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PURPOSE Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment. METHODS Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2–negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients. RESULTS We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2–negative, per-protocol–treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% [95% CI, 1.6% to 13.0%]; hazard ratio, 1.78 [95% CI, 1.02 to 3.12]). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2–negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2–positive patients ( P = .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% [95% CI, 90.7% to 95.5%] v 80.9% [95% CI, 72.2% to 89.7%]; P = .0011). CONCLUSION In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2–negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.

classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL.OBJECTIVE To evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL. DESIGN, SETTING, AND PARTICIPANTSThis was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible.INTERVENTIONS Systemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy. MAIN OUTCOMES AND MEASURESComplete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group. RESULTSOf 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy.CONCLUSIONS AND RELEVANCE 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 CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL.

Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n ¼ 82) or ipilimumab and additional LPT (n ¼ 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P ¼ 0.0028). Adverse immunerelated events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31-1.01, P ¼ 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation.