Vitamin D Insufficiency and Prognosis in Non-Hodgkin's Lymphoma

Article (PDF Available)inJournal of Clinical Oncology 28(27):4191-8 · September 2010with78 Reads
DOI: 10.1200/JCO.2010.28.6674 · Source: PubMed
Abstract
Vitamin D insufficiency is common in the United States, with low levels linked in some studies to higher cancer incidence, including non-Hodgkin's lymphoma (NHL). Recent data also suggest that vitamin D insufficiency is related to inferior prognosis in some cancers, although there are no data for NHL. We tested the hypothesis that circulating 25-hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were measured by liquid chromatography-tandem mass spectrometry. Mean age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient 25(OH)D levels (< 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL) had inferior EFS (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 1.99; 95% CI, 1.27 to 3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR, 1.94; 95% CI, 1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). There were no associations with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)(2)D levels were associated with better EFS and OS, suggesting that any putative tumor 1-α-hydroxylase activity did not explain the 25(OH)D associations. 25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. Whether normalizing vitamin D levels in these patients improves outcomes will require testing in future trials.
Vitamin D Insufficiency and Prognosis in
Non-Hodgkin’s Lymphoma
Matthew T. Drake, Matthew J. Maurer, Brian K. Link, Thomas M. Habermann, Stephen M. Ansell,
Ivana N. Micallef, Jennifer L. Kelly, William R. Macon, Grzegorz S. Nowakowski, David J. Inwards,
Patrick B. Johnston, Ravinder J. Singh, Cristine Allmer, Susan L. Slager, George J. Weiner, Thomas E. Witzig,
and James R. Cerhan
See accompaning articles on pages 4184, 4199, and 4207
From the College of Medicine, Mayo
Clinic, Rochester, MN; the College of
Medicine, University of Iowa, IA City,
IA; and the University of Rochester,
Rochester, NY.
Submitted February 12, 2010; accepted
May 28, 2010; published online ahead
of print at www.jco.org on August 16,
2010.
Supported in part by Grant No. P50
CA97274 from the National Institutes of
Health and the Mayo Hematologic
Malignancies Fund.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: James R.
Cerhan, MD, PhD, Division of Epidemiol-
ogy, College of Medicine, Mayo Clinic,
200 1st ST SW, Rochester, MN 55905;
e-mail: cerhan.james@mayo.edu.
© 2010 by American Society of Clinical
Oncology
0732-183X/10/2827-4191/$20.00
DOI: 10.1200/JCO.2010.28.6674
ABSTRACT
Purpose
Vitamin D insufficiency is common in the United States, with low levels linked in some studies to
higher cancer incidence, including non-Hodgkin’s lymphoma (NHL). Recent data also suggest that
vitamin D insufficiency is related to inferior prognosis in some cancers, although there are no data
for NHL.
Patients and Methods
We tested the hypothesis that circulating 25-hydroxyvitamin D [25(OH)D] levels are predictive of
event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed
patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)
2
D] levels were measured by
liquid chromatography-tandem mass spectrometry.
Results
Mean age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient
25(OH)D levels ( 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months;
404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic
factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL)
had inferior EFS (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 1.99; 95% CI, 1.27 to
3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR, 1.94; 95% CI,
1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). There were no associations with EFS for
the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)
2
D
levels were associated with better EFS and OS, suggesting that any putative tumor 1-
-
hydroxylase activity did not explain the 25(OH)D associations.
Conclusion
25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma.
Whether normalizing vitamin D levels in these patients improves outcomes will require testing in
future trials.
J Clin Oncol 28:4191-4198. © 2010 by American Society of Clinical Oncology
INTRODUCTION
Vitamin D insufficiency is common in the United
States. Multiple studies have demonstrated that 25%
to 50% of patients seen in clinical practice have vita-
min D levels below the optimal range.
1-3
Vitamin D
is obtained either from skin exposure to ultraviolet B
radiation in the form of sunlight, or through dietary
sources including supplementation. Serum levels of
25-hydroxyvitamin D [25(OH)D] reflect whole
body vitamin D stores, and are used to assess indi-
vidual adequacy or insufficiency. 25(OH)D is con-
verted to 1,25-dihydroxyvitamin D [1,25(OH)
2
D],
considered the physiologically active form of vita-
min D, via the action of 1-
-hydroxylase. While
much of this conversion occurs in the kidney, mul-
tiple other tissues (including lymphoma tumor
cells) also have 1-
-hydroxylase activity, and can
thus regulate 1,25(OH)
2
D levels at the local tissue
level. Once formed, 1,25(OH)
2
D exerts its effects
through binding to the vitamin D nuclear transcrip-
tion factor receptor, where it may regulate the ex-
pression of nearly 200 genes.
4
Although the central role of vitamin D in main-
taining serum calcium and skeletal homeostasis has
long been appreciated, much recent work has dem-
onstrated that vitamin D also has pleiotropic effects
on cellular differentiation, proliferation, apoptosis,
JOURNAL OF CLINICAL ONCOLOGY
ORIGINAL REPORT
VOLUME 28 NUMBER 27 SEPTEMBER 20 2010
© 2010 by American Society of Clinical Oncology
4191
and angiogenesis.
5
Intriguingly, several reports now suggest low
serum 25(OH)D levels may be associated with increased cancer
incidence. At present, the strongest data for an inverse association
between circulating vitamin D levels and malignancy exists for studies
that have examined patients with colorectal
6,7
and breast
8,9
cancer.
While there is little evidence from case-control studies that dietary
intake of vitamin D is associated with non-Hodgkin’s lymphoma
(NHL) risk,
10
a pooled analysis of 10 such studies found that higher
levels of recreational sun exposure were associated with lower risk
of NHL.
11
Furthermore, data from two prospective cohort stud-
ies
12,13
provide suggestive evidence that low serum 25(OH)D levels
are associated with increased risk of NHL incidence.
In addition to risk of developing malignancy, there are recent
data that suggest low 25(OH)D levels at diagnosis may be associated
with poorer prognosis in colorectal
14
and breast
15
cancer, as well as
multiple myeloma.
16
To our knowledge, however, there are no data on
NHL prognosis except for a small study of 24 patients which reported
that alfacalcidol (a synthetic analog of 1,25(OH)
2
D) induced regres-
sion in follicular, small cleaved cell lymphoma.
17
To test the hypothe-
sis that vitamin D levels are predictive of event-free and overall survival
in patients with newly diagnosed NHL, we examined the prognostic
effects of circulating 25(OH)D levels in a prospective cohort of con-
secutively enrolled patients with newly diagnosed NHL.
PATIENTS AND METHODS
Study Population
This study was reviewed and approved by the human subjects institu-
tional review board at the Mayo Clinic and the University of Iowa, and written
informed consent was obtained from all participants. All subjects in this
analysis were from the Molecular Epidemiology Resource of the University of
Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence.
18
Since September 2002, we offered enrollment to consecutive, newly diagnosed
patients with NHL (within 9 months) who were evaluated at Mayo Clinic
Rochester and the University of Iowa, were age 18 years or older, and were a
resident of the United States. Exclusion criteria included known HIV infection
and unwillingness or inability to provide written informed consent.
All pathology was reviewed by a lymphoma hematopathologist to verify
the diagnosis and to classify each case according to the WHO classification.
19
We grouped the subtypes for analysis into diffuse large B-cell (DLBCL), man-
tle cell lymphoma (MCL), follicular lymphoma (FL), post-FL (consisting of
marginal zone and lymphoplasmacytic lymphoma), and T-cell lymphoma
(TCL; consisting of peripheral TCL, anaplastic large cell lymphoma, cutaneous
TCL, and TCL not otherwise specified [NOS]), as well as all other NHL.
Baseline clinical, laboratory, and treatment data were abstracted from
medical records using a standard protocol. Participants provided a peripheral
blood sample for serum and DNA banking. Timing of the sample collection
with respect to treatment (ie, pretreatment, during treatment, or post-
treatment) was recorded. All patients were systematically observed every 6
months for the first 3 years, and then annually thereafter. Disease progression,
retreatment, and deaths were verified through medical record review. We also
verified patients’ reports of no disease progression on an annual basis against
their physician’s report. For decedents, we obtained a copy of the death certif-
icate as well as medical records associated with death. Study physicians as-
signed a cause of death using definitions developed for the Eastern Cooperative
Oncology Group (ECOG) Intergroup trial 4494.
20
Vitamin D Measurements
We defined vitamin D insufficiency as a serum 25(OH)D level lower
than 25 ng/mL (62.5 nmol/L). Although consensus guidelines for the diagnosis
of vitamin D insufficiency have not been established, this is an accepted level
for the establishment of hypovitaminosis D, and is the current threshold used
Table 1. Demographic and Clinical Correlates of Vitamin D Levels and
Prevalence of 25-Hydroxyvitamin D Insufficiency
Covariate No.
25-
Hydroxyvitamin
D Levels
(ng/mL)
25-Hydroxyvitamin D
Insufficient
Mean SD No. % P
Timing of serum draw,
120 days of
diagnosis
Pretreatment 649 27.4 10.4 265 40.8 .002
During or post-
treatment 334 24.8 11.1 171 51.4
Sex
Male 540 26.3 10.2 242 44.8 .75
Female 443 26.7 11.3 194 43.8
Age, years
60 458 26.4 10.7 204 44.5 .91
61 525 26.5 10.8 232 44.2
Residence at diagnosis
MN, IA, IL, WI, ND, SD 874 26.2 10.6 399 45.7 .02
Outside six-state region 109 29.0 11.3 37 33.9
Month of diagnosis
March-May 212 25.0 10.1 110 51.9 .02
June-August 249 28.3 10.1 94 37.8
September-November 265 27.0 11.5 114 43.0
December-February 257 25.5 10.8 118 45.9
Performance status
0 or 1 845 27.7 10.3 336 39.8 .001
1 137 18.8 10.3 100 73.0
Subtype†
DLBCL 370 24.7 10.7 192 51.9 .02
TCL 70 23.2 11.8 40 57.1
MCL 71 27.0 9.1 26 36.6
FL 285 28.2 10.3 110 38.6
Post-FL 109 28.8 11.0 41 37.6
All other 78 28.1 10.5 27 34.6
IPI for DLBCL only
0-1 135 25.9 9.7 62 45.9 .07
2 97 25.6 11.0 50 51.6
3 81 24.9 11.2 42 51.9
4 or 5 57 19.9 10.7 38 66.7
IPI for TCL only
0-1 23 30.2 10.7 9 39.1 .17
2 18 20.5 10.5 11 61.1
3 14 19.9 10.3 9 64.3
4 or 5 15 18.9 12.5 11 73.3
FLIPI for FL only
0-1 127 28.5 10.2 48 37.8 .03
2 88 27.7 10.9 38 43.2
3 50 30.3 9.5 12 24.0
4-5 20 23.7 9.5 12 60.0
MIPI for MCL only
0-3 (low risk) 58 27.7 8.5 18 31.0 .04
4-12 (interm/high risk) 13 23.9 11.2 8 61.5
Abbreviations: DLBCL, diffuse large B-cell lymphoma; TCL, T-cell lymphoma;
MCL, mantle cell lymphoma; FL, follicular lymphoma; IPI, International Prognostic
Index; FLIPI, Follicular Lymphoma International Prognostic Index; MIPI, Mantle
Cell International Prognostic Index; PTCL, peripheral T-cell lymphoma; NOS, not
otherwise specified; CTCL, cutaneous T-cell lymphoma; ALCL, anaplastic large-
cell lymphoma; MZL, marginal-zone lymphoma; LPL, lymphoplasmacytic lym-
phoma; NHL, non-Hodgkin’s lymphoma; BL, Burtkitt’s lymphoma.
P value from
2
test of vitamin D sufficient v insufficient.
†TCL includes PTCL NOS (n 25), CTCL (n 9), ALCL (n 7), and
miscellaneous (n 29); Post-FL includes splenic MZL (n 13), extranodal MZL
(n 73), nodal MZL (n 6), and LPL (n 17); and other NHL includes BL (n 8),
composite NHL (n 10), other B-cell NOS (n 51), and miscellaneous (n 9).
Drake et al
4192 © 2010 by American Society of Clinical Oncology
J
OURNAL OF CLINICAL ONCOLOGY
by Mayo Medical Laboratories (http://www.mayomedicallaboratories.com).
In order to avoid assay variability, which can significantly confound vitamin D
determinations made using radioimmunoassay methods,
21
all vitamin D mea-
surements were made by liquid chromatography-tandem mass spectrometry
(LC-MS/MS). A single vitamin D measurement has been shown to be
highly reproducible.
22,23
Measurements of 25(OH)D were made by deuterated stable isotope
[d
6
-25(OH)D]-dilution LC-MS/MS on an API 4000 instrument (Applied
Biosystems, Forest City, CA), with sample introduction performed by a cohe-
sive four-channel multiplexed system (Thermo-Fisher, Waltham, MA). Cali-
bration utilized a 6-point standard curve over a concentration range of 0 to 200
ng/mL. Each subject’s total 25(OH)D was assessed as the additive sum of the
25(OH)D
2
and 25(OH)D
3
components. Intra- and interassay coefficients of
variation were all lower than 7% (Appendix Table A1, online only). All 983
samples were successfully assayed. For patients with DLBCL and TCL, we also
measured 1,25(OH)
2
D, which was the sum of each subject’s 1,25(OH)
2
D
2
and
1,25(OH)
2
D
3
as determined by isotope-dilution LC-MS/MS on an API 5000
instrument (Applied Biosystems) using deuterated internal standards for each
analyte. Intra- and interassay coefficients of variation are reported in Appendix
Table A1.
Statistical Analysis
2
and Fisher’s exact tests, where appropriate, were used to assess the
association of 25(OH)D insufficiency and clinical and demographic factors.
All survival analyses were analyzed within the following grouped subtypes:
DLBCL, FL, post-FL, MCL, TCL, and all other NHL. Event-free survival (EFS)
was defined as the time from diagnosis to disease progression, re-treatment, or
death due to any cause. Lymphoma-specific survival (LSS) was defined as the
time from diagnosis to death due to disease, and overall survival (OS) was
defined as the time from diagnosis to death due to any cause. Patients without
an event or death were censored at time of last known follow-up. Kaplan-
Meier
24
curves and Cox proportional hazards regression models
25
were used
to assess the association of vitamin D levels and outcome. Cox models were
adjusted for subtype specific prognostic factors. For DLBCL, this included the
International Prognostic Index (IPI)
26
and treatment (defined as immu-
nochemotherapy v other); for FL, this included the FLIPI score
27
and grade 3
FL; for TCL, this included the IPI
26
; for MCL, this included the mantle cell
IPI
28
; for post-FL, this included stage and performance status (PS); and for all
other NHL, this included stage and PS. We also analyzed the associations using
the actual, continuously distributed 25(OH)D levels values via penalized
smoothing splines, or P-splines.
29
Briefly, this is a nonparametric modeling
approach that is a generalization of polynomial splines. It allowed us to exam-
ine the unrestricted association of the 25(OH)D levels with EFS and OS,
without regard to functional form. For DLBCL and TCL, we further evaluated
1,25(OH)
2
D levels (categorized into quartiles based on histology-specific dis-
tribution) with the three outcomes, overall and stratified by 25(OH)D levels
(insufficient, sufficient). Analyses were performed using SAS version 9.1.3
(SAS Institute, Cary, NC) and R ( http://www.r-project.org/).
RESULTS
From September 2002 through February 2008, 1,691 patients with
NHL were enrolled onto the study; this does not include chronic
lymphocyte leukemia/small lymphocyte leukemia, which is being re-
ported elsewhere. Of the 1,691 patients, 701 were excluded because
they did not have a serum sample available and/or drawn within 120
days of diagnosis and seven were excluded for missing clinical or
outcome data, leaving a total of 983 subjects available for analysis.
Of the 983 patients with NHL, the mean age at diagnosis was
62 years (range, 19 to 94 years) and 55% were male. Overall, 56
patients (5.7%) had severe insufficiency ( 10 ng/mL), 380
AB
0
Log-rank P = .005 Log-rank P < .001
Event Free (%)
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
Alive (%)
CD
0
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
0
Alive (%)
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
0
Event Free (%)
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
Log-rank P = .003
HR = 2.47 (95% CI, 1.35 to 4.53)
IPI adjusted HR = 1.94 (95% CI, 1.04 to 3.61)
25 Vitamin D sufficient
25 Vitamin D insufficient
HR = 1.67 (95% CI, 1.17 to 2.38)
IPI & treatment adjusted HR = 1.41 (95% CI, 0.98 to 2.04)
HR = 2.34 (95% CI, 1.52 to 3.62)
IPI & treatment adjusted HR = 1.99 (95% CI, 1.27 to 3.13)
HR = 2.67 (95% CI, 1.80 to 6.04)
IPI adjusted HR = 2.38 (95% CI, 1.04 to 5.41)
25 Vitamin D sufficient
25 Vitamin D insufficient
25 Vitamin D sufficient
25 Vitamin D insufficient
25 Vitamin D sufficient
25 Vitamin D insufficient
Log-rank P = .01
Fig 1. Kaplan-Meier curves for 25-hydroxyvitamin D deficiency and (A) diffuse large B-cell (DLBCL) event-free survival (EFS), (B) DLBCL overall survival (OS), (C) T-cell
lymphoma (TCL) EFS and (D) TCL OS. HR, hazard ratio; IPI, International Prognostic Index.
Vitamin D and NHL Prognosis
www.jco.org
© 2010 by American Society of Clinical Oncology 4193
(38.7%) had mild to moderate insufficiency (10 to 24 ng/mL), and
547 (55.6%) were in the optimal range (25 to 80 ng/mL) for
25(OH)D; 436 (44%) were classified as 25(OH)D insufficient
(combination of severe and mild to moderate insufficiency).
25(OH)D insufficiency was not correlated with age or sex, but was
positively correlated with having a serum drawn during or post-
treatment; residence in the six state region of the upper Midwest;
diagnosis from March through May; PS higher than 1; and DLBCL
or TCL subtypes (Table 1). Subtype-specific prognostic indices
were also positively correlated with 25(OH)D insufficiency (Table
1), and this was most strongly driven by performance status within
each of the subtypes (Appendix Table A2, online only). Disease
stage was not correlated with 25(OH)D insufficiency for DLBCL,
FL, or post-FL, but higher disease stage was correlated with
25(OH)D insufficiency in TCL (Appendix Table A2).
During a median follow-up of 34.8 months (range, 0.5 to 77
months), there were 404 events and 193 deaths, of which 168 were
attributed to lymphoma. For DLBCL, 52% of the patients were
25(OH)D insufficient, and as shown in Figure 1, insufficient patients
had inferior EFS (log-rank P .005) and OS (log-rank P .001);
details on univariate HRs for all outcomes are available in Appendix
Table A3 (online only). After adjusting for the IPI and treatment
(Table 2), 25(OH)D insufficient patients continued to have inferior
EFS (HR, 1.41; 95% CI, 0.98 to 2.04), LSS (HR, 2.16; 95% CI, 1.33 to
3.51) and OS (HR, 1.99; 95% CI, 1.27 to 3.13). The association of
25(OH)D levels with EFS (Fig 2A) and OS (Fig 2B) was mainly ob-
served over the range of 15 to 25 ng/mL, and was relatively flat above
30 ng/mL.
For TCL (which included PTCL and CTCL, see Table 1 for
details), 57% of the patients were 25(OH)D insufficient, and insuf-
ficient patients had inferior EFS (log-rank P .003) and OS
(log-rank P .01). After adjustment for IPI (Table 2), 25(OH)D
insufficient patients continued to have inferior EFS (HR, 1.94; 95%
CI, 1.04 to 3.61), LSS (HR, 2.26; 95% CI, 0.99 to 5.17) and OS (HR,
2.38; 95% CI, 1.04 to 5.41). Inferior EFS (Fig 2C) and OS (Fig 2D)
was observed among TCL patients in both the insufficient ( 25
ng/mL) and the lower end of the optimal range (25 to 80 ng/mL) of
25(OH)D levels.
The prevalence of 25(OH)D insufficiency for the remaining
subtypes in Table 2 ranged from 27% to 39%, and there were no
associations of 25(OH)D insufficiency with EFS. However, with the
exception of LSS in FL, HRs for LSS and OS for the remaining subtypes
were all above 1, although the confidence intervals were wide, reflect-
ing the small number of deaths in these subtypes.
Further adjustment of results in Table 1 for season of diagnosis or
residence in the upper six Midwest states did not materially alter the
associations ( 10% change in HRs) reported in Table 2 (data
not shown).
All serum samples tested were drawn within 120 days of diag-
nosis, and from a physiologic perspective we would expect little
Table 2. Multivariable-Adjusted Hazard Ratios for 25-Hydroxyvitamin Insufficiency and Event-Free, Lymphoma-Specific, and Overall Survival
Variable No.
Distribution
(%)
Adjustment
Factor(s)
Event-Free Survival Lymphoma-Specific Survival Overall Survival
No. of
Events
%
Events HR 95% CI
No. of
Events
%
Events HR 95% CI
No. of
Events
%
Events HR 95% CI
DLBCL IPI, treatment
Sufficient 178 48.1 50 28.1 1.00 Reference 27 15.2 1.00 Reference 31 17.4 1.00 Reference
Insufficient 192 51.9 82 42.7 1.41 0.98 to 2.04 63 32.8 2.16 1.33 to 3.51 69 35.9 1.99 1.27 to 3.13
P .07 .002 .003
TCL IPI
Sufficient 30 42.9 16 53.3 1.00 Reference 8 26.7 1.00 Reference 8 26.7 1.00 Reference
Insufficient 40 57.1 33 82.5 1.94 1.04 to 3.61 20 50.0 2.26 0.99 to 5.17 21 52.5 2.38 1.04 to 5.41
P .04 .05 .04
MCL MIPI
Sufficient 45 63.4 27 60.0 1.00 Reference 11 24.4 1.00 Reference 11 24.4 1.00 Reference
Insufficient 26 36.6 18 69.2 1.09 0.59 to 2.01 8 30.8 1.35 0.53 to 3.39 8 30.8 1.35 0.53 to 3.39
P .78 .53 .53
FL FLIPI, FLIII,
treatment†
Sufficient 175 61.4 65 37.1 1.00 Reference 5 2.9 1.00 Reference 10 5.7 1.00 Reference
Insufficient 110 38.6 39 35.5 1.07 0.71 to 1.62 4 3.6 0.90 0.23 to 3.49 9 8.2 1.52 0.60 to 3.88
P .75 .88 .38
Post-FL Stage, PS
Sufficient 68 62.4 25 36.8 1.00 Reference 4 5.9 1.00 Reference 4 5.9 1.00 Reference
Insufficient 41 37.6 14 34.2 0.98 0.51 to 1.89 4 9.8 2.76 0.58 to 13.1 4 9.8 2.76 0.58 to 13.1
P .95 .20 .20
All other Stage, PS
Sufficient 51 63.0 21 41.2 1.00 Reference 7 13.7 1.00 Reference 8 15.7 1.00 Reference
Insufficient 27 27.0 14 51.9 1.15 0.57 to 2.32 7 25.9 1.73 0.58 to 5.17 10 37.0 2.08 0.79 to 5.49
P .71 .33 .14
Abbreviations: HR, hazard ratio; DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; TCL, T-cell lymphoma; MCL, mantle cell lymphoma; MIPI,
Mantle Cell International Prognostic Index; FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; FLIII, follicular lymphoma grade 3; PS,
performance status.
Immunochemotherapy v all other therapy.
†Rituximab-based therapy, other chemotherapy v observation.
Drake et al
4194 © 2010 by American Society of Clinical Oncology
J
OURNAL OF CLINICAL ONCOLOGY
change of 25(OH)D levels from chemotherapy over this short
interval. Nevertheless, 34% of samples were drawn during or after
initial therapy, and mean 25(OH)D levels and the prevalence of
25(OH)D insufficiency were modestly associated with timing of
blood draw overall (Table 1). This overall association varied by
subtype, and was seen only for TCL, MCL, and all other NHL, but
not for DLBCL, FL, and post-FL (Appendix Table A2). Adjustment
for timing of serum draw did not materially alter the associations in
Table 2 (data not shown). Further, when restricted to pretreatment
serum samples (Appendix Table A4, online only), our basic find-
ings held, although the CIs around the point estimates became
unstable due to small numbers for subset analyses in the lym-
phoma subtypes.
One potential interpretation of the association of low 25(OH)D
levels with inferior DLBCL and TCL prognosis is that patients with a
larger tumor burden might have increased conversion of 25(OH)D to
1,25(OH)
2
D due to increased 1-
-hydroxylase activity from the tu-
mor, leading to artificially low serum 25(OH)D levels.
30
As such,
tumor size or aggressiveness might be a confounding factor. Although
adjustment for IPI should remove most of the potential confounding,
residual confounding remains a concern. Calcium levels were similar
between 25(OH)D sufficient and insufficient patients with DLBCL
and TCL (Appendix Table A5, online only). In addition, further ad-
justment of the results in Table 1 for albumin-corrected-calcium (as a
surrogate for tumor activity, since high 1-
-hydroxylase activity
would be expected to also increase serum calcium levels) did not
materially change the DLBCL results (Appendix Table A5). The re-
sults for TCL attenuated for EFS (HR, 1.35; 95% CI, 0.63 to 2.88) and
to a lesser extent for LSS (HR, 2.00; 95% CI, 0.74 to 5.37), while OS
remained similar (HR, 2.17; 95% CI, 0.82 to 5.76).
To further address this issue, we measured 1,25(OH)
2
D levels in
patients with DLBCL and TCL. For DLBCL, patients in the lowest
three quartiles of 1,25(OH)
2
D had inferior EFS, LSS, and OS (Fig 3
and Table 3); this association was maintained when stratified by
25(OH)D sufficient versus insufficient. For TCL, patients below the
median (too few patients to use quartiles) also had inferior outcomes
in a pattern similar to that seen for DLBCL, although all estimates were
imprecise and not statistically significant, likely due to small subject
numbers (Fig 3 and Table 3). Overall, these data do not support the
hypothesis that the association of lower 25(OH)D levels with poor
prognosis in DLBCL and TCL is confounded by tumor production
of 1-
-hydroxylase. Further, these data also indicate that there
appears to be a direct association of lower 1,25(OH)
2
D levels with
inferior outcome.
AB
Total Vitamin D Total Vitamin D
0 10 20 30 40 50 60 0 10 20 30 40 50 60
DLBCL Event-Free Survival
Risk Ratio
5.0
1.0
0.5
0
5.0
1.0
0.5
DLBCL Overall Survival
Risk Ratio
5.0
1.0
0.5
CD
Total Vitamin D Total Vitamin D
01020304050 1020304050
TCL Event-Free Survival
Risk Ratio
TCL Overall Survival
Risk Ratio
5.0
1.0
0.5
Fig 2. Estimated hazard ratios (solid line) and 95% CI (dotted lines) from multivariate models for 25-hydroxyvitamin D level (ng/mL) and (A) diffuse large B-cell (DLBCL)
event-free survival, (B) DLBCL overall survival, (C) T-cell lymphoma (TCL) event-free survival, and (D) TCL overall survival.
Vitamin D and NHL Prognosis
www.jco.org
© 2010 by American Society of Clinical Oncology 4195
DISCUSSION
Over 40% of patients with NHL in this cohort had insufficient
25(OH)D levels within 120 days of diagnosis, and low levels were
associated with inferior EFS, LSS, and OS for DLBCL and TCL, two of
the most aggressive NHL subtypes in this study. These associations
remained after adjustment for clinical factors, including IPI, timing of
blood draw (pretreatment v not), and season of diagnosis. While there
was no association of vitamin D insufficiency and EFS for MCL, FL,
post-FL or all other NHL, HRs were elevated for OS. These estimates
were not statistically significant, most likely due to either the small
number of patients with these types of NHL included in the cohort
and/or few deaths during the relatively short follow-up time. Further
studies in larger groups of patients should be performed to learn the
longer-term implications of vitamin D insufficiency in these less ag-
gressive NHL types.
Strengths of our study include the large, prospective cohort study
design of consecutively enrolled patients with newly diagnosed NHL;
availability of key baseline clinical and treatment data; and nearly
complete follow-up of patients to define EFS, LSS, and OS. In addi-
tion, we used LC-MS/MS methods for the measurement of serum
25(OH)D and 1,25(OH)
2
D levels, a technique which is considered to
be the most reliable and accurate for 25(OH)D determination.
21
The
major limitation of the study is the use of an observational study
design, which is susceptible to confounding, although we were able to
adjust for key clinical prognostic factors. Also, our study does not
answer the question of whether replacing vitamin D would lead to a
better prognosis.
Our finding that lower levels of both 25(OH)D and 1,25(OH)
2
D
were associated with inferior EFS, LSS, and OS in two aggressive NHL
subtypes suggests that the prognostic effect of vitamin D may be
directly related to its impact on the lymphoma and not simply a
general host effect. Biologically, this is plausible, as vitamin D has been
well-documented to be capable of modulating several critical cellular
processes, including inhibition of carcinogenesis by induction of cel-
lular differentiation, inhibition of proliferation and angiogenesis, and
promotion of apoptosis.
5
Notably, in vitro vitamin D has been shown
to inhibit proliferation and induce differentiation of both lympho-
cytes
31
and lymphoma cell lines.
32
The associations with OS, but not EFS, which were hinted at in
the other NHL subtypes, raise the hypothesis that vitamin D also likely
impacts other health outcomes in these diseases with a long natural
history, and thereby improves OS.
33
This will need to be evaluated in
larger datasets with sufficient power.
In our study, we measured both the storage form of vitamin D
[25(OH)D] and its biologically active metabolite [1,25(OH)
2
D]. This
examination was prompted by our concern that the low levels of
25(OH)D found in subjects with worse prognosis might be a function
of greater tumor burden with resultant increased 1-
-hydroxylase
activity, leading to increased conversion of 25(OH)D to 1,25(OH)
2
D.
However, this was not the case. Rather, both lower 25(OH)D and
1,25(OH)
2
D levels were associated with inferior EFS and OS. Whether
AB
0
Log-rank P = .01 Log-rank P = .01
Event Free (%)
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
Alive (%)
CD
0
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
0
Alive (%)
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
0
Event Free (%)
Time (months)
1.0
0.8
0.6
0.4
0.2
126 2418 30 36 60544842
Log-rank P = .07
Median+ (46+ pg/mL)
< Median (< 46 pg/mL)
Median+ (46+ pg/mL)
< Median (< 46 pg/mL)
Log-rank P = .35
Quartile 4 (62+ pg/mL)
Quartile 3 (46-61 pg/mL)
Quartile 2 (34-45 pg/mL)
Quartile 1 (<34 pg/mL)
Quartile 4 (62+ pg/mL)
Quartile 3 (46-61 pg/mL)
Quartile 2 (34-45 pg/mL)
Quartile 1 (<34 pg/mL)
Fig 3. Kaplan-Meier curves for 1,25-dihydroxyvitamin D levels and (A) diffuse large B-cell (DLBCL) event-free survival (EFS), (B) DLBCL overall survival (OS), (C) T-cell
lymphoma (TCL) EFS, and (D) TCL OS. 1,25-dihydroxyvitamin D levels in pg/mL.
Drake et al
4196
© 2010 by American Society of Clinical Oncology
J
OURNAL OF CLINICAL ONCOLOGY
25(OH)D exerts biologic effects independent of 1,25(OH)
2
D, or
serves merely as a substrate for conversion to 1,25(OH)
2
D is unclear,
although the affinity of 1,25(OH)
2
D relative to 25(OH)D for the
vitamin D receptor has been shown to be approximately 650-
fold greater.
34
Whether vitamin D supplementation in patients with newly di-
agnosed lymphoma and 25(OH)D levels below the optimal range will
lead to improved outcomes is unknown, but warrants further investi-
gation. The results for TCL, but not DLBCL, suggest supplementation
even within the optimal range might be useful. None of the patients
were above the optimal range, and there is no justification from our
study to consider supraphysiologic levels. Finally, the role of vitamin D
supplementation to maintain 25(OH)D levels within the optimal
range for the primary prevention of NHL, which our study did not
address, is not known.
In summary, our study provides strong data on the relationship
between vitamin D and prognosis in NHL, and suggests a need for
additional studies both to confirm our findings and to prospectively
assess the role of vitamin D supplementation in NHL progression and
survival. At this time, there is no definitive evidence for a causative
relationship between lower vitamin D levels and poorer outcomes in
lymphoma, and our study did not answer the question of whether
normalizing vitamin D levels in these patients improves outcome. We
do note that there are general clinical recommendations for vitamin D
testing and replacement in patients with serum 25(OH)D levels below
the optimal range.
35
Our data may provide additional incentive to
follow these general guidelines particularly closely in DLBCL and
TCL patients.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Matthew T. Drake, James R. Cerhan
Financial support: Matthew T. Drake, James R. Cerhan
Administrative support: James R. Cerhan
Provision of study materials or patients: Brian K. Link, Thomas M.
Habermann, Stephen M. Ansell, Ivana N. Micallef, William R. Macon,
Table 3. Multivariable-Adjusted HRs for 1,25-Dihydroxyvitamin D Levels (overall, and stratified by 25-hydroxyvitamin D insufficiency) and Event-Free,
Lymphoma-Specific, and Overall Survival
1,25-Dihydroxyvitamin D level (pg/mL) No.
Event-Free Survival Lymphoma-Specific Survival Overall Survival
No. of
Events
%
Events HR 95% CI
No. of
Events
%
Events HR 95% CI
No. of
Events
%
Events HR 95% CI
DLBCL, all
Q4 (62) 91 19 20.9 1.00 Reference 11 12.1 1.00 Reference 12 13.2 1.00 Reference
Q3 (46-61) 98 35 35.7 1.86 1.06 to 3.26 26 26.5 2.42 1.19 to 4.92 30 30.6 2.61 1.33 to 5.11
Q2 (34-45) 86 35 40.7 2.22 1.27 to 3.90 25 29.1 2.63 1.29 to 5.37 28 32.6 2.73 1.38 to 5.40
Q1 (34) 92 43 46.7 2.18 1.26 to 3.76 28 30.4 2.16 1.07 to 4.37 30 32.6 2.14 1.09 to 4.21
P for trend .01 .10 .11
DLBCL, insufficient 25-hydroxyvitamin D
Q4 (62) 40 11 27.5 1.00 Reference 7 17.5 1.00 Reference 8 20.0 1.00 Reference
Q3 (46-61) 46 19 41.3 1.74 0.83 to 3.65 15 32.6 2.44 0.99 to 6.01 17 37.0 2.42 1.04 to 5.63
Q2 (34-45) 50 23 46.0 2.00 0.97 to 4.10 19 38.0 2.50 1.05 to 5.96 21 42.0 2.44 1.08 to 5.53
Q1 (34) 54 29 53.7 1.95 0.96 to 3.97 22 40.7 1.99 0.84 to 4.71 23 42.6 1.88 0.83 to 4.26
P for trend .11 .33 .36
DLBCL, sufficient 25-hydroxyvitamin D
Q4 (62) 51 8 15.7 1.00 Reference 4 7.8 1.00 Reference 4 7.8 1.00 Reference
Q3 (46-61) 52 16 30.8 2.07 0.88 to 4.91 11 21.1 2.81 0.88 to 9.02 13 25.0 3.40 1.09 to 10.59
Q2 (34-45) 36 12 33.3 2.10 0.84 to 5.24 6 16.7 1.77 0.47 to 6.64 7 19.4 2.23 0.62 to 7.95
Q1 (34) 38 14 36.8 2.32 0.93 to 5.34 6 15.8 1.66 0.47 to 5.93 7 18.4 1.92 0.56 to 6.58
P for trend .17 .73 .62
TCL, all
Median (46) 36 22 61.1 1.00 Reference 11 30.6 1.00 Reference 11 30.6 1.00 Reference
median ( 46) 34 27 79.4 1.62 0.92 to 2.88 17 50.0 1.83 0.86 to 3.93 18 52.9 1.94 0.91 to 4.12
P .09 .12 .08
TCL, insufficient 25-hydroxyvitamin D
Median (46) 16 13 81.3 1.00 Reference 7 43.8 1.00 Reference 7 43.8 1.00 Reference
median ( 46) 24 20 83.3 2.07 0.93 to 4.62 13 54.2 1.84 0.70 to 4.85 14 58.3 1.95 0.75 to 5.05
P .08 .22 .17
TCL, sufficient 25-hydroxyvitamin D
Median (46) 20 9 45.0 1.00 Reference 4 20.0 1.00 Reference 4 20.0 1.00 Reference
median ( 46) 10 7 70.0 1.10 0.40 to 3.01 4 40.0 1.82 0.45 to 7.36 4 40.0 1.82 0.45 to 7.36
P .86 .40 .40
NOTE. Adjusted for International Prognostic Index. Quartile distribution based on histology specific cut points.
Abbreviations: HR, hazard ratio; DLBCL, diffuse large B-cell lymphoma; Q, quartile; TCL, T-cell lymphoma.
Vitamin D and NHL Prognosis
www.jco.org © 2010 by American Society of Clinical Oncology 4197
Grzegorz S. Nowakowski, David J. Inwards, Patrick B. Johnston, George
J. Weiner, Thomas E. Witzig
Collection and assembly of data: Matthew T. Drake, Matthew J. Maurer,
Brian K. Link, Thomas M. Habermann, Ravinder J. Singh, Cristine
Allmer, James R. Cerhan
Data analysis and interpretation: Matthew T. Drake, Matthew J.
Maurer, Cristine Allmer, Susan L. Slager, James R. Cerhan
Manuscript writing: Matthew T. Drake, James R. Cerhan
Final approval of manuscript: Matthew T. Drake, Matthew J.
Maurer, Brian K. Link, Thomas M. Habermann, Stephen M. Ansell,
Ivana N. Micallef, Jennifer L. Kelly, William R. Macon, Grzegorz S.
Nowakowski, David J. Inwards, Patrick B. Johnston, Ravinder J.
Singh, Cristine Allmer, Susan L. Slager, George J. Weiner, Thomas E.
Witzig, James R. Cerhan
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■■■
Drake et al
4198 © 2010 by American Society of Clinical Oncology
J
OURNAL OF CLINICAL ONCOLOGY
    • "Moreover, recent data also suggest that VD insufficiency is related to inferior prognosis in some hematologic malignancies. In a prospective cohort of 983 newly diagnosed patients with non-Hodgkin's lymphomas, 25-OH-D 3 insufficiency was associated with an inferior event-free survival and overall survival in patients with DLBCL and T-cell lymphoma [12]. Shanafelt et al. revealed inferior prognosis in CLL patients with VD insufficiency . "
    Full-text · Article · May 2016
    • "Vitamin D deficiency is common in cancer patients and correlates with disease progression. In observational studies, vitamin D deficiency is associated with increased incidence of breast and colon cancer, as well as with an unfavorable course of non-Hodgkin lymphoma [30,919293949596. A recent meta-analysis found a 12% (95% CI = 3%–22%) reduction of lung cancer incidence with respect to 25(OH)D concentrations for an increase from 20 to 50 nmol/L. "
    [Show abstract] [Hide abstract] ABSTRACT: Nutritional supplements are widely used among patients with cancer who perceive them to be anticancer and antitoxicity agents. Depending on the type of malignancy and the gender 30%-90% of the cancer patients supplement their diets with antioxidant and immuno-stabilizing micronutrients, such as selenium, vitamin C, and vitamin D, often without the knowledge of the treating physician. From the oncological viewpoint, there are justifiable concerns that dietary supplements decrease the effectiveness of chemotherapy and radiotherapy. Recent studies, however, have provided increasing evidence that treatment is tolerated better-with an increase in patient compliance and a lower rate of treatment discontinuations-when micronutrients, such as selenium, are added as appropriate to the patient's medication. Nutritional supplementation tailored to an individual's background diet, genetics, tumor histology, and treatments may yield benefits in subsets of patients. Clinicians should have an open dialogue with patients about nutritional supplements. Supplement advice needs to be individualized and come from a credible source, and it is best communicated by the physician.
    Full-text · Article · Mar 2016
    • "Genotyping in the validation patient population. We attempted to validate the top three SNPs from the PFS analysis (rs2243828 in MPO, rs10508293 in AKR1C3 and rs1883112 in NCF4) using data and biospecimens from the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE [24,25]. The validation study was reviewed and approved by the Human Subjects Review Boards at the University of Iowa and Mayo Clinic in accordance with an assurance filed with and approved by the U.S. Department of Health and Human Services. "
    [Show abstract] [Hide abstract] ABSTRACT: Variable survival outcomes are seen following treatment for aggressive non-Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B-cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress-related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline-based therapies. Their associations with progression-free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top 3 SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR]=1.87, 95% confidence interval [CI]=1.14-3.06, P = 0.013), AKR1C3 rs10508293 (HR=2.09, 95% CI=1.28-3.41, P=0.0032) and NCF4 rs1883112 (HR=0.66, 95% CI=0.43-1.02, P=0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR=0.66, 95% CI=0.44-1.01, P=0.05) and the meta-analysis was significant (HR=0.66, 95% CI=0.49-0.89, P<0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta-analysis remained significant (HR=1.64, 95% CI=1.12-2.41). These two SNPs showed similar trends with OS in the meta-analysis (for NCF4, HR=0.72, 95% CI 0.51-1.02, P=0.07 and for MPO, HR=2.06, 95% CI 1.36-3.12, P<0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL.
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