Article Text
PDF
Abstract
Background High-dose systemic immunosuppression (ISP) is associated with poorer survival outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs).1–3 However, the effect of ISP timing on survival is not well-studied. The aim of this retrospective study is to examine the association between immunosuppression timing and overall survival among ICI recipients using a large multi-institutional cohort.
Methods We identified 2,077 ICI recipients who did not receive chemotherapy within 18 months before or after ICI initiation at the Mass General Brigham Healthcare System and the Dana-Farber Cancer Institute from 2011–2021 (figure 1). ISP use was defined as either 1) at least 10 mg/day prednisone equivalent of glucocorticoids for at least a week, 2) 1 dose of biologic immunosuppression, or 3) at least 1 week of non-steroidal systemic immunosuppression within the time window. Using this definition, 912 patients received ISP within 18 months before or after ICI initiation. Case and control cohorts are defined in (table 1). Multivariate Cox proportional hazard models were computed at different times relative to ICI initiation, adjusting for demographics, Charlson comorbidity index at ICI initiation, ICI type, and cancer type. The control group for all analyses was patients who did not receive ISPs (n=1,165).
Results The median follow-up was 23.0 (IQR: 6–42) months from ICI start. High-dose systemic glucocorticoids were the most common form of ISP (97.7%), followed by biologics (11.7%), and non-steroidal systemic immunosuppressants (10.9%). After covariate adjustment, we found that ISP use within 18 months before or after ICI initiation was associated with significantly increased mortality (HR: 1.44; 95% CI: 1.27–1.64; p<0.001)(table 2). When performing sliding window time analyses, we found that the increased risk of mortality escalated with ISP administration closer to ICI initiation and was the highest when patients received ISP within 1 month before or after ICI initiation (HR: 2.49; 95% CI: 2.05–3.01; p<0.001)(figure 2). The negative effect of ISP exposure tapered off 8–12 months after ICI initiation (HR: 1.29; 95% CI: 0.89, 1.29; q-value: 0.56)(figure 3).
Conclusions Overall, high-dose systemic immunosuppression (primarily glucocorticoid immunosuppression as observed in this cohort) is associated with increased mortality among ICI recipients and correlates with increasingly poorer survival the closer it is administered to ICI initiation. However, the deleterious effects of ISP seem to taper off if administered more than 8 months after ICI initiation. Clinicians should include the timing of ISP administration in the risk and benefit analysis of ISP therapy when counseling cancer patients receiving ICI.
References
Bai X, Hu J, Betof Warner A, et al. Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy. Clinical Cancer Research. 2021;27(21):5993–6000. doi:10.1158/1078–0432.CCR-21–12833.
Petrelli F, Signorelli D, Ghidini M, et al. Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Cancers (Basel). 2020;12(3):546. doi:10.3390/cancers120305462.
Tison A, Quéré G, Misery L, et al. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study. Arthritis Rheumatol. 2019;71(12):2100–2111. doi:10.1002/art.41068
Ethics Approval This study has been approved by the Mass General Brigham Institutional Review Board (protocol number 2020P002307).
Patient inclusion and exclusion criteria
Clinicopathologic baseline characteristic of ICI patient
Association of ISP use with overall survival using a multivariate Cox proportional hazards model for all patients
Survival of ICI recipients based on timing of ISP relative to ICI initiation. Table shows the hazard ratio of the case cohort within each window relative to the overall control cohort using a multivariate Cox proportional hazards model, adjusting for demographics, Charlson Comorbidity Index at ICI initiation, ICI type, and cancer type.
Risk of mortality among ICI recipients starting ISP within a 4-month sliding window. This figure shows the number of cases in each time window. The same overall control cohort of 1,165 patients ws used for all sliding windows. Sliding windows are in 4-month increments. Months starting with n refer to months prior to ICI initiation and thos starting with p refer to months post-ICI initiation.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.