Histopathological growth patterns in patients with advanced nodular lymphocyte-predominant Hodgkin lymphoma treated within the randomized HD18 study: a report from the German Hodgkin Study Group.

We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET-2) tended to be more common (P = 0·1078). Five-year progression-free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49-1·47] and overall survival (HR = 0·85; 95% CI = 0·49-1·51) did not differ between the groups after study treatment with PET-2-guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET-2-guided escalated BEACOPP.

9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial.

High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.

Involved-Field Radiation Therapy Prevents Recurrences in the Early Stages of Hodgkin Lymphoma in PET-Negative Patients After ABVD Chemotherapy: Relapse Analysis of GHSG Phase 3 HD16 Trial.

PURPOSE: The HD16 trial of the German Hodgkin Study Group (NCT00736320) demonstrated that radiation therapy in early-stage Hodgkin lymphoma without risk factors cannot be safely omitted, and therefore combined modality therapy (CMT) remains the standard treatment. To demonstrate the local effect of consolidating involved-field radiation therapy (IF-RT), we performed an analysis of the recurrence pattern of positron emission tomography (PET)-negative HD16 patients. METHODS AND MATERIALS: Between 2009 and 2015, 1150 patients with early-stage Hodgkin lymphoma without risk factors were randomly assigned to PET guided to 20 Gy IF-RT after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the HD16 study of the German Hodgkin Study Group. The study was designed as a prospective randomized controlled trial. We correlated the localization of recurrence with the panel-based IF-RT plan, which was drawn up for all patients prospectively, blinded to treatment allocation. Accordingly, we were able to identify recurrences that occurred at least in part inside or outside of the (potential) radiation field (in-field and out-field, respectively). RESULTS: There were 328 and 300 PET-negative patients assigned to CMT and PET-guided treatment (ie, chemotherapy alone), respectively. Within a median 47-month follow-up, disease progression or recurrence was documented for 15 and 29 patients treated with and without IF-RT, respectively. Relapse localization was unknown in 1 CMT patient. Without IF-RT, 5-year incidence of in-field relapses was 10.5% (95% confidence interval, 6.5-14.6) compared with 2.4% (0.5-4.3) with CMT (P = .0008). There were no relevant differences in out-field recurrences (5-year incidence 4.1% [1.7-6.6] vs 6.6% [3.0-10.3], P = .54). There was no grade 4 toxicity observed during IF-RT, and incidence of second primary malignancies was similar in both groups. CONCLUSIONS: PET-negative patients of the HD16 study showed no significant toxicity after 20 Gy IF-RT, and we demonstrated that omission of IF-RT resulted in more, particularly local, recurrences. Therefore, consolidation IF-RT should still be considered as standard therapy in this setting.

PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial.

BACKGROUND: The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. METHODS: HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1-3], 100 mg/m2 oral procarbazine [day 1-7], 40 mg/m2 oral prednisone [day 1-14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed. FINDINGS: Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2]). INTERPRETATION: Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. FUNDING: Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Non-Hodgkin lymphoma after treatment for classical Hodgkin lymphoma: a report from the German Hodgkin Study Group.

Data on non-Hodgkin lymphoma (NHL) after classical Hodgkin lymphoma (cHL) are scarce. We therefore performed a retrospective analysis comprising 11·841 cHL patients who had first-line treatment within the randomized German Hodgkin Study Group (GHSG) HD7-HD15 studies. After a median follow-up of 106 months, 175 patients (1·5%) had developed NHL. The median time to NHL was 44 months, the median age at NHL diagnosis was 54 years. The five-year event-free survival and overall survival estimates from the diagnosis of NHL were 36·9% and 44·2%, respectively. Thus, NHL after cHL is a rare event primarily affecting older individuals and often resulting in the patient´s death.

Early Response to First-Line Anti-PD-1 Treatment in Hodgkin Lymphoma: A PET-Based Analysis from the Prospective, Randomized Phase II NIVAHL Trial.

PURPOSE: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (ΔMTV and ΔTLG), measured on PET, might provide additional relevant information for response assessment in this setting. Hence, the current analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. PATIENTS AND METHODS: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arms A and B were assessed for early treatment response after two courses of doxorubicin, vinblastine, and dacarbazine with two concomitant nivolumab infusions per cycle (2 × N-AVD) and 4 × nivolumab, respectively. In the current analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. RESULTS: At interim restaging, we determined a mean ΔMTV and ΔTLG of -99.8% each in arm A after 2 × N-AVD, compared with -91.4% and -91.9%, respectively, for treatment group B undergoing 4 × nivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. CONCLUSIONS: Our study showed that nivolumab-based first-line treatment leads to rapid, near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PET-derived biomarkers might allow reduction or even omission of chemotherapy and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

Health-Related Quality of Life in Patients With Hodgkin Lymphoma: A Longitudinal Analysis of the German Hodgkin Study Group.

PURPOSE: Many important details of health-related quality of life (HRQoL) after diagnosis and treatment of Hodgkin lymphoma (HL) are still unknown because large longitudinal studies of HRQoL are rare. Therefore, we analyzed a systematically assessed, comprehensive range of HRQoL domains in patients with HL of all stages from diagnosis up to 5 years of survivorship. PATIENTS AND METHODS: We included patients with HL age 18-60 years at diagnosis from the German Hodgkin Study Group trials HD13, HD14, and HD15. We analyzed HRQoL using all functional and symptom scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 including deviations from reference values. We estimated the effect of different disease, patient, and treatment characteristics using multiple regression and repeated measures analysis and computed correlations of HRQoL scores. RESULTS: We analyzed 4,215 patients with any HRQoL assessment within 5 years after treatment. Higher tumor burden at diagnosis was associated with impaired baseline scores in many HRQoL domains. During survivorship, cognitive, emotional, role, and social functioning and fatigue, dyspnea, sleep, and financial problems were severely and persistently affected. From year 2 on, mean deviations from reference values ranged between 12 and 29 points, with 10 points being a commonly used margin of clinical relevance. In all 3 trials, HRQoL domains 2 and 5 years after therapy were significantly influenced by baseline scores and age but not by randomized treatments. Fatigue was most closely correlated with other symptoms and scales. CONCLUSION: Our results show a high and persistent amount of different HRQoL deficits in survivors of HL that are largely independent of the applied chemotherapies. Our analysis underscores the high, unmet medical need of these rather young survivors of HL regarding the psychosocial adverse effects of the cancer experience.

The interplay between cancer-related fatigue and functional health in Hodgkin lymphoma survivors.

OBJECTIVE: Cancer-related fatigue (CRF) is among the most distressing symptoms reported by cancer survivors as compromising their quality of life. This study investigates the complex interplay between CRF and functional health (FH) in survivors of Hodgkin lymphoma by using longitudinal data to clarify the etiology of CRF. METHODS: Data from N = 3596 survivors (HD13-15) from the German Hodgkin Study Group was analyzed using bivariate latent curve models with structured residuals to model how the interplay between CRF and FH unfolds over time across and within individuals. CRF and FH were measured with the EORTC QLQ-C30. Assessed FH domains were physical, cognitive, emotional, social, and role functioning. Age at diagnosis, gender, country, baseline fatigue, and cancer stage were included as covariates. RESULTS: The latent curve models with structured residuals had an adequate model fit (χ² = 416.63-548.28, df = 114, p < .001, root mean square error of approximation = .03, comparative fit index = .98-.99, Tucker-Lewis index = .97-.98). On the between-person level, CRF and all FH domains were strongly negatively correlated (r = -.72 to r = -.84). On the within-person level, earlier CRF (ρF = -.05 to ρF = -.12) and FH deviations (ρFH = -.05 to ρFH = -.13) negatively predicted subsequent deviations of the respective other variable. Time-specific within-person improvements in physical, cognitive, and emotional functioning reduced CRF more than vice versa, whereas the effect of CRF was stronger for social functioning. Role functioning had a balanced relation with CRF. CONCLUSIONS: This analysis reveals a complex reciprocal relation between CRF and FH with distinct between- and within-person effects. The results contribute to a better understanding of CRF in survivors of Hodgkin lymphoma and could inform the development of much-needed targeted interventions. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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

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. Trial Registration: ClinicalTrials.gov Identifier: NCT03004833.

Suicide in European Hodgkin Lymphoma Patients.

The purpose of this study was to determine whether there is an increased risk of suicide in European Hodgkin Lymphoma (HL) patients compared to the general European population. European HL patients enrolled in the German Hodgkin Study Group (GHSG) HD7 through HD15 studies were analyzed and standardized mortality ratio (SMR) was calculated using suicide mortality rates for the general European population. Case-control analysis was performed to identify characteristics associated with risk of death by suicide. Among 12,202 European HL patients observed for 94,972 person-years, 19 suicides (17 males and 2 females) were identified resulting in a SMR 1.63 (95% CI: 1.01-2.50, p = 0.046). The only characteristic associated with a statistically significant increased risk of suicide was male sex with an odds ratio (OR) 8.42 (95% CI = 1.04-67.85; p = 0.046) on multivariate analysis. These findings were confirmed in an independently analyzed Surveillance, Epidemiology, and End Results Program (SEER) validation dataset. European HL patients have a significantly increased incidence of suicide compared to the general European population. Male HL patients have a greater than 8-fold increased risk of suicide compared to female HL patients. Further study of social risk factors associated with an increased risk of suicide in HL patients is needed.

Pretreatment Vitamin D Deficiency Is Associated With Impaired Progression-Free and Overall Survival in Hodgkin Lymphoma.

PURPOSE: Vitamin D deficiency is described as a modifiable risk factor for the incidence of and mortality in many common cancers; however, data in Hodgkin lymphoma (HL) are lacking. PATIENTS AND METHODS: We thus performed a study measuring pretreatment vitamin D levels in prospectively treated patients with HL and correlated this with clinical outcomes. A total of 351 patients from the German Hodgkin Study Group clinical trials (HD7, HD8, and HD9) were included. RESULTS: Fifty percent of patients were vitamin D deficient (< 30 nmol/L) before planned chemotherapy. Pretreatment vitamin D deficiency was more common in relapsed/refractory patients than matched relapse-free controls (median baseline vitamin D, 21.4 nmol/L v 35.5 nmol/L; proportion with vitamin D deficiency, 68% v 41%; P < .001). Vitamin D-deficient patients had impaired progression-free survival (10-year difference, 17.6%; 95% CI, 6.9% to 28.4%; hazard ratio, 2.13; 95% CI, 1.84 to 2.48; P < .001) and overall survival (10-year difference, 11.1%; 95% CI, 2.1% to 20.2%; hazard ratio, 1.82; 95% CI, 1.53 to 2.15; P < .001), consistent across trials and treatment groups. We demonstrated that vitamin D status is an independent predictor of outcome and hypothesized that vitamin D status might be important for the chemosensitivity of HL. We subsequently performed experiments supplementing physiologic doses of vitamin D (calcitriol) to cultured HL cell lines and demonstrated increased antiproliferative effects in combination with chemotherapy. In an HL-xenograft animal model, we showed that supplemental vitamin D (dietary supplement, cholecalciferol) improves the chemosensitivity of tumors by reducing the rate of tumor growth compared with vitamin D or chemotherapy alone. CONCLUSION: On the basis of our clinical and preclinical findings, we encourage that vitamin D screening and replacement be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement therapy in HL.

Positron Emission Tomography-Guided Treatment in Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase III HD16 Trial by the German Hodgkin Study Group.

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.

Survivors' perspectives on risks and benefits of Hodgkin lymphoma treatment: results of a survey by the German Hodgkin Study Group.

We performed a survey in Hodgkin lymphoma survivors to learn more about their perspectives on treatment risks and benefits. We sent questions to 1149 survivors from the GHSG's HD13-15 trials with (N = 249) or without (N =900) documented progression or relapse. The participation rate was 52% (N =581). After median follow-up of 106 months, 40% of relapse-free and over 60% of relapsed survivors were still worried about late effects and the possibility of relapse. Chemotherapy, largely independent of its intensity, had been a strain on 74% of relapse-free and 90% of relapsed survivors. Most physical, psychological, and socio-economic sequelae were more frequent among relapsed survivors (p < .05) and described as very burdensome. 74% of relapse-free and 61% of relapsed survivors considered primary cure from Hodgkin lymphoma as the most important aspect in the choice of treatment. Accordingly, primary optimal lymphoma control is of utmost importance from the patients' perspective.

Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials.

BACKGROUND: Although intensified chemotherapy regimens have improved tumour control and survival in advanced-stage Hodgkin's lymphoma, data on the long-term sequelae are scarce. We did preplanned follow-up analyses of the German Hodgkin Study Group (GHSG) trials HD9 and HD12 to assess whether the primary results of these trials-which had shown that intensive initial therapy in advanced-stage Hodgkin's lymphoma has a beneficial effect on treatment outcomes-would continue with longer follow-up. METHODS: In HD9 (Feb 1, 1993, to March 10, 1998), 1282 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight alternating cycles of COPP and ABVD (COPP/ABVD), eight cycles of bBEACOPP, or eight cycles of eBEACOPP. In HD12 (Jan 4, 1999, to Jan 13, 2003; registered with ClinicalTrials.gov [NCT00265031]), 1670 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight cycles of eBEACOPP or four cycles of eBEACOPP plus four cycles of bBEACOPP (4 + 4), plus consolidation radiotherapy to initial bulk and residual disease or no radiotherapy, to analyse two non-inferiority objectives. In both trials, randomisation was done centrally in the GHSG trial coordination centre using the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, the presence or absence of a large mediastinal mass, and bulky disease. Patients and investigators were not masked to treatment allocation. All analyses were done on the intention-to-treat principle. The primary endpoint of this follow-up analysis was progression-free survival (time from first diagnosis to progressive disease, relapse, or death from any cause or censoring at the date of last information on disease status). To assess whether long-term outcome might be impaired by long-term sequelae, we analysed overall survival and second primary malignant neoplasm incidence as key secondary endpoints. FINDINGS: Median observation time was 141 months (IQR 101-204) in HD9 and 97 months (69-143) in HD12. For HD9 trial patients, 15-year progression-free survival was 57·0% (95% CI 50·0-64·0) for COPP/ABVD, 66·8% (61·9-71·8) for bBEACOPP, and 74·0% (69·0-79·0) for eBEACOPP, 15-year overall survival was 72·3% (95% CI 66·5-78·1), 74·5% (70·1-78·9), and 80·9% (76·7-85·0), respectively. Progression-free survival and overall survival in the eBEACOPP group remained significantly better than in the COPP/ABVD group (hazard ratio [HR] 0·53, 95% CI 0·41-0·69, p<0·0001, and 0·68, 0·50-0·93, p=0·015, respectively). The 15-year cumulative incidence of second primary malignant neoplasms was 7·2% (95% CI 3·7-10·7) after COPP/ABVD, 13·0% (9·1-16·9) after bBEACOPP, and 11·4% (7·6-15·1) after eBEACOPP. For HD12 trial patients, non-inferiority of 4 + 4 was shown, with 10-year progression-free survival of 82·6% (95% CI 79·6-85·6) for eBEACOPP and 80·6% (77·4-83·7) for 4 + 4 (HR 1·13 [0·89-1·43], within non-inferiority margin of 1·50), and 10-year overall survival of 87·3% (95% CI 84·7-89·9) and 86·8% (84·2-89·4), respectively (HR 1·02 [95% CI 0·77-1·36]). Among 555 (37%) patients with residual disease after chemotherapy, omission of radiotherapy was associated with significantly worse 10-year progression-free survival (89·7% [95% CI 85·8-93·6] radiotherapy vs 83·4% [78·2-88·5] for no radiotherapy; p=0·027) and 10-year overall survival (94·4% [91·4-97·3] vs 88·4% [83·8-93·0]; p=0·025). 10-year cumulative second primary malignant neoplasms incidence was 6·4% (95% CI 3·3-9·5) for 4 + 4 and 8·8% (5·2-12·4) for eBEACOPP. INTERPRETATION: Long-term follow-up of HD9 and HD12 shows an ongoing benefit of intensive first-line treatment and consolidation radiotherapy to residual disease in terms of progression-free survival and overall survival. Our results support the use of eBEACOPP in advanced-stage Hodgkin's lymphoma. However, because late toxicities such as second primary malignant neoplasms contribute to mortality, less toxic but equally effective treatments need to be developed to further improve overall survival. FUNDING: Deutsche Krebshilfe e.V.

Outcome-based interpretation of early interim PET in advanced-stage Hodgkin lymphoma.

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 = .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Three-year 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 = .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.

Outcome of Patients With Early-Stage Infradiaphragmatic Hodgkin Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group.

Purpose The prognostic effect of isolated infradiaphragmatic involvement in Hodgkin lymphoma (HL) is controversial, and there are little data about patients treated with current therapies. Therefore, we performed a risk factor analysis to focus on isolated nodal infradiaphragmatic disease in patients treated within the German Hodgkin Study Group trials HD13 (clinical trial information: ISRCTN63474366) and HD14 (clinical trial information: ISRCTN04761296) for early-stage HL. Patients and Methods Characteristics and outcomes of patients who had infradiaphragmatic HL were compared with patients who had supradiaphragmatic disease. Progression-free survival (PFS) and overall survival (OS) were estimated according to Kaplan-Meier methods and were compared between groups using the log-rank test and Cox proportional hazards regression, which was also applied for multivariable analyses that adjusted for relevant baseline characteristics. Results Of 2,903 qualified patients, 223 (7.7%) were diagnosed with isolated nodal infradiaphragmatic disease. In general, these patients were older, had a poorer performance status, were more often male, and had the nodular sclerosis subtype less often than those with supradiaphragmatic disease. After a median follow-up time of 51 months, PFS and OS were significantly worse in patients with infradiaphragmatic disease (5-year PFS and OS, 80.1% and 91.5% v 91.2% and 97.6% in patients with supradiaphragmatic disease; each P < .001). In multivariable analyses, infradiaphragmatic HL remained a significant risk factor in terms of PFS (hazard ratio [HR], 1.5; 95% CI, 1.04 to 2.2; P = .03) and OS (HR, 2.0; 95% CI, 1.2 to 3.5; P = .01). However, inferior PFS and OS could not be observed among those patients treated with the more intensive chemotherapy (two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD] in HD13, and two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPPescalated] plus two cycles of ABVD in HD14; all patients received 30 Gy of involved-field radiotherapy). Conclusion Early-stage HL that presents with infradiaphragmatic disease only represents a distinct patient group with an inferior outcome. However, this adverse outcome can be outweighed by appropriate combined modality treatment.