Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study

Abstract

Purpose: Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies.

Methods: In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti-PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression.

Results: Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks.

Conclusion: Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

Trial registration: ClinicalTrials.gov NCT01592370.

Fig 1.

Kinetics of response for individual patients with (A) diffuse large B-cell lymphoma (DLBCL), (B) follicular lymphoma (FL), (C) mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL), and (D) peripheral T-cell lymphoma (PTCL) who were treated with nivolumab 3 mg/kg. The horizontal line at –50 indicates the threshold for defining an objective response in DLBCL, FL, MF-CTCL, and PTCL. Most objective responses were sustained. The DLBCL and FL groups had individuals with responses maintained beyond 88 weeks. (closed square) first response; (X) first occurrence of new lesion.

Fig 2.

Immunohistochemical staining for PD-L1 in patient biopsy samples. (A) Orientation of chromosomal probes for fluorescent in situ hybridization. (B) Fluorescent in situ hybridization analysis of MF #1 (left) and disruption of chromosome 9 between PD-L1 and PD-L2 and three copies of chromosome 9 (arrowheads) and of MF #3 (right), which shows disomy 9. (C) Immunohistochemical staining of MF #1 (top and bottom left) and MF #3 (top and bottom right) for PD-L1 (brown = positive staining [top]) and for PD-L2 (brown) and for pSTAT3 (red [bottom]). Images in (B) and (C), magnification ×1,000. Scale bars = 50 μm. MF, mycosis fungoides; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; pSTAT3, phosphorylated signal transducer and activator of transcription 3.

Fig 3.

Immunohistochemical staining for programmed death ligand 1 (PD-L1; brown) and the B-cell lineage marker PAX5 (red) in three cases of follicular lymphoma (FL) show positive cell membrane expression of PD-L1 among the nonmalignant (PAX5-negative) cells within the tumor microenvironment. Magnification, ×1,000. Scale bars = 50 μm.