The Unique Characteristics and Management of Patients Over 60 Years of Age with Classic Hodgkin Lymphoma

In recent decades, the prognosis of Hodgkin lymphoma has been substantially improved, but these successes have been restricted to younger patients and could not be translated into a major benefit for older patients, especially those with advanced-stage disease. Major problems in treating older patients include a different biology, frailty, comorbidities, and poorer tolerance of therapy. Additionally, these patients are often excluded from randomized trials, so an evidence-based standard of care is lacking. Importantly, the proportion of older patients with HL will increase over the next 50 years. Currently, ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) is considered to be the gold standard, even though it has some toxicity in older patients and prospective data are not available. Thus, further studies are required, including the assessment of comorbidities and the incorporation of new drugs such as immunomodulatory agents, antibody-drug conjugates, mTOR inhibitors, or histone deacetylase (HDAC) inhibitors

Phase 2 study of BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in older patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG)

For older patients with early unfavorable or advanced stage Hodgkin lymphoma (HL) the prognosis is much worse than for younger HL patients. We thus developed a new regimen, BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone), to improve both tolerability and efficacy of treatment for older HL patients. Between 2004 and 2005, 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were enrolled in this phase 2 trial. Treatment consisted of 6 to 8 cycles of BACOPP. Residual tumor masses were irradiated. Primary endpoints were feasibility as determined by adherence to protocol and overall response rate. Secondary endpoints included toxicity, freedom from treatment failure, and progression free and overall survival. For the final analysis 60 patients (92%) were eligible; 75% of treatment courses were administered according to protocol. World Health Organization grade 3/4 toxicities occurred in 52 patients. Fifty-one patients (85%) achieved complete remission, 2 (3%) partial remission, and 4 (7%) developed progressive disease. With a median observation time of 33 months, 18 patients died (30%), including 7 treatment-associated deaths. Three patients died before response assessment. Thus, the BACOPP regimen is active in older HL patients but is compromised by a high rate of toxic deaths. This trial was registered at www.clinicaltrials.gov as #NCT00284271. (Blood. 2010;116(12):2026-2032

Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial

Question What is the efficacy of concomitant or sequential nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) as first-line treatment for early-stage unfavorable classic Hodgkin lymphoma? Findings In this investigator-sponsored phase 2 randomized clinical trial including 109 adult patients, very high interim complete remission rates were observed after treatment with 2 cycles of N-AVD (87%) or 4 doses of nivolumab (51%). After end of treatment with 4 cycles of N-AVD and 30-Gy involved-site radiotherapy, efficacy measures, such as complete remission rates, 1-year progression-free survival, and 1-year overall survival were excellent in both groups. Meaning Nivolumab-based first-line treatment is highly effective in patients with early-stage unfavorable classic Hodgkin lymphoma and warrants further investigation. This phase 2 randomized clinical trial assesses the efficacy of concomitant and sequential treatment with nivolumab and doxorubicin, vinblastine, and dacarbazine (AVD) for patients with early-stage unfavorable Hodgkin lymphoma. IMPORTANCE In early-stage unfavorable 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 PARTICIPANTS This 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 Measures Complete 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. RESULTS Of 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

PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING Deutsche Krebshilfe