrations of 1,25(OH)D in human AML cell lines.
In the present study, AML patients were classified according to vitamin D levels into vitamin D-insufficient patients and vitamin D-sufficient patients. A statistically lower hemoglobin level was detected in vitamin D-insufficient patients compared with vitamin D-sufficient patients. Moreover, a significantly higher LDH level, peripheral blood blasts, and bone marrow blasts were detected in vitamin D-insufficient patients compared with vitamin D-sufficient patients. Previously, Ahn et al.  showed that low vitamin D levels may be associated with an increased risk of aggressive disease.
In our study, the level of vitamin D showed a significant negative correlation with peripheral blood blasts and bone marrow blasts. In agreement with our results, Thomas et al.  reported that there was a correlation between 25(OH)D level and percentage of leukemic cells infiltrating bone marrow in AML patients at diagnosis. Moreover, our study found no significant association between vitamin D level and BMI. Thomas et al.  reported that BMI is not related to circulatory 25(OH)D in AML patients. However, they found some AML patients who were overweight at diagnosis showed a low 25(OH)D level. The latter findings were explained by Wortsman et al.  by the fact that higher BMI or obesity has been found to be associated with considerably lower circulatory concentrations of 25(OH)D because of its deposition in body fat compartments.
In the current work, a significantly higher vitamin D level was detected in AML patients who had favorable cytogenetics and a definitely better prognosis, thus relating vitamin D level to cytogenetics as the best parameter of prognosis in AML as established by many researches. One of these researches was carried out by Van der Holt et al.  , who reported the role of cytogenetic subgroups in identifying prognosis better than any other factor in both younger and older adult AML patients, and that stratification of therapy on the basis of cytogenetic prognostic group has become the standard point of care in AML.
Moreover, vitamin D level was significantly higher in our patients who showed complete remission than those who had been newly diagnosed or in relapse. Similarly, Thomas et al.  reported a significant difference in vitamin D levels between AML patients with long-term disease-free survival and those tested at diagnosis or those tested at the time of relapse. Other studies carried out by Berman et al.  and Fitter et al.  reported that acute leukemias may directly or indirectly have an impact on the 25(OH)D levels if patients with advanced disease are less able to perform outdoor activities or have unsatisfactory dietary habits with respect to 25(OH)D. This could be the case for AML patients.
The survival analysis of our patients showed that vitamin D-insufficient patients had a significantly shorter overall survival time compared with vitamin D-sufficient patients. This is in agreement with Giovannucci et al.  and Freedman et al.  , who observed that low levels of 25(OH)D may be associated with increased cancer incidence and mortality. In agreement with these results, Lappe et al.  have shown that serum 25(OH)D concentration was a significant independent predictor of the risk of cancer, and supplemental calcium and vitamin D are associated with a reduced risk of cancer. Recently, Thomas et al.  observed a significant association between circulatory 25(OH)D and malignant cell burden. They observed that lower levels of circulatory 25(OH)D appeared to be related to a progressive stage of the disease and poor response to therapy, and therefore, to the aggressiveness of the disease; thus, it is potential marker of prognosis in AML patients.
| Conclusion|| |
Our study showed a significantly lower vitamin D level in AML patients than the control group as well as a higher level in patients showing complete remission than patients who had a relapse or patients at diagnosis. Vitamin D level can be used as a prognostic biomarker for survival in AML patients, although future studies with larger series of patients and longer duration may be needed before its routine use.
| Acknowledgements|| |
| References|| |
|1.||Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266-281. |
|2.||Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009; 94: 26-34. |
|3.||Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, et al. The role of vitamin D in cancer prevention. Am J Public Health 2006; 96: 252-261. |
|4.||Zhou W, Heist RS, Liu G, Asmaning K, Neuberg DS, Hollis BW, et al. Circulating 25-hydroxyvitamin D level predict survival in early-stage non-small lung cancer patients. J Clin Oncol 2007 ; 25: 479-485. |
|5.||Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC. Prospective study of predicators of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006; 98: 451-459. |
|6.||Kim M, Mirandola L, Pandey A, Ngugen DD, Turcel M, Cobas E, Chiriva-Internati M. Application of vitamin D and derivatives in hematological malignancies. Cancer Lett 2012; 319: 8-22. |
|7.||Suzuki T, Koyama Y, Hayakawa S, Munakata HJ, Isemura M. 1,25-Dihydroxyvitamin D3 suppresses export in expression in human promyelocytic leukemia HL-60 cells. Biomed Res 2006; 27: 89-92. |
|8.||Yin L, Grandi N, Raum E, Haug U, Amdt V, Brenner H. Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther 2009; 30: 113-125. |
|9.||Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clin Oncol 2009; 27: 3757-3763. |
|10.||Newton-Bishop JA, Beswick S, Randerson-Moor J, Chang MY, Affleck P, Elliott F, et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J Clin Oncol 2009; 27: 5439-5444. |
|11.||Bobilev I, Novik V, Levi I, Shpilberg O, Levy J, Sharoni Y, et al. The NrF2 transcription factor is a positive regulator of myeloid differentiation of acute myeloid leukemia cells. Cancer Biol Ther 2011; 11: 317-392. |
|12.||Ahn J, Peters U, Albanes D, Purdue HP, Abent CC, Chatterjee N, et al. Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 2008; 100: 796-804. |
|13.||Thomas X, Chelghoumy Y, Fanari N, Cannas G. Serum 25(OH) vit. D levels are associated with prognosis in hematological malignancies. Hematology 2011; 16: 278-283. |
|14.||Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavavlability of vitamin D in obesity. Am J Clin Nutr 2007; 72: 690-693. |
|15.||Van der Holt B, Breems DA, Berna Beverloo H, van den Berg E, Burnett AK, Sonneveld P, Löwenberg B. Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value: results from a prospective clinical trial. Br J Haematol 2007; 136: 96-105. |
|16.||Berman E, Nicolaider M, Maki RG, Fleisher M, Chanel S, Scheu K, et al. Altered bone and mineral metabolism in patients receiving imatinibmesylate. N Engl J Med 2006; 354: 2006-2013. |
|17.||Fitter S, Dewar AL, Kostakis P, To LB, Hughes TP, Roberts MM, et al. Long-term imatinib therapy promotes bone formation in CML patients. Blood 2008; 111: 2538-2547. |
|18.||Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007; 99: 1594-1602. |
|19.||Lappe M, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85: 1586-1591. |
[Table 1], [Table 2], [Table 3]