Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial

Abstract

Background: Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma.

Methods: We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m(2) intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722.

Findings: We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15.4 months (IQR 10.1-21.0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%).

Interpretation: The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma.

Funding: National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.

Conflict of interest statement

Conflicts of interest

SSN received research support from Cure Tech Ltd, Yavne, Israel. RRY is an employee of Cure Tech Ltd.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Clinical response after pidilizumab and rituximab therapy

a) Best response after pidilizumab and rituximab therapy. Percent change in tumors size from baseline was determined by measuring the sum of the product of the diameters of up to six tumors on CT scans. Asterisk (*) indicates patients whose complete response (CR) was confirmed by PET-CT scan. PR, partial response; SD, stable disease; PD, progressive disease. b) Time to best response is shown for each of the 25 patients that had tumor reduction. Arrow on x-axis indicates the first time point at which tumor response was assessed after start of therapy. Asterisks (*) indicate patients with ongoing response at last assessment.

Figure 2. Progression-free survival (PFS) after pidilizumab and rituximab therapy

a) Kaplan-Meier curve of PFS with 95% confidence intervals (CI). b and c) Kaplan-Meier curves of PFS for low/intermediate vs high risk groups for FLIPI 1 (b) and FLIPI 2 (c). The number of events (E) and the total number of patients at risk (N) over time and the p values by log-rank test are shown.

Figure 2. Progression-free survival (PFS) after pidilizumab and rituximab therapy

a) Kaplan-Meier curve of PFS with 95% confidence intervals (CI). b and c) Kaplan-Meier curves of PFS for low/intermediate vs high risk groups for FLIPI 1 (b) and FLIPI 2 (c). The number of events (E) and the total number of patients at risk (N) over time and the p values by log-rank test are shown.

Figure 3. Expression of PD-1, PD-L1, and PD-L2 on peripheral blood T cells and monocytes

a–c) The mean fluorescence intensity (MFI) of PD-1 (a), PD-L1 (b), and PD-L2 (c) on peripheral blood CD4+ and CD8+ T cells and monocytes was determined by flow cytometry on 25 patients (18 responders and 7 non-responders) with available PBMC samples at baseline. The horizontal line indicates the mean for each group. Wilcoxon rank-sum test was used to evaluate differences in marker expression between the two patient groups.