Regaining the Tumor Control in Relapsed/Refractory Hodgkin Lymphoma after Nivolumab Failure with Addition of Another Antineoplastic Agent

Background: Nivolumab induces a high response rate in patients with relapsed and refractory Hodgkin lymphoma (r/r HL). However, a significant proportion of patients eventually becomes refractory to nivolumab monotherapy, representing the group with uncertain prognosis with limited treatment options. The brentuxinab vedotine and bendamustine hydrochloride are two agents with prominent activity in monotherapy for patients with r/r HL.

The goal of this preliminary study was to evaluate the safety and the efficacy of two treatment combinations with nivolumab (nivolumab+bendamustine and nivolumab + brentuximab vedotin) in patients with r/r HL after failure of nivolumab therapy.

Patients and Methods: 29 (18 m/11 f) patients were included in the study after signing informed consent. The median age was 30 years (range 21-60). There were 2 subgroups of patients: a) the patients received the nivolumab-bendamustine combination (Benda group, n=19) and patients received the nivolumab-brentuximab vedotin combination (BV group, n=10). All patients received previous nivolumab treatment with a median number of infusions 18 (12-24) and had disease progression according to Lugano criteria. 14/19 (74%) of the pts in Benda group had received bendamustine earlier during the course of the disease. In BV group 5/10 (50%) of patients had received brentuximab vedotin therapy at any time during prior treatment. In Benda group, patients received 90 mg/m² bendamustine on D1 and 2 and 3 mg/kg nivolumab on Day 1 and 14 of the 28-day cycle up to 3 cycles. In BV group patients were treated with 3 mg/kg nivolumab and 1.8 mg/kg brentuximab vedotin on Day 1 of 21-day cycles up to 3 cycles. All patients received at least one cycle of therapy were included in safety analysis. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) (version 4.03). After completion of the Cycle 3 the response evaluation was performed by PET-CT scan and assessed by investigators using Lugano criteria. The duration of median follow-up period was 3 months (range 1-9).

Results: In Benda group, 17/19 (89%) of the pts had drug-related adverse events (AEs) of any grade. Grade 3-4 AE's was noted in 6/19 (32%) of treated patients. Fatigue 16/19 (84%), nausea 12/19 (63%) and pyrexia 6/19 (32%) were the most common AEs. Grade 3-4 AE's included 4 cases of pneumonia, 1 uveitis, 1 severe infusion reaction. One patient discontinued treatment prematurely due to adverse events. In BV group, the AEs of any grade have occurred in 5/10 (50%) of the patients. The most common AE was pyrexia, fatigue in 3/10 (33%) and pruritus in 1/10 patient. Grade 3 AEs included 1 case of grade 3 thrombocytopenia, and 1 case of grade 3 skin rash. No Grade 4 AEs were observed during treatment. The response to treatment in Benda group was assessed in 10 patients. The objective response rate (ORR, was defined by achievement of complete or partial response) to the therapy was observed in 9/10 patients with CR rate 40% (4/10). One patient showed disease progression. All patients with CR failed the bendamustine-containing regimen earlier during disease course. In BV group, the response was assessed in 8 patients. The ORR was 75% (6/8), with 3 patients (37,5%) achieving CR and 3 patients (37,5%) obtaining PR. The rest 2 patients (25%) had SD. Among 4 patients who had prior BV treatment and undergo assessment, 1 had CR, 1 had PR and 2 patients had SD after combination treatment. All patients included in safety and response analysis are alive.

Conclusion: Early data suggest that although an elevated incidence of AEs in Benda group has been observed,the toxicities with this regimen appear to be manageable and the combination of bendamustine and nivolumab may be an effective salvage therapy in the patients with r/r HL. The combination of nivolumab and brentuximab vedotin represents an effective and tolerable outpatient regimen in the patients with r/r HL after failure of nivolumab therapy. The efficiency of combination in the patients that have failed both of the drugs in monotherapy may suggest the clinical synergy of nivolumab and brentuximab vedotin/bendamustine.