PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma

Abstract

Background: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.

Methods: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.

Results: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.

Conclusions: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).

Conflict of interest statement

No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1. Response Characteristics and Changes in Tumor Burden in Patients with Hodgkin's Lymphoma Receiving Nivolumab

Panel A shows the response onset and duration for the 20 study patients who had a response to treatment with nivolumab. The color of each bar indicates whether previous autologous stem-cell transplantation (ASCT) or brentuximab therapy had failed in that patient. The length of the bar shows the time until the patient had a complete response or a partial response, along with the duration of the response. Six patients elected to discontinue the study in order to undergo stem-cell transplantation after having a response to nivolumab. Eleven patients continued to have a response at the time of this writing (indicated by an arrowhead). Panel B shows the percentage reduction in tumor burden from baseline in all 23 study patients. Two patients met the criteria for a complete response without having a 100% decrease in tumor burden. One patient with a partial response had a 99% decrease in tumor burden but had positive results on positron-emission tomography.

Figure 2. Genetic and Immunohistochemical Analyses of PDL1 and PDL2 Loci, PD-L1 and PD-L2 Protein Expression, and Epstein–Barr Virus Status in Patients with Hodgkin's Lymphoma

Shown are the results of analyses of the PDL1 and PDL2 loci and PD-L1 and PD-L2 protein expression in Reed–Sternberg cells. Panel A shows the location and color labeling of bacterial artificial chromosome clones used for the fluorescence in situ hybridization (FISH) assay for PDL1 (red) and PDL2 (green) on chromosome 9p24.1. Representative images obtained from patients show a copy-number gain in PDL1 and PDL2 (Panel B, left), with six green–red (yellow overlap) signals (signifying a fusion signal), as compared with three centromeric signals (aqua), or PDL1 and PDL2 amplification (Panel B, right), with more than three times as many green–red (yellow overlap) signals as centromeric signals (aqua). In Panel C, the expression of PD-L1 (upper row) and PD-L2 (lower row) is indicated by brown staining in Reed–Sternberg cells obtained from the same patients as in Panel B. Arrows indicate malignant cells. PD-L1 is evaluated in conjunction with PAX5 to identify PAX5-positive cells (shown in red in the upper row). PD-L2 is assessed in association with phosphorylated signal transducer and activator of transcription 3 (pSTAT3), which reflects Janus kinase–STAT activation (shown in red in the lower row). The scale bars represent 50 μm. Panel D shows PD-L1 and PD-L2 protein expression and status with respect to Epstein–Barr virus–encoded messenger RNA (EBER) in study patients who could be evaluated. All the patients who were included in the analysis had structural bases for increased copy numbers in PDL1 and PDL2 on chromosome 9p24.1, including extra copies of 9p (polysomy 9p), copy gain in PDL1 or PDL2, or amplification in PDL1 or PDL2 (Table S2 and Fig. S2 in the Supplementary Appendix). Epstein–Barr virus status was evaluated by means of a FISH assay. HRS denotes Hodgkin's Reed–Sternberg, and IHC immunohistochemical.