Profile of Inflammatory Biomarkers in Hodgkin Lymphoma. Differences between HIV-Negative and HIV-Positive Patients
Authors: Botafogo Vitor , Usas Andrea , Verdú-Bou Miriam , Moreno Miram , Fernández-Rivas Gema , Cardona Pere-Joan , Fondelli Federico , Martínez-Cáceres Eva , Doladé Maria , Blanco Ignacio , Moltó José , Tapia Gustavo , Sancho Juan-Manuel , Ribera Josep-Maria , Navarro Jose Tomas 
Published: December 2024

Introduction: People living with HIV have a 5-26 times higher risk of developing Hodgkin's lymphoma (HL) than the general population and its clinical presentation is usually more aggressive. Recent studies described an increase in inflammatory markers such as Interleukin-10 (IL-10), tumor necrosis factor α (TNFα) and IL-6 in both HIV-positive (HIVpos) and HIV-negative (HIVneg) patients with advanced HL compared to patients with localized disease. However, differences in the levels of inflammatory markers between HIVpos and HIVneg patients were not reported. Our aim was to compare the profile of inflammatory markers between HIVpos and HIVneg patients with HL at diagnosis and after treatment.

Methods: We retrospectively analyzed 78 frozen serum samples from 58 patients (42 HIVneg and 16 HIVpos) diagnosed with HL from 1996 to 2022. In the HIVneg group, 22 samples were obtained at diagnosis and 32 after treatment. In the HIVpos, 11 samples were collected at diagnosis and 13 after treatment. IL-6 and TNFα were measured by ELISA and procalcitonin (PCT) values by chemiluminescence immunoassay. Leukocyte, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and β2-microglobulin values were collected from hospital records at diagnosis and after treatment as well as clinical and demographic data. For comparisons, the Mann-Whitney test was used for continuous variables and the chi-square test, for categorical variables. For survival analyses, the log-rank test was used.

Results: All patients were initially treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and HIVpos patients received concomitant antiretroviral therapy. The median age was 39 years in both groups (20-79 in HIVneg and 18-55 in HIVpos). In the HIVneg group 50% were male, being 87,5% in HIVpos group (p=0.01). The main histological subtype was nodular sclerosis (69% in HIVneg vs. 56% in HIVpos; p=0.3), followed by mixed cellularity (24% in HIVneg vs. 38% in HIVpos; p=0.3). Most HIVneg patients had stage II disease at diagnosis (57%; n=24), while HIVpos, stage IV (56%; n=9)(p=0.003). Further, 88% of HIVneg and 81% of HIVpos patients (p=0.2) achieved complete remission (CR) with ABVD +/- radiotherapy. The remaining patients relapsed and received a second treatment line, achieving CR in all cases. The 5-year overall survival (OS) was 98% for the HIVneg and 75% for the HIVpos group (p=0.006), while the 5-year progression-free survival was 88% for the HIVneg and 81% for the HIVpos (p=0.2). There was only 1 death in the HIVneg group, due to secondary leukemia, and there were 4 in the HIVpos group: secondary neoplasia (n=1), HIV-related complications (n=2) and digestive hemorrhage due to lymphoma progression (n=1).

At diagnosis, HIVpos patients showed lower leukocyte counts than HIVneg (median: 5.5, range 0.6-11.8 vs. 10.5, range 4.2-20 x 10e9/L; p=0.04). β2 microglobulin was significantly increased in HIVpos patients (median: 2.2, range 1.1-5.2 vs. 1.65, range 1-20.6 mg/L; p=0.02). Similarly, TNFα values were higher in the HIVpos group (median: 0.41, range 0-5.1 vs. 0, range 0-268 pg/mL; p=0.02). After HL treatment, HIVpos patients had significantly increased ESR (median: 15, range 4-73 vs. 9, range 1-64 mm; p=0.01), β2 microglobulin (median: 2.2, range 1.1-5.2 vs. 1.7, range 1-5 mg/L; p=0.01), PCT (median: 0.004, range 0-0.48 vs. 0, range 0-0.7 ng/mL; p=0.004) and TNFα values (median: 0.79, range 0-23.6 vs. 0, range 0-44 pg/mL; p=0.002), compared to the HIVneg group. However, CRP values were higher in the HIVneg group (median: 1.8, range 0.2-23.4 vs. 1.4, range 0.3-12 mg/L; p=0.01). When comparing samples at diagnosis vs. after treatment, HIVneg patients showed significant reduction in ESR (median: 44, range 3-116 vs. 9, range 1-64 mm; p=0.0001), CRP (median: 21.9, range 0.6-323 vs. 1.8, range 0.2-23.4 mg/L; p=0.0001) and IL-6 (median: 19.1, range 6.2-75400 vs. 6.8, range 1.8-54.3 pg/mL; p=0.0001). Conversely, HIVpos presented a significant reduction only in CRP (median: 7.1, range 2.1-38.3 vs. 1.4, range 0.3-12 mg/L; p=0.007).

Conclusion: HIVpos patients showed significantly increased β2 microglobulin and TNFα levels at HL diagnosis compared to HIVneg. After HL treatment, most inflammatory markers decreased in HIVneg patients, while HIVpos patients only presented a significant reduction in CRP. These findings could be related to the persistence of the proinflammatory state associated with HIV infection.