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M.M. Epstein et al.
Table 4. Independent associations of multiple pre-diagnosis plasma immune markers with risk of non-Hodgkin lymphoma (NHL) by major histo- logical subtype of B-cell NHL, for the complete follow-up period and stratified by years of follow up.
Complete follow-up period
0 to less than 5
5 to less than 10
10 or more N cases/
Years from blood draw to diagnosis/index date
Marker N cases/ controls
DLBCL
sTNF-R2 107/570 sIL-2Rα 107/570 CXCL13 107/570 sCD30 107/570 BAFF 107/570
FL
sTNF-R2 83/569 sIL-2Rα 83/569 CXCL13 83/569 sCD30 83/569 BAFF 83/569
CLL/SLL
sTNF-R2 153/569 sIL-2Rα 153/569 CXCL13 153/569 sCD30 153/569 BAFF 153/569
Other B-NHL§
sTNF-R2 111/569 sIL-2Rα 111/569 CXCL13 111/569 sCD30 111/569
BAFF 111/569
OR (95% CI) per 1-SD*,†
0.81 (0.62, 1.07) 1.18 (0.91, 1.53) 1.17 (0.95, 1.45) 1.23 (0.95, 1.59) 0.95 (0.76, 1.18)
1.03 (0.77, 1.38) 1.06 (0.78, 1.46) 1.24 (0.98, 1.58) 1.69 (1.26, 2.26) 0.76 (0.59, 0.98)
1.21 (0.96, 1.52) 1.50 (1.18, 1.90) 0.90 (0.74, 1.10) 1.15 (0.89, 1.48) 0.47 (0.38, 0.58)
1.17 (0.92, 1.49) 1.15 (0.89, 1.48) 1.45 (1.19, 1.77) 1.08 (0.82, 1.41)
0.78 (0.64, 0.95)
N cases/ controls
25/140 25/140 25/140 25/140 25/140
18/140 18/140 18/140 18/140 18/140
36/140 36/140 36/140 36/140 36/140
31/140 31/140 31/140 31/140
31/140
OR (95% CI) per 1-SD*,†
0.61 (0.34, 1.10) 1.83 (1.00, 3.37) 0.71 (0.43, 1.19) 0.90 (0.48, 1.67) 0.96 (0.59, 1.55)
0.45 (0.16, 1.25) 0.93 (0.35, 2.44) 1.10 (0.58, 2.06) 4.85 (2.02, 11.61) 0.70 (0.38, 1.30)
0.98 (0.49, 1.93) 3.71 (1.77, 7.76) 0.78 (0.48, 1.27) 1.43 (0.71, 2.87) 0.32 (0.19, 0.53)
1.28 (0.78, 2.12) 1.07 (0.62, 1.83) 1.50 (0.98, 2.30) 1.28 (0.73, 2.26)
0.74 (0.53, 1.04)
N cases/ controls
25/161 25/161 25/161 25/161 25/161
22/160 22/160 22/160 22/160 22/160
44/160 44/160 44/160 44/160 44/160
27/160 27/160 27/160 27/160
27/160
OR (95% CI)
per 1-SD*,†
1.05 (0.60, 1.85) 1.19 (0.67, 2.11) 1.42 (0.95, 2.12) 1.76 (1.07, 2.89) 0.69 (0.44, 1.08)
0.95 (0.53, 1.69) 1.09 (0.63, 1.89) 1.12 (0.72, 1.75) 1.88 (1.04, 3.40) 0.72 (0.41, 1.24)
1.27 (0.81, 1.98) 1.39 (0.90, 2.15) 0.80 (0.54, 1.20) 1.54 (0.96, 2.46) 0.39 (0.25, 0.61)
1.17 (0.73, 1.90)
1.05 (0.63, 1.74)
1.52 (1.07, 2.17)
1.37 (0.81, 2.32)
0.72 (0.48, 1.07)
controls
57/267 57/267 57/267 57/267 57/267
43/267 43/267 43/267 43/267 43/267
73/267 73/267 73/267 73/267 73/267
53/267
53/267
53/267
53/267
53/267
OR P‡ (95% CI)
per 1-SD*,†
0.83 (0.56, 1.24) 0.42 1.09 (0.75, 1.58) 0.35 1.30 (0.95, 1.79) 0.09 1.09 (0.75, 1.59) 0.19 1.08 (0.78, 1.50) 0.27
1.35 (0.93, 1.96) 0.11 1.09 (0.70, 1.68) 0.95 1.48 (1.03, 2.13) 0.56
1.06 (0.68, 1.64)
0.007
0.78 (0.55, 1.12) 0.94
1.16 (0.85, 1.58) 0.82 1.26 (0.87, 1.83) 0.04 1.04 (0.77, 1.41) 0.48 0.90 (0.62, 1.30) 0.17 0.63 (0.46, 0.86) 0.05
1.11 (0.77, 1.61) 0.90
1.29 (0.87, 1.91) 0.77
1.36 (0.98, 1.88) 0.88
0.79 (0.52, 1.21) 0.20
0.89 (0.64, 1.24) 0.66
N: number; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; CLL/SLL: chronic lymphocytic leukemia/small lymphocytic lymphoma; B-NHL: B-cell NHL; OR: Odds Ratio; CI: Confidence Interval; SD: Standard Deviation; sTNF-R2: soluble tumor necrosis factor receptor-2; sIL-2Rα: soluble interleukin-2 receptor-α; CXCL13: CXC chemokine lig- and 13; sCD30: soluble CD30; BAFF: B-cell activating factor of the TNF family. *All models were adjusted for age at blood draw (continuous), cohort (sex), time of blood draw (continuous) and race/ethnicity (Caucasian, non-Caucasian), and were mutually adjusted for all markers listed, except that models for other B-NHL were not adjusted for race. †Odds Ratios and 95% Confidence Intervals were calculated per 1-standard deviation increase in batch effect-corrected, log-transformed values (with cohort-specific outliers excluded) from the Nurses’ Health Study and Health Professionals Follow-up Study combined. ‡P-values from tests for heterogeneity comparing immune marker-specific esti- mates across time strata. §Other B-NHL subtypes included Burkitt lymphoma (n=4), lymphoplasmacytic lymphoma (n=19), mantle cell lymphoma (n=20), marginal zone lym- phoma (n=39), other B-NHL (n=20), and unclassified B-NHL (n=25).
ified results for the multi-marker models identified with stepwise selection largely agreed with the main results described above (Online Supplementary Table S6).
Discussion
In this pooled analysis within the NHS and HPFS cohorts, we observed significant associations between NHL risk and pre-diagnosis levels of specific plasma immune markers, including a novel, inverse association between levels of BAFF and risk of CLL/SLL. Positive asso- ciations between levels of sIL-2Rα, CXCL13, and sCD30 and risk of all NHL and all B-NHL, as well as the inverse association of BAFF with risk of all NHL and CLL/SLL, were consistent and independent across several analytical approaches to constructing a multi-marker profile associ- ated with risk. In contrast, the individual positive associa- tions noted for sTNF-R2 with risk of all NHL and some B-
NHL end points were attenuated upon adjustment for other immune markers, suggesting a lack of independence in the association between sTNF-R2 levels and NHL risk. Manual selection and automated stepwise selection of multi-marker profiles yielded fairly consistent results for all NHL, but also some differences for individual histolog- ical subtypes, particularly for CLL/SLL. We also observed some variation in the associations between NHL risk and immune markers by time between blood draw and diag- nosis.
Our findings are in agreement with previous studies reporting associations between elevated CXCL13 and/or sCD30 levels and increased NHL risk in HIV-positive and immunocompetent populations, including several reports analyzing blood samples taken many years prior to NHL diagnosis.2,3,8-13 In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Purdue et al.11 prospectively investigated multi-marker models similar to those in our analysis and observed independent positive associations
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haematologica | 2018; 103(10)