PD-1 Blockade With Nivolumab Produces High Response Rate in Relapsed/Refractory Hodgkin Lymphoma
Anti–PD-1 antibodies have been shown to be effective in solid tumors. There is evidence that the malignant Reed-Sternberg cells in Hodgkin lymphomas use the PD-1 pathway to evade immune detection, with alterations in chromosome 9p24.1 increasing levels of PD-L1 and PD-L2 and promoting induction of the ligands through JAK-STAT signaling. In an ongoing phase I study reported in The New England Journal of Medicine, Ansell et al found that treatment with the PD-1 inhibitor nivolumab produced a high response rate in heavily pretreated patients with Hodgkin lymphoma.
Study Details
In the study, 23 patients with relapsed/refractory Hodgkin lymphoma received nivolumab at 3 mg/kg every 2 weeks until complete response, progression, or excessive toxicity. Patients had a median age of 35 years (range = 20–54 years); 12 (52%) were male; 20 (87%) were white; Eastern Cooperative Oncology Group performance status was 0 in 6 (26%) and 1 in 17 (74%); 22 (96%) had nodular sclerosis; number of previous systemic therapies was two or three in eight patients (35%), four or five in seven (30%), and six or more in eight (35%); four (17%) had extranodal involvement; 19 (83%) had previous radiotherapy; and 18 (73%) enrolled in the study after relapse following autologous stem cell transplantation and 18 (73%) after relapse following brentuximab vedotin (Adcetris) treatment.
Responses
Objective response occurred in 20 patients (87%), including 4 (17%) with complete response and 16 (70%) with partial response; the remaining 3 patients (13%) had stable disease. Of the four patients with complete response, three had not received previous brentuximab. Among 15 patients with recurrence after autologous stem cell transplantation and brentuximab, the response rate was 87%, with 1 patient (7%) having complete response, 12 (80%) having partial response, and 2 (13%) having stable disease. All three patients who did not undergo autologous stem cell transplantation before brentuximab treatment had partial responses. Among five patients who did not receive brentuximab, four (80%) had responses, including complete response in three, and one patient had stable disease. In the 20 patients who responded, 12 (60%) had the first response by 8 weeks (range = 3–39 weeks).
Additional Results
Progression-free survival at 24 weeks was 86% (95% confidence interval = 62%–95%). At the time of reporting, 6 patients had chosen to undergo stem cell transplantation at the time of the best overall response, and 11 patients continued to maintain response. Median overall survival had not been reached after median duration of follow-up of 40 weeks (range = 0–75 weeks).
Analyses of pretreatment tumor specimens from 10 patients showed PDL1 and PDL2 copy number increases and increased expression of the ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicating active JAK-STAT signaling.
Treatment Exposure and Adverse Events
Patients received a median of 16 nivolumab doses (range = 6–37) over a median treatment duration of 36 weeks (range = 13–77) weeks, with 15 patients (65%) receiving ≥ 90% of the intended overall dose. Reasons for discontinuation of treatment included stem cell transplantation in six patients, disease progression in four patients, and drug toxicity in two patients.
The most common drug-related adverse events of any grade were rash (22%), decreased platelets (17%), fatigue (13%), pyrexia (13%), diarrhea (13%), nausea (13%), and pruritus (13%). There were no drug-related grade 4 or 5 adverse events. Drug-related grade 3 adverse events occurred in 5 patients (22%) and included myelodysplastic syndrome, pancreatitis, pneumonitis, stomatitis, colitis, gastrointestinal inflammation, thrombocytopenia, increased lipase level, decreased lymphocyte level, and leukopenia.
Serious adverse events occurred in three patients, consisting of grade 3 pancreatitis, grade 3 myelodysplastic syndrome, and grade 2 lymph node pain. The patient with myelodysplastic syndrome had undergone six previous systemic chemotherapies, radiation therapy, and autologous stem cell transplantation but had not received prior bendamustine.
Dose delay was required in nine patients (39%), and was due to nonhematologic adverse events in 5. The adverse events leading to discontinuation were myelodysplastic syndrome and thrombocytopenia in one patient and pancreatitis in one patient. Infusion was interrupted in two patients (9%) due to grade 1 hypersensitivity reaction.
The investigators concluded: “Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma.” They noted: “The frequent clinical responses to nivolumab therapy in heavily pretreated patients with relapsed or refractory Hodgkin’s lymphoma and genetic alterations of the PD-1 ligand loci highlight the importance of the PD-1 immune evasion pathway and the genetically defined sensitivity to PD-1 blockade in this disease.”
Stephen M. Ansell, MD, PhD, of Mayo Clinic, is the corresponding author for The New England Journal of Medicine article. Dr. Ansell and Alexander M. Lesokhin, MD, of Memorial Sloan Kettering Cancer Center, and Margaret A. Shipp, MD, and Philippe Armand, MD, PhD, both of Dana-Farber Cancer Institute, contributed equally to the New England Journal of Medicine article.
The study was funded by Bristol-Myers Squibb and others. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
