First-Line Concomitant and Sequential Nivolumab/AVD for Early-Stage Unfavorable Classical Hodgkin Lymphoma

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In a phase II German Hodgkin Study Group trial (NIVAHL) reported in JAMA Oncology, Bröckelmann et al found that both concomitant and sequential nivolumab plus AVD (doxorubicin, vinblastine, and dacarbazine) regimens showed efficacy in first-line treatment of early-stage unfavorable classical Hodgkin lymphoma.

Study Details

In the open-label multicenter trial, 109 patients were randomly assigned between April 2017 and October 2018 to receive four cycles of nivolumab/AVD (N-AVD; n = 55) or sequential treatment with four doses of nivolumab, two cycles of N-AVD, and two cycles of AVD, both followed by 30 Gy involved-site radiotherapy. Nivolumab was given at 240 mg every 14 days (including on the days of AVD administration in concomitant therapy) and AVD was given at standard doses. The primary outcome measure was complete remission aimed at excluding a rate of ≤ 80% within the two-sided 95% confidence interval (CI) for each treatment group.

Complete Remission Rates

At interim staging after two cycles of N-AVD or four doses of nivolumab monotherapy, 54 (100%) of 54 and 49 (96%) of 51 evaluable patients had achieved objective response, with complete remission in 47 (87%) and 26 patients (51%) patients reported, respectively.

Among 101 patients evaluable for the primary analysis, 46 of 51 patients receiving concomitant therapy (90%, 95% CI = 79%–97%) and 47 of 50 receiving sequential therapy (94%, 95% CI = 84%–99%) had achieved complete remission after study treatment. After median follow-up of 13 months, 12-month progression-free survival was 100% among patients receiving concomitant treatment and 98% among those receiving sequential treatment.


  • Complete remission was achieved in 90% and 94% of patients receiving concomitant and sequential nivolumab plus AVD.
  • Progression-free survival at 12 months was 100% and 98%.

Adverse Events

Treatment-related grade ≥ 3 adverse events were reported in 76% of patients in the concomitant group vs 80% in the sequential group, with most being hematologic adverse events (71% vs 65%). Grade ≥ 3 infections occurred in 5% vs 2% of patients and febrile neutropenia was observed in 7% vs 7%. Serious adverse events were reported in 38% vs 28%. At last analysis, potential immune-related late adverse events consisted of grade ≤ 2 hypothyroidism in seven patients and grade 2 intermittent pneumonitis and grade 1 colitis in one patient each.

The investigators concluded, “Both strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high complete remission rate after four doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage classical Hodgkin lymphoma.”

Andreas Engert, MD, of University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University of Cologne, is the corresponding author for the JAMA Oncology article.  

Disclosure: The study was supported by Bristol-Myers Squibb. For full disclosures of the study authors, visit

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