Serum Level Kinetic of Key Cytokines in Newly Diagnosed Lymphoma Patients during First Line Treatment: Correlation with PET/CT Scan Results and Treatment Outcome

Background: Cytokines are soluble proteins that play a key role in mediating and regulating inflammation and immune responses. Further, they are involved in lymphoid development and differentiation, as well as in lymphoid tumorigenesis. Aim of the present study was to verify if the serum-cytokine levels could be an early marker of treatment response.

With this purpose, we analyzed the serum concentration kinetic of key cytokines in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) pts comparing it with PET/CT scan results and treatment outcome.

Patients and Methods: After Ethic Committee approval, we start to enroll lymphoma pts treated at Modena Cancer Center. Until now, 29 patients entered the study, including 12 pts with DLBCL, 11 with FL, and 6 with HL. DLBCL lymphoma were treated with R-CHOP and FL patients with R-CVP or R-Benda or R-CHOP, while HL patients with ABVD + ABVD or BEACOP following indications of intermediate PET. A panel of eight serum cytokines/chemokines (IL6, IL2, IL8, IL10, IFNγ, TNFα, CXCL10/IPI10, CCL17/TARC) was analyzed using the Simple Plex system (Protein Simple, San Jose, CA, USA) according to the manufacturer's recommendations. Serum samples were collected at the day of staging (PET-0), at the day of intermediate PET (I-PET) and at the day of end treatment PET (EOT-PET). Samples were analyzed in duplicate. Continuous variables were compared by Mann-Whitney test and categorical variables by Chi2 test. Matched data were analyzed by paired Wilcoxon or Friedman test. Statistical significance was defined as p < 0.05.

Results: The median age of all 29 pts was 60 yr (range 21-86), and 65 % were male. Patients with HL were younger (50 yr) than pts with FL (61 yr) and DLBCL (68 yr).

In all 29 pts, median concentration of IL10, IL6, TNFα at EOT-PET decreased in comparison with the levels at PET-0, while IFNγ and IPI10 increased. IL8 increased in DLBCL and in HL, while decreased in FL. IL2 levels did not show relevant changes. No statistically significant differences were found between the concentrations of these cytokines at PET-0 and EOT-PET. The mean serum TARC level at PET-0 were 854 pg/mL (range 130-5829), 1209 pg/mL (range 134-6903) and 8327 pg/mL (range 6488-10885) in DLBC, FL and HL pts, respectively. At EOT-PET the mean concentration of TARC were 562 pg/mL (range 130-854) (p=0.49), 989 pg/mL (range 134-6903) (p=0.74), 591 pg/mL (range 353-932) (p=0.03 ) in DLBCL, FL and HL pts, respectively. In HL patients, TARC values were significantly lower at I-PET with a mean of 525 pg/mL (range 210-1062) compared to PET-0 (p=0.016), with a p value along the 3 timepoint =0.009. EOT-PET and I-PET, evaluated by Deauville score shows that almost all patients achieved CR at the end of treatment: 11 out of 12 DLBCL pts have a Deauville score between 1 and 3, as well as all FL and HL pts. Only 1 DLBCL patient had a Deauville score of 4 at the end of treatment, achieving CR after further radiotherapy.

Conclusion: Our study, despite the limitations due to the small number of pts enrolled to date, shows that the concentrations of cytokines/chemokines, with the exception of TARC, do not undergo significant changes, before and after first-line therapy. The TARC values, on the other hand, correlate well with the results of PET/CT and therefore also with the response to therapy in all subtypes of lymphoma. This correlation is statistically significant in pts with HL. TARC assessment could therefore become a useful, inexpensive and easy to determine predictive marker of response to therapy and may be important for determining treatment strategy in lymphoma patients. Further, the TARC levels assessed during the follow-up could be early markers of relapse.

No relevant conflicts of interest to declare.