Body mass index is not associated with survival outcomes and immune-related adverse events in patients with Hodgkin lymphoma treated with the immune checkpoint inhibitor nivolumab

Abstract

Background: Overweight and obese patients with solid tumors receiving anti-programmed cell death-1 (PD-1)/PD-ligand-1(PD-L1) immune checkpoint inhibitors exhibit improved survival and higher risk of immune-related adverse events (irAEs) than those with a normal body mass index (BMI). In classic Hodgkin lymphoma (cHL), the impact of BMI on survival and immune-related toxicity is unknown. We evaluated for the first time associations of BMI with survival and irAEs in patients with relapsed/refractory (RR)-cHL undergoing PD-1 blockade.

Methods: Data from a multicenter study on 133 patients treated with the anti-PD1 antibody nivolumab (July 2015-December 2016) were retrieved from a prospective database. Progression-free (PFS), overall survival (OS), incidence and severity of irAEs according to BMI categories were estimated by Kaplan-Meier method, landmark-analyses and Cox regressions.

Results: Patients, mostly males (63%, n = 84) with a median age of 35 years (range, 15-82), advanced stage (75%), B symptoms (63%), bulky disease (24%), a median of 4 previous treatments (range, 1-9), received a median of 18 nivolumab doses (range, 1-57). No statistically significant differences across BMI subgroups emerged as to PFS, with 1-year rates of 67.1% for both normal weight (n = 66; 49.6%) and overweight (n = 31; 23.3%) patients. Underweight (n = 12; 9%) and obese (n = 24; 18%) patients had a 1-year PFS of 54.5% and 49%, respectively. In survival analyses, BMI either as a continuous (P = 0.5) or categorical (P for trend = 0.63) variable failed to associate with PFS. Response rates and time-to-response did not cluster in any BMI subset. No BMI-related differences in OS emerged across normal, overweight and obese patients but underweight patients had the worst survival. Occurrence of irAEs of whatever severity did not statistically associate with BMI.

Conclusions: In patients with RR-cHL receiving nivolumab, no statistically significant differences emerged in response rates, PFS and OS across BMI categories of normal weight, overweight and obese. Overweight/obese patients did not display an increased risk of irAEs. The exquisite sensitivity to anti-PD-1 antibodies, the unique cytokine milieu and effector pathways triggered by nivolumab in cHL, may represent biologic 'equalizers' counteracting the immunoregulatory effects of adiposity. Differently from solid tumors, BMI is not associated with treatment efficacy and immune-related toxicity and does not represent a predictive tool for PD-1-targeted immunotherapies in cHL.

Keywords: Body mass index; Hodgkin lymphoma; Immune checkpoint inhibitors; Immune-related adverse events.

Fig. 1

Cumulative proportion of partial responses or better (a) and complete responses (b) over time by body mass index categories. PR partial response, CR complete response

Fig. 2

Kaplan–Meier estimates of PFS in patients with RR-cHL treated with anti-programmed Cell Death-1 monotherapy (nivolumab). PFS in the full study cohort (a), (b) landmark analysis of PFS by best response to nivolumab and (c) landmark analysis of PFS by treatment discontinuation due to toxicity compared with cases who remained on nivolumab therapy. The choice of landmark time was based on the median time to reach a CR, which was 3.7 months. PFS events noted by landmark time were excluded from the analysis. CR complete response, < CR partial responses and disease stabilization, irAE immune-related adverse event, AE non immune-related adverse event, LTD leading to treatment discontinuation, OnNivo patients who did not discontinued nivolumab

Fig. 3

Kaplan–Meier survival estimates in patients with RR-cHL treated with anti-PD-1 monotherapy (nivolumab) according to BMI categories. PFS by BMI (a), landmark analysis of PFS by best response and BMI (b), OS in the full study cohort (c), OS by BMI (d). At a median follow-up of 16.4 months, median OS was not reached. Underweight patients had a significantly shorter OS as compared with those of normal weight (P = 0.027). PD-1 programmed cell death-1, RR-cHL relapsed and refractory classic Hodgkin Lymphoma, BMI body mass index, PFS progression-free survival, OS overall survival

Fig. 4

Receiver operating characteristic (ROC) analysis of body mass index (BMI) to identify patients who progressed during nivolumab monotherapy. The red line represents the reference line of predictive usefulness

Fig. 5

Occurrence of irAEs and AEs of any grade (a), of Grade 3–4 (b), and irAEs/AEs LTD (c) across the different body mass index categories. irAE immune-related adverse event, AE non immune-related adverse event, LTD leading to treatment discontinuation