Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study

Abstract

Purpose: Treatment options are limited for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Tumor cells can exploit the programmed death-1 checkpoint pathway to evade immune surveillance. In the current study, we evaluated the efficacy and safety of programmed death-1 blockade by nivolumab in patients with relapsed/refractory DLBCL.

Methods: In this phase II, open-label study, patients with relapsed/refractory DLBCL who were ineligible for autologous hematopoietic cell transplantation (auto-HCT) or who had experienced failure with auto-HCT received nivolumab 3 mg/kg every 2 weeks. We assessed the efficacy and safety of nivolumab as well as genetic alterations of 9p24.1.

Results: Among 121 treated patients, patients in the auto-HCT-failed cohort (n = 87) received a median of four nivolumab doses and a median of three doses were administered to those in the auto-HCT-ineligible cohort (n = 34). At a median follow-up of 9 months in the auto-HCT-failed cohort and 6 months in the auto-HCT-ineligible cohort, independently assessed objective response rates were 10% and 3%, and median durations of response were 11 and 8 months, respectively. Median progression-free survival and overall survival were 1.9 and 12.2 months in the auto-HCT-failed cohort and 1.4 and 5.8 months in the auto-HCT-ineligible cohort respectively. All three patients with complete remission-3% of the auto-HCT-failed cohort-had durable response (11 or more, 14 or more, and 17 months). Treatment-related grade 3 and 4 adverse events were reported in 24% of patients. The most common were neutropenia (4%), thrombocytopenia (3%), and increased lipase (3%). Of all evaluable samples for 9p24.1 analysis, 16% exhibited low-level copy gain and 3% had amplification.

Conclusion: Nivolumab monotherapy is associated with a favorable safety profile but a low overall response rate among patients with DLBCL who are ineligible for auto-HCT or who experienced failure with auto-HCT. Genetic alterations of 9p24.1 are infrequent in DLBCL.

Trial registration: ClinicalTrials.gov NCT02038933.

FIG 1.

Change in target lesion burden per independent radiology review committee by best overall response in all response-evaluable patients. Best reduction in target lesion in patients (A) who experienced failure with autologous hematopoietic cell transplantation (auto-HCT) and (B) who were ineligible for auto-HCT. Tumor burden change over time in patients (n = 9) of the auto-HCT–failed cohort who had (C) complete remission (CR) or partial remission (PR) and (D) stable disease (SD; n = 15). Horizontal reference line indicates 50% reduction consistent with a response per revised 2007 International Working Group criteria. Response-evaluable patients had assessments at baseline and at one or more postbaseline time point.

FIG 2.

(A) Progression-free survival (PFS) and (B) overall survival (OS) as assessed by independent radiology review committee. Symbols represent censored observations. auto-HCT, autologous hematopoietic cell transplantation.

FIG 3.

Prevalence and spectrum of 9p24.1 genetic alterations and association of residual disomy with 9p24.1 genetic categories. (A) Prevalence of 9p24.1 genetic alterations in evaluated diffuse large B-cell lymphomas (DLBCLs). (B) Spectrum of 9p24.1 alterations in evaluated DLBCLs. Each patient is classified by the highest observed level of 9p24.1 alteration in tumor cells: polysomy, copy gain, amplification (Ampl), or rearrangement (Rearr). Individual patients are visualized as columns on the x-axis. Percentages of tumor cells with monosomy/relative copy loss (gray), disomy (black), polysomy (light red), copy gain (medium red), amplification (dark red), and rearrangement (brown) are depicted on the y-axis. In cases with evaluable 9p24.1 status and PD-L1 immunohistochemistry (n = 46), programmed death ligand 1 (PD-L1) expression (H-score) on PAX5-positive malignant B cells is indicated below the x-axis (membranous PD-L1 in red, cytoplasmic PD-L1 in blue). (C) Percentage of tumor cells with residual 9p24.1 disomy in DLBCLs classified by 9p24.1 genetic categories (P < .001 from ordinary one-way analysis of variance of unpaired t test data). Coampl, coamplification; PD-L2, programmed death ligand 2.

FIG A1.

Flow diagram.

FIG A2.

Comparison of the incidence and magnitude of 9p24.1 alterations in diffuse large B-cell lymphoma (DLBCL; this study) and classic Hodgkin lymphoma (cHL). (A) Prevalence and (B) spectrum of 9p24.1 alterations in DLBCL. (C) Percentage of tumor cells with residual 9p24.1 disomy in DLBCLs classified by 9p24.1 genetic categories. (D) Prevalence and (E) spectrum of 9p24.1 alterations in cHL. (F) Percentage of tumor cells with residual 9p24.1 disomy in cHLs classified by 9p24.1 genetic categories. As noted, DLBCLs have a much lower incidence of 9p24.1 copy gain and amplification than cHLs. In addition, DLBCLs with low-level 9p24.1 alterations have a higher percentage of residual disomy than cHLs. Ampl, amplification; Coampl, coamplification; PD-L2, programmed death ligand 2; Rearr, rearrangement. [Reprinted with permission. © 2018 American Society of Clinical Oncology.]