Assessment of cytokine levels in the patients with relapsed/refractory Hodgkin’s lyphoma during nivolumab therapy
Andrey M. Chekalov, Kirill V. Lepik, Nikita D. Yolshin, Albert R. Muslimov, Natalia B. Mikhailova, Elena V. Kondakova, Lubov’ A. Tsvetkova, Yury R. Zalyalov, Eugenia S. Borzenkova, Ivan S. Moiseev, Vadim V. Baykov, Boris V. Afanasyev
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Contact: Dr. Natalya B. Mikhailova, PhD
E-mail: bmt.lymphoma@gmail.com, a.m.chekalov@gmail.com
Summary
PD-1 inhibitors have changed the prognosis of patients with relapsed/refractory Hodgkin’s lymphoma (overall response rate> 65%), however, only a small number of patients achieve a stable remission (2-year progression-free survival (PFS) <50% ) Predicting a response and prognosis could help to optimize the therapy with checkpoint inhibitors. The aim of our study was a search for serum cytokine levels as a predictive marker for response to immunotherapy.
Materials and methods
The study included 80 patients with relapsed/refractory Hodgkin’s lymphoma, who underwent the treatment at the Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, I. P. Pavlov First Saint Petersburg, receiving 3 mg/kg of nivolumab, a PD-1 inhibitory drug. Median age of patients was 32 years, 55% men (n=44), 45% women (n=36), median follow-up was 32 months, overall survival (OS) was 96.3%, 2-year progression-free survival (PFS) was 40 % (median, 18.8 months) As a part of this study, the blood serum samples were taken for subsequent analysis before therapy initiation, at 1.5 months, 3 months, 6 and 12 months post-treatment. An enzyme-linked immunosorbent assay (ELISA) was used to determine the concentrations of interleukin-6 (IL-6) (80 patients), interleukin-15 (IL-15) (30 patients) and PDL-1 (42 patients). Associations between clinical characteristics and outcomes were analyzed in accordance with the level of cytokines at the studied points.
Results
Before starting immune therapy, the mean levels for IL-6, IL-15, and PDL-1 were determined as 7.23 pg/ml, 9.98 pg/ml, and 16.23 pg/ml, respectively. Subsequent evaluation using proportional hazards model revealed a statistically significant relationship between the values of IL-6 (p=0.009), and IL-15 (p=0.018) before therapy; IL-6 levels after 1.5 months (p=0.008), after 3 months (p=0.003), after 6 months (p=0.004), and 2-year progression-free survival (PFS). A positive correlation was revealed between IL-6 and PDL-1 at the points before starting the therapy (p=0.001), after 1.5 months (p=0.023), after 6 months (p=0.011). The values of all studied cytokines significantly decreased after 6 months of therapy (p <0.05). By the U-criterion, a relationship was detected prior to the start of nivolumab therapy between the levels of IL-6, and manifestation of B-symptoms (p=0.004). Using ROC analysis, a cut-off value was determined for IL-6 before therapy (2.5 pg/ml; AUC=0.589). The pre-treatment level of IL-6 exceeding 2.5 pg/ml was associated with decreased 2-year PFS (22.7% versus 50%, the median PFS 12.77 versus 23.17 months, p=0.049).
Conclusion
Our analysis showed that the level of serum IL-6 in patients with relapsed/refractory Hodgkin lymphoma before nivolumab therapy was associated with lower progression-free survival. Despite limited number of observations the level of IL-15 before the start of therapy also had a statistically significant relationship with PFS (p=0.018). A study of the level of PDL-1 did not show any statistical significance in our study.
Keywords
Hodgkin’s lymphoma, nivolumab, ELISA, interleukin-6, interleukin-15, PDL-1.
