Armand, Philippe

Background: Patients (pts) with classical Hodgkin lymphoma (cHL) frequently experience reduced health-related quality of life (HRQoL) (Oerlemans et al, Ann Hematol 2011). Nivolumab, a fully human IgG4 anti-programmed death-1 (PD-1) immune checkpoint inhibitor monoclonal antibody, demonstrated efficacy and clinically meaningful improvement in pt-reported outcomes (PROs) in pts with relapsed/refractory cHL in cohorts A, B, and C of CheckMate 205 (NCT02181738) (Armand et al, J Clin Oncol 2018; Engert et al, ASH 2017). Nivolumab monotherapy followed by nivolumab + doxorubicin, vinblastine and dacarbazine (N-AVD) demonstrated an objective response rate of 84% in newly diagnosed cHL (cohort D of CheckMate 205; Ramchandren et al, EHA 2018). We present PROs in CheckMate 205 cohort D. Methods: Pts ≥18 years of age with untreated, advanced-stage cHL, with ECOG performance status (PS) of 0–1 received 4 doses of nivolumab monotherapy (240 mg IV Q2W) followed by N-AVD for 6 cycles (12 doses). Pts then entered the follow-up (FU) period. PROs were an exploratory endpoint, assessed using the EuroQol 5 Dimensions-3 level (EQ-5D-3L) and associated visual analog scale (EQ-VAS) in all treated pts who had both a baseline (monotherapy cycle 1) and post-baseline assessment. EQ-VAS ranges from 0–100, with higher scores indicating better HRQoL. In EQ-5D-3L, pts can report no, some, or extreme problems in each of 5 dimensions (mobility, self-care, activity, pain, and anxiety). Results: 51 pts were treated. At baseline, median age was 37 years, 63% were male, 59% had ECOG PS of 0. 49 pts (96%) completed baseline EQ-VAS. Mean EQ-VAS scores exceeded the mean baseline score at the end of monotherapy, after 2 combination cycles, at the end of therapy, and during follow-up (Table 1). The proportion of pts reporting some or extreme problems in EQ-5D-3L was numerically lower than or similar to baseline after monotherapy for all dimensions, but was numerically higher than baseline (dimensions of mobility and activity) after 2 combination cycles, and remained close to or numerically below baseline during follow-up (dimensions of self-care, activity, pain, and anxiety). Conclusions: Pt-reported HRQoL, as assessed by observed mean EQ-VAS scores, did not deteriorate from baseline during treatment with nivolumab followed by N-AVD. Proportions of pts reporting problems in individual EQ-5D-3L dimensions were generally similar to baseline during treatment and follow-up.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org .

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.

Key Points HSCT after PD-1 blockade is feasible, although may be associated with increased early immune toxicity. PD-1 blockade may cause persistent depletion of PD1+ T cells and alterations in T-cell differentiation impacting subsequent treatment.

AbstractUniformly adopted response criteria are essential for assessment of therapies incorporating conventional chemotherapy and chemoimmunotherapy regimens. Recently, immunomodulatory agents, such as immune checkpoint inhibitors, have demonstrated impressive activity in a broad range of lymphoma histologies. However, these agents may be associated with clinical and imaging findings during treatment suggestive of progressive disease (PD) despite evidence of clinical benefit (eg, tumor flare or pseudo-progression). Considering this finding as PD could lead to patients being prematurely removed from a treatment from which they actually stand to benefit. This phenomenon has been well described with checkpoint blockade therapy in solid tumors and anecdotally seen in lymphoma as well. To address this issue in the context of lymphoma immunomodulatory therapy, a workshop was convened to provide provisional recommendations to modify current response criteria in patients receiving these and future agents in clinical trials. The term “indeterminate response” was introduced to identify such lesions until confirmed as flare/pseudo-progression or true PD by either biopsy or subsequent imaging.

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.