Abstract
It has been proposed that Vitamin D has a significant influence on disease progression in malignancy. This study aims to investigate whether serum levels of 25-hydroxyvitamin D [25(OH)D] are associated with prognosis in patients with hematological malignancies. This study is based on 105 patients with hematological disease (acute and chronic leukemias, myelodysplastic syndromes, monoclonal gammapathies, and chronic lymphoid disorders), seen over a 6-months period. 25(OH)D deficiency (<20 ng/ml) appeared very common and an inverse relationship was observed between 25(OH)D levels and the response to therapy: lower levels being related to poorer response. In acute leukemias, a significant difference was noted between patients with long-term disease-free survival in those tested at diagnosis (P = 0·001) or in those tested at the time of relapse (P = 0·05). Similarly in patients with Philadelphia-positive leukemias, there was a correlation between molecular response and levels of 25(OH)D (P = 0·01). Previously identified factors, such as age, season, gender, or nutritional index, were not related to circulating 25(OH)D levels. Lower levels of circulating 25(OH)D appeared related to a progressive stage of the disease and poor response to therapy, and, therefore, to the aggressiveness of the disease. It is a potential marker of prognosis in patients with leukemia.
Introduction
Vitamin D, a steroid hormone produced in skin, acts through a nuclear transcription factor to regulate many aspects of cellular growth and differentiation,Citation1,Citation2 and exerts its action via specific intracellular receptors, which are found in normal as well as cancer cells.Citation3 The biologically most active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D [1,25(OH)2D]), is formed from calcidiol (25-hydroxyvitamin D [25(OH)D]) in the kidney, and acts by binding to nuclear vitamin D receptors, and regulates gene transcription. The major circulating metabolite of vitamin D is serum 25(OH)D, which has a half life of between 10 and 19 days, and represents the best indicator of vitamin D status reflecting levels from dietary intake and synthesis in the skin.Citation4 Observational studies have indicated that inadequate 25(OH)D levels are a risk factor for certain types of cancer.Citation5 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.Citation6,Citation7 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.Citation5,8–Citation11 Recently, results have shown an association of 25(OH)D level less than 50 nmol/l with increased breast cancer risk and provided the first direct evidence that vitamin D may be an important host factor influencing breast cancer prognosis.Citation12 Results from another study have suggested that high levels of 25(OH)D were associated with reduced development of leukemia.Citation8
Based on these first intriguing results, in this study we investigated the relationship between vitamin D levels and disease status and prognosis in patients with hematological malignancies using individual serum levels of 25(OH)D.
Patients and Methods
Study population
25(OH)D levels were examined in a cohort of 105 patients with hematological malignancies at different stages of their disease, hospitalized in the Leukemia Unit (acute leukemias) or followed in consultation (chronic hematological disorders or acute leukemias with long-term follow-up) at the Edouard Herriot Hospital (Lyon, France) between June and November 2008. The patients were split into different groups according to diagnosis and status of their disease. Fifty-four patients had acute myeloid leukemia (AML), of whom one with secondary AML following acute transformation of essential thrombocythemia; 9 had acute lymphoblastic leukemia (ALL), of whom one had transformation of chronic myeloid leukemia (CML); 20 had a myeloproliferative syndrome (MPS), of whom 19 had CML and one essential thrombocythemia; 8 had myelodysplastic syndrome (MDS), 10 had a monoclonal gammapathy, of whom 6 had multiple myeloma (MM) and 4 monoclonal gammapathy of unknown significance (MGUS); and 4 presented with another chronic lymphoproliferative disorder (2 with chronic lymphocytic leukemia and 2 with low grade non-Hodgkin’s lymphoma). Eighty patients had an active disease (37 were at diagnosis, 30 in a chronic phase, and 13 at relapse), while 25 were in complete response. Among patients, 27 presented with Philadelphia chromosome-positive leukemia (19 CML, 7 ALL or ALL-transformed CML, and one AML).
Serum 25(OH)D assessment
25(OH)D is the major circulating vitamin D metabolite and the best indicator of an individual’s vitamin D status.Citation13 For each patients the 25(OH)D was measured once; either at the time of diagnosis or during the evolution of the disease. Twenty-five milliliters of peripheral venous blood, collected in tubes with heparin, were drawn from each patient’s sample for the 25(OH)D analyses. Serum/plasma samples were separated and circulating 25(OH)D levels were measured using a radioimmunoassay kit (DIASORIN, Stillwater, MN, USA), coefficient of variation less than 15%.Citation14 All samples were assayed at the same laboratory. Vitamin D deficiency was defined as a 25(OH)D level of less than 20 ng/ml. A level of 21 to 29 ng/ml was considered to indicate a relative insufficiency of vitamin D, and a level of 30 ng/ml or greater was considered to indicate sufficient vitamin D.Citation2
Statistical analysis
From the existing literature, a number of factors are known to influence circulating 25(OH)D concentrations; among these, sunlight exposure and vitamin D intake are the most important.Citation15 Other factors related to these main factors included region as a surrogate of residential ultraviolet radiation exposure,Citation16 physical activity level, skin pigmentation, nutritional indexes such as body mass index (BMI),Citation8 season,Citation17 cigarette smoking, gender and age. Clinical information and functional status at time of analysis was retrieved from the medical records. Patient information from the medical records was collected without the knowledge of the individual 25(OH)D level. Performance status, defined by Eastern Cooperative Oncology GroupCitation18 was <2 for all patients. Data on sunlight exposure behaviors or outdoor activities, vitamin D intake from diet and supplements and cigarette smoking were not available. Nutritional index was assessed in patients with acute leukemia tested at the time of diagnosis. Body mass index was defined by a person’s weight in kilograms divided by height in meters squared. The relationship between 25(OH)D levels and molecular response in leukemias with Philadelphia chromosome was assessed by comparison of 25(OH)D levels in patients with no major molecular response (%Bcr-Abl/Abl ⩾0·1%), and patients having a major molecular response (%Bcr-Abl/Abl <0·1%). In the statistical analysis, 25(OH)D levels were considered as continuous variables. The relationship between 25(OH)D levels and quantitative characteristics were studied by the Spearman rank correlation test. The relationships between 25(OH)D levels and qualitative parameters were studied by the Mann-Whitney or Kruskal-Wallis tests. All reported P values were from two-sided tests. Computations were performed using BMDP PC90 statistical program (BMDP Statistical Software, Los Angeles, CA, USA).
Results
Characteristics of patients
A cohort of 105 patients (median age, 57 years; range: 21–85 years) was studied. Mean serum 25(OH)D level±standard deviation (SD) was 22·9±10·5 ng/ml. The range of 25(OH)D concentrations was 6 to 50 ng/ml. Forty-nine patients (46%) had 25(OH)D levels less than 20 ng/ml and were defined as vitamin D deficiency, while 27 (26%) ranged between 20 and 30 ng/ml, and 29 (28%) were at 30 ng/ml or more. Patient characteristics (age, sex, diagnosis, and disease status) and 25(OH)D are presented in .
Table 1. Serum 25(OH)D levels according to patients characteristics
Assessment of factors potentially influencing circulating 25(OH)D
In the entire cohort, 25(OH)D levels were not associated with gender (23·3±10·5 ng/ml in males versus 24·3±13·7 ng/ml in females). Increasing age was also not associated with a lower level of 25(OH)D (20·0±7·6 ng/ml in patients <30 years old, 23·8±11·4 ng/ml between 30 and 60 years, and 22·0±10·0 ng/ml over 60 years). This was still the case when considering only patients tested at the time of diagnosis (17·0±6·5 ng/ml in patients <30 years old, 18·6±10·7 ng/ml between 30 and 60 years, and 20·1±7·1 ng/ml over 60 years). No difference was noted when 25(OH)D was drawn in summer (June–August) versus autumn (September–November) months, as well as in the entire cohort (21·6±10·3 ng/ml versus 25·6±10·3 ng/ml) than in the group of patients tested at the time of diagnosis (16·5±9·1 ng/ml versus 16·0±6·7 ng/ml). In acute leukemia patients studied at the time of diagnosis for this factor (24 patients), the BMI appeared not related to circulating 25(OH)D level (r = 0·025). However, the two patients presenting with under weight at diagnosis (BMI<18·5 kg/m2) showed low 25(OH)D levels (15 and 16 ng/ml). Over weight (BMI>25 kg/m2) was observed in 14 patients (58%) and showed circulating 25(OH)D levels similar to those from patients with BMI in the normal range (16·7±6·7 ng/ml versus 20·6±8·3 ng/ml, respectively).
Association between 25(OH)D levels and malignant cell burden
Although there was no correlation between 25(OH)D level and the percentage of leukemic cells infiltrating bone marrow (BM) in patients with acute leukemia at diagnosis, as well as when studied as a continuous variable (r = −0·23) or when divided into two groups by the median value (19·8±6·8 ng/ml for BM blasts <60% versus 18·8±7·6 ng/ml for BM blasts ⩾60%), lower 25(OH)D levels were associated with higher malignant cell burden as indicated by the correlation observed between the stage of the disease in acute leukemias and levels of 25(OH)D. The difference was significant between patients with long-term disease-free survival and those tested at diagnosis (29·2±6·1 ng/ml versus 17·7±6·7 ng/ml; P = 0·001) or those tested at the time of relapse (29·2±6·1 ng/ml versus 19·9±9·1 ng/ml; P = 0·05) (). Similarly in patients with Philadelphia-positive leukemias, the study of molecular residual disease showed a correlation between molecular response and levels of 25(OH)D (31·2±12·0 ng/ml in patients with %Bcr-Abl/Abl<0·1% versus 17·4±8·9 ng/ml in patients with %Bcr-Abl/Abl⩾0·1%; P = 0·01) (). In those patients, serum levels of parathyroid hormone (PTH) and calcium remained in the normal range: 15 to 65 ng/l (median: 45 ng/l) and 2·12 to 2·52 mmol/l (median: 2·22 mmol/l), respectively. Although the cohort of patients with monoclonal gammapathy was small, there was a trend toward higher circulating levels of 25(OH)D for patients with an active disease as compared to those in MGUS (18·0±6·1 ng/ml versus 28·5±23·1 ng/ml, respectively). In patients with active disease, 25(OH)D levels were not significantly different among myeloid and lymphoid malignancies (21·5 ±10·2 ng/ml versus 23·2±14·1 ng/ml, respectively). In relapsing patients with acute leukemia, we assessed whether the value of circulating 25(OH)D was modified by the time interval between relapse and last complete response to therapy, defined into two groups by the median value (32 months). No difference was noted between the two groups (15·6 ±6·0 ng/ml for patients with shorter remission duration versus 15·5 ±3·8 ng/ml for those with longer remission duration). No correlation was found when considering the duration of last remission as a continuous variable (r = 0·17), but the analysis involved only 9 patients.
Figure 1. Correlations between outcome and 25(OH)D levels are illustrated by (A) the relationship between 25(OH)D levels and the stage of the disease in acute leukemias: patients at the time of diagnosis (n = 27), patients with CR of less than 3 years (n = 11), patients with CR of more than 5 years (n = 13), and patients in relapse (n = 12); and (B) the relationship between 25(OH)D levels and molecular response in leukemias with Philadelphia chromosome: patients with no major response (n = 12), and patients with major response (n = 13).
Discussion
There are increasing molecular and clinical evidence in favor of an anticarcinogenic effect of vitamin D.Citation19,Citation20 Epidemiologic studies have shown that low levels of 25(OH)D may be associated with increased cancer incidence and mortality.Citation4,Citation8,Citation21 This hypothesis has received experimental support and the demonstration that activation of the vitamin D receptor by 1,25(OH)2D induces differentiation and apoptosis, and inhibits proliferation, invasiveness and angiogenesis.Citation22 The vitamin D-sensitive cancers that have been found associated with predicted 25(OH)D levels were those of rapidly proliferating tissue, such as the bone marrow.Citation8 These results are of interest for leukemias given that 1,25(OH)2D induces differentiation of mouse myeloid leukemia cellsCitation23 and improves survival in mice inoculated with murine myeloid leukemia cells.Citation24 However, there is still controversy, a recent study showing that a high circulating 25(OH)D level may be associated with an increased risk of aggressive disease.Citation25
In the present study, we observed a significant association between circulating 25(OH)D and malignant cell burden. To our knowledge, this is the first study examining and demonstrating such an association. Mechanisms that may explain this association are highly speculative because there is a lack of understanding of the molecular mechanism by which vitamin D regulate the expression of genes involved in carcinogenesis. Several limitations of our study deserve comments. Our analysis used a single measurement of plasma 25(OH)D. Potentially 25(OH)D level could represent a confounder such as exercise, outdoor sunlight exposure, or correlated dietary factor. Although the series is large, sample sizes drop in the subgroup analyses by diagnosis or different stages. In addition, there is the problem of missing or non-sufficient data regarding certain subgroups. The strength of our study includes its prospective design with 25(OH)D status being assessed only on few months, thereby reducing the influence of reverse causality. Although the magnitude of the difference was relatively small in our series, patients who were diagnosed with cancer of the breast, colon, prostate, lung or lymphoma during summer or autumn were found to have better prognosis than patients diagnosed during the winter months.Citation6,Citation26–Citation28 We also did not observe significant interactions by gender, age, or nutritional status that have been previously described as factors influencing circulating 25(OH)D levels.Citation8 Higher BMI or obesity has been found to be associated with substantially lower circulating concentrations of 25(OH)D probably as a result of decreased bioavailability of 25(OH)D because of its deposition in body fat compartments.Citation29 Although we did not confirm those results, we cannot exclude an impact of those factors, our study having limited power to observe interactions involving these factors because of our small cohort or because few subjects were out of the normal range regarding nutritional index (BMI). Other influencing factors previously described, but not tested in our study, could also be suspected for influencing our results. Residual confounding by cigarette smoking is possible,Citation8 however not likely because few subjects were current smokers. A single measurement of 25(OH)D may also not reflect long-term vitamin D status. In a steady-state context, it represents the past several weeks to several months of exposureCitation30 and associations between one measure of 25(OH)D and cancer have already been reported.Citation4,Citation31 Although most of the patients included had inadequate levels of 25(OH)D, we do not know whether there is an optimal level with respect to leukemias. There is no general consensus on the optimal level of 25(OH)D for maintaining health. Vitamin D intake has been shown to predict a relatively small proportion of the variance in 25(OH)D.Citation8 It has been hypothesized that vitamin D can amplify the effect of cancer treatment; a synergistic effect that has been observed in both experimental and clinical studies.Citation32,Citation33 In a case report, adequate vitamin D intake (with apparently no other treatment) was associated with clinical remission of CLL for at least 16 years.Citation34
The disease may, directly or indirectly, have an impact on the 25(OH)D level if patients with advanced disease are less able to attend outdoor activities or have unsatisfactory dietary habits with respect of 25(OH)D. This could be the situation for the group of patients with acute leukemia, for whom we found a significant difference between those with progressive disease as compared to those with long-term CR. However, this hypothesis is not consistent with our results regarding minimal residual disease detected by molecular biology in Philadelphia-positive leukemias. In those patients treated by imatinib mesylate, previous studies have strongly suggested that imatinib treatment results in decreased serum phosphate levels and an increase in serum levels of PTH, secondary to decreased calcium levels, and increased serum 1,25(OH)2D.Citation35–Citation38 However, none of our patients with Philadelphia-positive leukemia exhibited PTH levels or calcium levels outside the normal range. Imatinib has shown direct effects on bone-resorbing osteoclasts and bone-forming osteoblasts through inhibition of c-fms, c-kit, carbonic anhydrase II, and the platelet-derived growth factor receptor.Citation39 The strength of the association of 25(OH)D and minimal residual disease suggests that leukemia patients can benefit from increasing the level of serum 25(OH)D. A randomized study, giving or not vitamin D in addition to the treatment with tyrosine kinase inhibitor, should find here an application. In the present study, correlations observed between lower 25(OH)D levels and active diseases are also consistent with the inverse relationship between serum 25(OH)D levels and early mortality that have been previously reported for solid tumors.Citation7,Citation40 In those studies, high 25(OH)D levels were also associated with high vitamin D intake. However, we cannot exclude the possibility that a correlate to serum 25(OH)D status that is unknown and not controlled could also explain the associations we observed.
In conclusion, 25(OH)D deficiency appeared very common in hematological malignancies since only 28% of the patients studied were 25(OH)D sufficient. The lowest blood levels appeared related to active stages of the disease, poor response to therapy, and therefore aggressiveness of the disease. Whether lower 25(OH)D levels have other explanations remains a challenge, like the exact role of vitamin D in malignant cells and its potential need for a therapeutic or preventive approach. Additional efforts to understand the mechanisms through which the vitamin D pathway influences hematological malignancies are warranted.
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