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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. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) is a malignancy of the lymphatic system with an incidence of 2-3/100 000/year in Europe and North America. The disease generally occurs in all age groups, but young adults are most often affected. Thus, adolescents aged 15 or 16 to 21 represent a relevant portion of patients. The optimum treatment for this age group is undefined. Both pediatric protocols such as OEPA (vincristine, etoposide, prednisone, adriamycin) or ABVE-PC (adriamycin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) and adult regimens such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) or BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) have been shown to be safe and active, resulting in long-term survival rates of 80% and more. However, a prospective comparison of pediatric and adult treatment strategies in terms of efficacy and other important questions such as treatment-related acute and long-term toxicity has not been undertaken so far. This review aims at shedding some light on potential treatment approaches for adolescents with HL and includes more recent analyses in this patient group. [ABSTRACT FROM AUTHOR]

Pixantrone is a potentially more effective, less cardiotoxic alternative to doxorubicin for patients with aggressive non-Hodgkin lymphoma (aNHL). This phase I/II non-comparative study evaluated pixantrone in place of doxorubicin in the standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), i.e. CPOP (cyclophosphamide, pixantrone, vincristine, and prednisone), in patients with relapsed aNHL who had previously received CHOP ±± rituximab. Patients were administered pixantrone on day 1 of each 21-day cycle. Phase I ( n == 35) dose escalation from 80 mg/m2 to 180 mg/m2 established the phase II ( n == 30) dose as 150 mg/m2. In phase II, 20 patients (67%%) received all six planned cycles. The objective response rate was 73%%, complete response/complete response unconfirmed (CR/CRu) rate was 47%%, and median overall survival was 17.9 months. Myelosuppression was nearly universal. Six patients (20%%) developed febrile neutropenia. Overall, left ventricular ejection fraction (LVEF) declines ≥≥10%% occurred in 14 patients; declines seemed transient and unrelated to dose. Symptomatic cardiac failure occurred in four patients; however, pre-existing conditions confounded causality. [ABSTRACT FROM AUTHOR]

Background: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.Methods: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.Findings: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.Interpretation: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.Funding: Deutsche Krebshilfe. [ABSTRACT FROM AUTHOR]

Summary: About 30% of all Hodgkin lymphoma (HL) patients are ≥60 years old. As lenalidomide has promising single agent activity in multiple relapsed HL, we replaced bleomycin in ABVD with lenalidomide in this phase‐I trial. Patients aged ≥60 years with early‐unfavourable‐ or advanced‐stage HL (Eastern Cooperative Oncology Group performance status ≤2, Cumulative Illness Rating Scale for Geriatrics score 0–7) received 4–8 cycles of AVD (doxorubicin, vinblastine, dacarbazine) and lenalidomide in escalation with overdose control. Dose‐limiting toxicities (DLTs) included thromboembolism ≥grade 2, severe haematological toxicity, neutropenic fever and prolonged therapy delay. Twenty‐five patients with a median age of 68 years were included, 68% had advanced‐stage HL. A pre‐defined stopping criterion for dose escalation after DLT evaluation of 20/24 patients suggested a recommended phase II dose (RPTD) of 20 mg. DLTs occurred in 10/24 evaluable patients, all treated with ≥20 mg, however, median relative dose intensity was 97% (interquartile range 49–104%). Grade 3 or higher toxicities occurred in all 22 patients at ≥20 mg lenalidomide but no treatment‐related deaths occurred. Overall response rate was 80% for all patients (20/25) and 86% (19/22) at ≥20 mg lenalidomide. Three‐year estimates for progression‐free survival and OS were 69·7% (95% CI: 50·3–89·1%) and 83·8% (95%‐CI: 69·3–98·4%), respectively. In conclusion, AVD with lenalidomide 20 mg is feasible and highly effective in older HL patients. [ABSTRACT FROM AUTHOR]

The HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses (eBEACOPP) to guide further treatment. Here, we analyzed the impact of PET-2 results in the context of eBEACOPP according to the Deauville score (DS) in patients treated within the HD18 trial. Residual tissue was visually compared with reference regions according to DS. We analyzed the association between PET-2 uptake and baseline characteristics, progression-free survival (PFS), and overall survival (OS). One thousand five patients (52%) had DS1 or DS2, 471 (24%) had DS3, and 469 (24%) DS4. PET-2 uptake was associated with baseline risk factors large mediastinal mass, extranodal disease, and high International Prognostic Score (P < .0001 each). Among 722 patients receiving standard therapy with 6 cycles of eBEACOPP, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with DS1-2, DS3, and DS4, respectively. Univariate hazard ratio (HR) for PFS in patients with DS4 vs DS1-3 was 2.3 (1.3-3.8; P 5 .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Threeyear OS rates were 97.6% for DS1-2, 99.0% for DS3, and 96.8% for DS4, with a univariate HR for DS4 vs DS1-3 of 2.6 (1.0-6.6; P 5 .04). Residual uptake above that in the liver at PET-2 (ie, DS4) is an important risk factor regarding survival outcomes for patients treated with eBEACOPP upfront. We thus recommend DS4 as the cutoff value for PET-2 positivity. This trial was registered at www.clinicaltrials.gov as #NCT00515554 [ABSTRACT FROM AUTHOR]

Background: A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy.Methods: We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18-60 years) with newly diagnosed, advanced, classical Hodgkin's lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 200 mg/m2 on days 2-4, doxorubicin 35 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, procarbazine 100 mg/m2 on days 2-8, and prednisone 40 mg/m2 on days 2-15) or BrECADD (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 150 mg/m2 on days 2-4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13·2-21·5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204.Findings: Between Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73-94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83-99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77-96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3-4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3-4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1-2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period.Interpretation: Both eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkin's lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity.Funding: Takeda Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Summary: Background: Several treatment strategies are available for adults with advanced-stage Hodgkin's lymphoma, but studies assessing two alternative standards of care—increased dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—were not powered to test differences in overall survival. To guide treatment decisions in this population of patients, we did a systematic review and network meta-analysis to identify the best initial treatment strategy. Methods: We searched the Cochrane Library, Medline, and conference proceedings for randomised controlled trials published between January, 1980, and June, 2013, that assessed overall survival in patients with advanced-stage Hodgkin's lymphoma given BEACOPPbaseline, BEACOPPescalated, BEACOPP variants, ABVD, cyclophosphamide (mechlorethamine), vincristine, procarbazine, and prednisone (C[M]OPP), hybrid or alternating chemotherapy regimens with ABVD as the backbone (eg, COPP/ABVD, MOPP/ABVD), or doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone combined with radiation therapy (the Stanford V regimen). We assessed studies for eligibility, extracted data, and assessed their quality. We then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. We also reconstructed individual patient survival data from published Kaplan-Meier curves and did standard random-effects Poisson regression. Results are reported relative to ABVD. The primary outcome was overall survival. Findings: We screened 2055 records and identified 75 papers covering 14 eligible trials that assessed 11 different regimens in 9993 patients, providing 59 651 patient-years of follow-up. 1189 patients died, and the median follow-up was 5·9 years (IQR 4·9–6·7). Included studies were of high methodological quality, and between-trial heterogeneity was negligible (τ2=0·01). Overall survival was highest in patients who received six cycles of BEACOPPescalated (HR 0·38, 95% credibility interval [CrI] 0·20–0·75). Compared with a 5 year survival of 88% for ABVD, the survival benefit for six cycles of BEACOPPescalated is 7% (95% CrI 3–10)—ie, a 5 year survival of 95%. Reconstructed individual survival data showed that, at 5 years, BEACOPPescalated has a 10% (95% CI 3–15) advantage over ABVD in overall survival. Interpretation: Six cycles of BEACOPPescalated significantly improves overall survival compared with ABVD and other regimens, and thus we recommend this treatment strategy as standard of care for patients with access to the appropriate supportive care. Funding: None. [ABSTRACT FROM AUTHOR]

Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatmentrelated toxicity resulting in reduced overall dose intensity and more treatmentrelated mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%78%) and 58% (95% CI, 43%-71 %), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinlcaltrials.gov as #NCT00147875. [ABSTRACT FROM AUTHOR]

Background: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. Methods: We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment. Results: The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1). Conclusions: In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.) N Engl J Med 2010;363:640-52. [ABSTRACT FROM AUTHOR]