ORANGE, CA — Immune abnormalities persist in young adult classical Hodgkin lymphoma (YAcHL) patients long after cure. Yet, new research presented at the most recent Annual ASH Meeting and Exposition in New Orleans pointed out the difficulties in assessing whether those issues existed prior to diagnosis.
The study team, led by the University of California Irvine and including researchers from, the Walter Reed Army Institute of Research in Silver Spring, MD, explained that the cancer is rare and occurs in the late teens and 20s, making cohort studies impractical.
In response, researchers conducted a nested case-control study in the DoD Serum Repository, which includes samples from active duty U.S. military servicemembers, in an effort 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,” they noted.1
ICD-9 CM code 201, diagnosed from 1990-1999, was used to identify cases. Two unaffected controls were matched to each case by age within one year, sex, race/ethnicity, number of samples in the repository and blood draw date within one month. Excluded were subjects with HIV or a prior cancer (other than nonmelanoma skin cancer).
The study team measured CCL22 and sIL2Rα (reflecting Th2 immunity), sCD163 (reflecting innate immunity from macrophages), and CXCL9 and CXCL10 (reflecting Th1 immunity) from the earliest sample in 103 cases and 206 controls with pre-diagnosis serum samples archived in the repository.
“Most participants (>96%) had detectable levels of CCL22, sCD163 and sIL2Rα,” the authors advised. “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 three 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 indicate that the median age at Young Adult Classical Hodgkin Lymphoma diagnosis was 25 years (IQR: 22-31 years), and 90% were male. Most, 75% were non-Hispanic white with 12% Black, 11% Hispanic white and 2% Other/unknown. With the number of pre-diagnostic blood draws ranging from one (38%) to five (3%), the histology distribution was 65% nodular sclerosis (NS), 13% mixed cellularity and 22% other histology. In addition, 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 (ORCCL22=5.35, 95% CI=1.93, 14.85; ORsIL2Rα=5.37; 95% CI=2.06,14.00) but not 3-6 years prior to diagnosis (ORCCL22=1.18, 95% CI=0.49,2.84; ORsIL2Rα=1.43; 95% CI=0.59,3.45),” the researchers stated, adding, “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 (ORCD163= 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 (ORCXCL10 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.”
The study concluded that risk of YAcHL was associated with elevated CCL22 and sIL2Rα levels within three years before cHL diagnosis, which reflected a disease effect, not an etiological one. “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,” the authors added.
- Cozen W, Wan JY, Conti DV, Epeldequi M, et. al. Elevated CCL22 and sIL2Rα Levels Precede the Diagnosis of Young Adult Classical Hodgkin Lymphoma: A Nested Case-Control Study from the DoD Serum Repository. Presented at the 64th Annual ASH Meeting and Exposition; December 2022; New Orleans, LA.