Elevated CCL22 and sIL2Rα Levels Precede the Diagnosis of Young Adult Classical Hodgkin Lymphoma: A Nested Case-Control Study from the DoD Serum Repository

Background: Young adult classical Hodgkin lymphoma (YAcHL) patients have immune abnormalities that persist long after cure. It is difficult to assess whether manifestations are present prior to diagnosis because the cancer is rare and occurs in the late teens and twenties, and therefore cohort studies are generally impractical. We conducted a nested case-control study in the Department of Defense (DoD) Serum Repository, a repository of samples from active duty U.S. military service members, to determine whether levels of serum biomarkers of Th1, Th2 and innate immunity predicted risk of YAcHL. Active duty service members are an ideal population for a prospective study because they are the age group at risk for this subgroup of cHL patients and blood samples are collected upon entry into military service.

Methods: Cases were identified by the ICD-9 CM code 201, diagnosed from 1990-1999. Two unaffected controls were matched to each case by age (within 1 year), sex, race/ethnicity, number of samples in the repository and blood draw date (within 1 month). Subjects with HIV or a prior cancer (other than non-melanoma skin cancer) were excluded. CCL22 and sIL2Rα (reflecting Th2 immunity), sCD163 (reflecting innate immunity from macrophages), and CXCL9 and CXCL10 (reflecting Th1 immunity) were measured from the earliest sample in 103 cases and 206 controls with pre-diagnosis serum samples archived in the DoD Serum Repository. Most participants (>96%) had detectable levels of CCL22, sCD163 and sIL2Rα. We compared cases and controls using multivariable conditional logistic regression to estimate the effect of the biomarker levels (in tertiles) on risk of YAcHL, in two main strata: within 3 years of diagnosis and from 3-6 years prior to diagnosis. The middle tertile was considered the reference group. There was a high proportion of undetectable values for CXCL9 (57.6%) and CXCL10 (11.6%), thus these were dichotomized into detectable vs. undetectable levels for multivariable conditional logistic regression. Stratified analyses were also conducted examining the biomarkers by Epstein-Barr virus (EBV) status and histology.

Results: The median age at diagnosis was 25 years (IQR: 22-31 years) and 90% were male. The race/ethnicity distribution was: 75% non-Hispanic white, 12% Black, 11% Hispanic white, 2% Other/unknown. The number of pre-diagnostic blood draws ranged from 1 (38%) to 5 (3%). The distribution of histology was 65% nodular sclerosis (NS), 13% mixed cellularity and 22% other histology; 74% were EBV-negative, 22% EBV-positive and 4% undetermined.

The highest relative to the middle tertile of CCL22 and sIL2Ra levels were strongly associated with YAcHL risk 0-3 years prior to diagnosis (OR_CCL22=5.35, 95% CI=1.93, 14.85; OR_sIL2Rα=5.37; 95% CI=2.06,14.00) but not 3-6 years prior to diagnosis (OR_CCL22=1.18, 95% CI=0.49,2.84; OR_sIL2Rα=1.43; 95% CI=0.59,3.45) (Figure 1). These associations were present for EBV-negative and nodular sclerosis (NS) YAcHL, but not EBV-positive or other histological subtypes. The lowest tertile of sCD163 relative to the middle tertile was associated with an inverse risk 0-3 years prior to diagnosis (OR_CD163= 0.31, 95% CI=0.12,0.78). Detectable relative to undetectable levels of CXCL10 was associated with an increased risk of the EBV-negative subtype (OR_{CXCL10 EBV}-= 2.93, 95%CI= 1.01-8.44) only. When cytokine levels were examined in a single model, the associations remained significant although attenuated.

Conclusions: Risk of YAcHL was associated with elevated CCL22 and sIL2Rα levels within 3 years before cHL diagnosis, reflecting a disease, rather than an etiological effect. The stronger association within EBV-negative, NS cHL is consistent with the Th2 pattern observed in these subtypes in young adults. CCL22 in particular is correlated with TARC, a known predictor of YAHL. There may be a role for some Th2 cytokines as early diagnostic biomarkers.

Diepstra:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.