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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the investigator-sponsored randomized phase II NIVAHL trial for early-stage unfavorable classical Hodgkin lymphoma (HL), two schedules of four cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine followed by 30 Gy involved-site radiotherapy resulted in high complete remission rates and an unprecedented 1-year progression-free survival in 109 patients. In this article, we report the preplanned final analysis conducted three years after the registration of the last patient including long-term safety results. No survival events were observed since the primary analysis, and after a median follow-up (FU) of 41 months, the overall survival was 100% in both treatment groups. The progression-free survival was 98% and 100% in the sequential and concomitant nivolumab, doxorubicin, vinblastine, and dacarbazine treatment groups, respectively. At last FU, the mean forced expiratory pressure in one second was 95.5% (standard deviation 12.7%), the mean diffusion capacity for carbon monoxide adjusted for hemoglobin was 82.8% (standard deviation 15.4%), and the left ventricular ejection fraction was in the normal range in 95% of patients. Hypothyroidism requiring long-term medication occurred in 15% of patients, who were nearly exclusively female (87%). No second primary malignancies occurred, and no patient required corticosteroid treatment at last FU. Patient-reported normalized global quality-of-life score measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 improved over time. This preplanned FU analysis of the largest anti-programmed death protein 1 HL first-line trial to date confirms the outstanding efficacy and relatively favorable safety profile of this therapeutic approach.

Purpose: We evaluated disease and treatment characteristics of patients with relapse after risk-adapted first-line treatment of early-stage, favorable, classic Hodgkin lymphoma (ES-HL). We compared second-line therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) or conventional chemotherapy (CTx)., Methods: We analyzed patients with relapse after ES-HL treated within the German Hodgkin Study Group HD10+HD13 trials. We compared, by Cox proportional hazards regression, progression-free survival (PFS) after relapse (second PFS) treated with either ASCT or CTx and performed sensitivity analyses with overall survival (OS) from relapse and Kaplan-Meier statistics., Results: A total of 174 patients' disease relapsed after treatment in the HD10 (n = 53) and HD13 (n = 121) trials. Relapse mostly occurred > 12 months after first diagnosis, predominantly with stage I-II disease. Of 172 patients with known second-line therapy, 85 received CTx (49%); 70, ASCT (41%); 11, radiotherapy only (6%); and 4, palliative single agent therapies (2%). CTx was predominantly bleomycin, etoposide, doxorubicin cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [68%]), followed by the combination regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (19%), or other regimens (13%). Patients aged > 60 years at relapse had shorter second PFS (hazard ratio [HR], 3.0; P = .0029) and were mostly treated with CTx (n = 33 of 49; 67%) and rarely with ASCT (n = 8; 16%). After adjustment for age and a disadvantage of ASCT after the more historic HD10 trial, we did not observe a significant difference in the efficacy of CTx versus ASCT for second PFS (HR, 0.7; 95% CI, 0.3 to 1.6; P = .39). In patients in the HD13 trial who were aged ≤ 60 years, the 2-year, second PFS rate was 94.0% with CTx (95% CI, 85.7% to 100%) versus 83.3% with ASCT (95% CI, 71.8% to 94.8%). Additional sensitivity analyses including OS confirmed these observations., Conclusion: After contemporary treatment of ES-HL, relapse mostly occurred > 12 months after first diagnosis. Polychemotherapy regimens such as BEACOPP are frequently administered and may constitute a reasonable treatment option for selected patients with relapse after ES-HL.

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.

Purpose: The optimal treatment of newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is ill defined. We therefore conducted a retrospective analysis using the database of the German Hodgkin Study Group (GHSG)., Patients and Methods: The long-term course of 471 patients with NLPHL (early stages, n = 251; intermediate stages, n = 76; advanced stages, n = 144) who had received stage-adapted first-line treatment in the randomized GHSG HD7 to HD15 studies was investigated. Treatment consisted of radiotherapy alone, chemotherapy alone, or combined-modality approaches., Results: The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Patients were mostly male (75.8%). The median observation time was 9.2 years. At 10 years, progression-free survival and overall survival estimates were 75.5% and 92.1% (early stages, 79.7% and 93.3%; intermediate stages, 72.1% and 96.2%; advanced stages, 69.8% and 87.4%), respectively. A total of 48 patients (10.2%) developed a second malignancy during follow-up (non-Hodgkin lymphoma, n = 13; leukemia, n = 6; solid tumor, n = 25; unspecified malignancy, n = 4). Death occurred in 43 patients (9.1%). However, only a minority of deaths were NLPHL related (n = 10), whereas second malignancies (n = 20) and nonmalignant conditions possibly associated with radiotherapy or chemotherapy (n = 13) caused the death in the majority of patients., Conclusion: The overall outcome of patients with NLPHL who had received Hodgkin lymphoma-directed first-line treatment in randomized GHSG trial protocols was good. Nonetheless, treatment optimization is still necessary to reduce toxicity in standard-risk patients and to improve the prognosis in high-risk patients.

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.

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.

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 [BEACOPP escalated ] 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.

Purpose Genetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts. Methods This multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)-naïve (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee. Results Overall, 243 patients were treated; 63 in cohort A, 80 in cohort B, and 100 in cohort C. After a median follow-up of 18 months, 40% continued to receive treatment. The objective response rate was 69% (95% CI, 63% to 75%) overall and 65% to 73% in each cohort. Overall, the median duration of response was 16.6 months (95% CI, 13.2 to 20.3 months), and median progression-free survival was 14.7 months (95% CI, 11.3 to 18.5 months). Of 70 patients treated past conventional disease progression, 61% of those evaluable had stable or further reduced target tumor burdens. The most common grade 3 to 4 drug-related adverse events were lipase increases (5%), neutropenia (3%), and ALT increases (3%). Twenty-nine deaths occurred; none were considered treatment related. Conclusion With extended follow-up, responses to nivolumab were frequent and durable. Nivolumab seems to be associated with a favorable safety profile and long-term benefits across a broad spectrum of patients with relapsed/refractory cHL.

Purpose Combined-modality treatment is widely considered the standard of care in early-stage Hodgkin lymphoma (HL), and treatment intensity has been reduced over the last years. Long-term follow-up is important to judge both efficacy and safety of the different therapies used. Patients and Methods We analyzed updated follow-up data on 4,276 patients treated within the German Hodgkin Study Group trials HD7 and HD10 for early-stage favorable HL and HD8 and HD11 for early-stage unfavorable HL between 1993 and 2003. Results In HD7 (N = 627; median follow-up, 120 months), combined-modality treatment was superior to extended-field radiotherapy (RT), with 15-year progression-free survival (PFS) of 73% versus 52% (hazard ratio [HR], 0.5; 95% CI, 0.3 to 0.6; P < .001), without differences in overall survival (OS). In HD10 (N = 1,190; median follow-up, 98 months), noninferiority of two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) plus 20 Gy involved-field (IF)-RT to more intensive four cycles of ABVD plus 30 Gy IF-RT was confirmed with 10-year PFS of 87% each (HR, 1.0; 95%, 0.6 to 1.5) and OS of 94% each (HR, 0.9; 95% CI, 0.5 to 1.6), respectively. In both trials, no differences in second neoplasias were observed. In HD8 (N = 1,064; median follow-up, 153 months), noninferiority of involved-field RT to extended-field RT regarding PFS was confirmed (HR, 1.0; 95% CI, 0.8 to 1.2). In HD11 (N = 1,395; median follow-up, 106 months), superiority of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline over ABVD was not observed. After BEACOPP baseline , 20 Gy IF-RT was noninferior to 30 Gy (10-year PFS, 84% v 84%; HR, 1.0; 95% CI, 0.7 to 1.5). In contrast, PFS was inferior in ABVD-treated patients receiving 20 Gy instead of 30 Gy IF-RT (10-year PFS, 76% v 84%; HR, 1.5; 95% CI, 1.0 to 2.1). No differences in OS or second neoplasias were observed in in both trials. Conclusion Long-term follow-up data of the four randomized trials largely support the current risk-adapted therapeutic strategies in early-stage HL. Nevertheless, continued follow-up is necessary to assess the long-term safety of currently applied therapeutic strategies.

Purpose Clinical characteristics, therapeutic approaches, and prognosis of late relapse (LR) in patients with classic Hodgkin lymphoma (cHL) are poorly understood. We performed a comprehensive analysis of LR of Hodgkin lymphoma (LR-HL). Methods To estimate the incidence of LR-HL, we retrospectively analyzed 6,840 patients with cHL included in the German Hodgkin Study Group trials HD7 to HD12. Patients who experienced a relapse > 5 years into remission were compared with patients in continued remission for > 5 years and with those who experienced a relapse ≤ 5 years after first diagnosis. Results With a median observation time of 10.3 years, 141 incidences of LR-HL were observed. Cumulative incidences at 10, 15, and 20 years rose linearly and were 2.5%, 4.3%, and 6.9%, respectively. The standardized incidence ratio for HL with respect to age- and sex-matched German reference data was 84.5 (95% CI, 71.2 to 99.7). LR-HL was more frequently observed in patients with early-stage favorable than unfavorable or advanced stage at first diagnosis (15-year cumulative incidence, 5.3% v 3.9% and 3.9%, respectively; P = .01). Overall survival from first diagnosis was worse after LR compared with nonrelapse survivors (10-year estimate, 95.8% v 86.1%; hazard ratio, 2.5; 95% CI, 1.7 to 3.5; P < .001). In patients with LR-HL, survival was better compared with 466 patients with earlier relapse (hazard ratio, 0.6; 95% CI, 0.4 to 0.9, P = .01). Forty-four percent and 49% of patients with LR-HL and earlier relapse, respectively, received stem cell transplantations. Conclusion Apart from treatment-associated adverse effects, survivors after initially successful therapy for cHL are at an 85-fold risk for recurrence of disease compared with the general German population. After risk-adapted treatment strategies, especially in early-stage favorable HL, regular clinical follow-up is recommended for timely detection of LR-HL. With adequate treatment, prognosis of LR-HL is better compared with early relapses.

Purpose Cancer-related fatigue occurs frequently in patients with Hodgkin lymphoma (HL) and has a major impact on their quality of life. We hypothesized that severe fatigue (sFA) might have an impact on patients' treatment outcome and social reintegration. Methods Of 5,306 patients enrolled in the German Hodgkin Study Group's fifth generation of clinical trials in HL (HD13, HD14, and HD15; nonqualified and older [> 60 years] patients excluded), 4,529 provided data on health-related quality of life. We describe sFA (defined as a score ≥ 50 on the 0 to 100 scale from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) before and up to 9 years after therapy and analyze its impact on treatment outcome and social reintegration. Results The proportion of patients reporting sFA was 37% at baseline and ranged from 20% to 24% during follow-up. Baseline sFA was associated with significantly impaired progression-free survival and a trend to impaired overall survival, which can be overcome in patients receiving highly effective HL therapies as applied in our fifth-generation trials. Our analysis revealed a significant negative association of sFA and employment in survivors: 5 years after therapy, 51% and 63% of female and male survivors, respectively, with sFA were working or in professional education, compared with 78% and 90% without sFA, respectively ( P < .001 adjusted for age, sex, stage, baseline employment status, and treatment outcome). sFA was also associated with financial problems and the number of visits to a general practitioner and medical specialists. Conclusion sFA is an important factor preventing survivors from social reintegration during follow-up. This observation underscores the need to address fatigue as a significant diagnosis when treating patients with and survivors of cancer.

Purpose: The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group., Patients and Methods: The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009., Results: The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL., Conclusion: Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population., (© 2015 by American Society of Clinical Oncology.)

Purpose: The role of bleomycin and vincristine in the treatment of patients with advanced Hodgkin lymphoma (HL) is unclear, and the impact of dose reductions of these drugs on outcome and tolerability has not been systematically assessed. Because both drugs can cause significant toxicity and are frequently discontinued, we performed an analysis of patients with HL treated with BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in the German Hodgkin Study Group HD12 and HD15 trials., Patients and Methods: Characteristics and outcome of patients were analyzed with respect to discontinuation of bleomycin and/or vincristine., Results: With 3,309 patients with HL analyzed, bleomycin was discontinued in 17.6% and vincristine in 32.6%. A total of 157 patients (4.7%) received ≤ four cycles of bleomycin, and 218 (6.6%) received ≤ three cycles of vincristine; these were compared with patients receiving > four cycles of bleomycin or > three cycles of vincristine, respectively. After a median follow-up of 59 and 67 months for progression-free survival (PFS) and overall survival (OS), respectively, there was no significant difference in PFS or OS in patients receiving ≤ or > four cycles of bleomycin (5-year PFS difference, 1.7%; 95% CI, -4.2% to 7.6%; 5-year OS difference, 1.5%; 95% CI, -2.6% to 5.5%). Similarly, there was no significant difference in patients receiving ≤ or > three cycles of vincristine (5-year PFS difference, -1.3%; 95% CI, -5.6% to 3.1%; 5-year OS difference, -0.1%; 95% CI, -3.1% to 2.9%)., Conclusion: Bleomycin and vincristine discontinuation because of drug-specific adverse effects does not affect the efficacy of treatment in this setting., (© 2015 by American Society of Clinical Oncology.)

Purpose: Positron emission tomography (PET) after chemotherapy can guide consolidating radiotherapy in advanced-stage Hodgkin lymphoma (HL). This analysis aims to improve outcome prediction by integrating additional criteria derived by computed tomography (CT)., Patients and Methods: The analysis set consisted of 739 patients with residues≥2.5 cm after chemotherapy from a total of 2,126 patients treated in the HD15 trial (HD15 for advanced stage Hodgkin's disease: Quality assurance protocol for reduction of toxicity and the prognostic relevance of fluorodeoxyglucose-positron-emission tomography [FDG-PET] in the first-line treatment of advanced-stage Hodgkin's disease) performed by the German Hodgkin Study Group. A central panel performed image analysis and interpretation of CT scans before and after chemotherapy as well as PET scans after chemotherapy. Prognosis was evaluated by using progression-free survival (PFS); groups were compared with the log-rank test. Potential prognostic factors were investigated by using receiver operating characteristic analysis and logistic regression., Results: In all, 548 (74%) of 739 patients had PET-negative residues after chemotherapy; these patients did not receive additional radiotherapy and showed a 4-year PFS of 91.5%. The 191 PET-positive patients (26%) receiving additional radiotherapy had a 4-year PFS of 86.1% (P=.022). CT alone did not allow further separation of patients in partial remission by risk of recurrence (P=.9). In the subgroup of the 54 PET-positive patients with a relative reduction of less than 40%, the risk of progression or relapse within the first year was 23.1% compared with 5.3% for patients with a larger reduction (difference, 17.9%; 95% CI, 5.8% to 30%)., Conclusion: Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse., (© 2014 by American Society of Clinical Oncology.)

Purpose: Progression or relapse of Hodgkin lymphoma (HL) is common among older patients. However, prognosis and effects of second-line treatment are thus far unknown., Patients and Methods: We investigated second-line treatment and survival in older patients with progressive or relapsed HL. Patients treated within German Hodgkin Study Group first-line studies between 1993 and 2007 were screened for refractory disease or relapse (RR-HL). Patients with RR-HL age ≥ 60 years at first-line treatment were included in this analysis., Results: We identified 105 patients (median age, 66 years); 28%, 31%, and 41% had progressive disease, early relapse, or late relapse, respectively. Second-line treatment strategies included intensified salvage regimens (22%), conventional polychemotherapy and/or salvage-radiotherapy with curative intent (42%), and palliative approaches (31%). Median overall survival (OS) for the entire cohort was 12 months; OS at 3 years was 31% (95% CI, 22% to 40%). A prognostic score with risk factors (RFs) of early relapse, clinical stage III/IV, and anemia identified patients with favorable and unfavorable prognosis (≤ one RF: 3-year OS, 59%; 95% CI, 44% to 74%; ≥ two RFs: 3-year OS, 9%; 95% CI, 1% to 18%). In low-risk patients, the impact of therapy on survival was significant in favor of the conventional polychemotherapy/salvage radiotherapy approach. In high-risk patients, OS was low overall and did not differ significantly among treatment strategies., Conclusion: OS in older patients with RR-HL can be predicted using a simple prognostic score. Poor outcome in high-risk patients cannot be overcome by any of the applied treatment strategies. Our results might help to guide treatment decisions and evaluate new compounds in these patients.

Purpose: The introduction of BEACOPP(escalated) (escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has significantly improved tumor control and overall survival in patients with advanced-stage Hodgkin lymphoma. However, this regimen has also been associated with higher treatment-related mortality (TRM). Thus, we analyzed clinical course and risk factors associated with TRM during treatment with BEACOPP(escalated)., Patients and Methods: In this retrospective analysis, we investigated incidence, clinical features, and risk factors for BEACOPP(escalated)-associated TRM in the German Hodgkin Study Group trials HD9, HD12, and HD15., Results: Among a total of 3,402 patients, TRM of 1.9% (64 of 3,402) was mainly related to neutropenic infections (n = 56; 87.5%). Twenty of 64 events occurred during the first course of BEACOPP(escalated) (31.3%). Higher risk of TRM was seen in patients age ≥ 40 years with poor performance status (PS) and in patients age ≥ 50 years. PS and age were then used to construct a new risk score; those with a score ≥ 2 had TRM of 7.1%, whereas patients who scored 0 or 1 had TRM of 0.9%., Conclusion: The individual risk of TRM associated with BEACOPP(escalated) can be predicted by a simple algorithm based on age and PS. High-risk patients should receive special clinical attention.

Purpose: Older patients with Hodgkin lymphoma (HL) account for approximately 20% of all HL patients. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy is regarded as standard of care in these patients. However, little is known on feasibility and efficacy of ABVD in this age group., Patients and Methods: We analyzed the feasibility and efficacy of four cycles of ABVD in older patients age 60 to 75 years with early-stage HL who were treated within the German Hodgkin Study Group (GHSG) HD10 and HD11 trials; results were compared with those of younger patients treated within these trials., Results: In total, 1,299 patients received four cycles of ABVD, and 117 of those patients were older than age 60 years (median, 65 years). In 14% of older patients, treatment was not administered according to protocol, mainly because of excessive toxicity. The mean delay of treatment was twice as high in the older patients (2.2 v 1.2 weeks). Fifty-nine percent of older patients achieved a relative dose-intensity of at least 80% compared with 85% of younger patients. Major toxicity (WHO grade 3 and 4), including leucopenia, nausea, infection, and others, was documented in 68% of older patients with a treatment-related mortality of 5%. Complete response was achieved in 89% of older patients, 3% had progressive disease, and 11% relapsed. At a median observation time of 92 months, 28% of the patients had died, and the 5-year progression-free survival estimate was 75% (95% CI, 66% to 82%)., Conclusion: In patients age ≥ 60 years with HL, four cycles of ABVD is associated with substantial dose reduction, treatment delay, toxicity, and treatment-related mortality.

Purpose: To optimize fertility advice in patients with Hodgkin lymphoma (HL) before therapy and during survivorship, information on the impact of chemotherapy is needed. Therefore, we analyzed gonadal functions in survivors of HL., Patients and Methods: Women younger than age 40 and men younger than 50 years at diagnosis in ongoing remission at least 1 year after therapy within the German Hodgkin Study Group HD13 to HD15 trials for early- and advanced-stage HL were included. Hormone parameters, menstrual cycle, symptoms of hypogonadism, and offspring were evaluated., Results: A total of 1,323 (55%) of 2,412 contacted female and male survivors were evaluable for the current analysis (mean follow-up, 46 and 48 months, respectively). Follicle-stimulating hormone, anti-Müllerian hormone, and inhibin B levels correlated significantly with therapy intensity (P < .001). Low birth rates were observed in survivors after advanced-stage treatment within the observation time (women, 6.5%; men, 3.3%). Regular menstrual cycle was reported by more than 90% of female survivors of early-stage HL (recovery time mostly ≤ 12 months). After six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, menstrual activity was strongly related to age (< v ≥ 30 years: 82% v 45%, respectively; P < .001; prolonged recovery time). Thirty-four percent of women age ≥ 30 years suffered severe menopausal symptoms (three- to four-fold more frequently than expected). In contrast, male survivors had mean levels of testosterone within the normal range and reported no increased symptoms of hypogonadism., Conclusion: The present analysis in a large group of survivors of HL provides well-grounded information on gonadal toxicity of currently used treatment regimens and allows risk-adapted fertility preservation and comprehensive support during therapy and follow-up.

Purpose: Although the outcome of patients with HIV-related Hodgkin lymphoma (HIV-HL) has markedly improved since the introduction of combined antiretroviral therapy, standard therapy is still poorly defined. This prospective study investigates a stage- and risk-adapted treatment strategy in patients with HIV-HL., Patients and Methods: Patients with early favorable HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field (IF) radiation. In patients with early unfavorable HIV-HL, four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP baseline) or four cycles of ABVD + 30 Gy of IF radiation were administered. Six to eight cycles of BEACOPP baseline were given in patients with advanced-stage HIV-HL. In patients with advanced HIV infection, BEACOPP was replaced with ABVD., Results: Of 108 patients (including eight female patients) included in the study, 23 (21%) had early favorable HL, 14 (13%) had early unfavorable HL, and 71 (66%) had advanced-stage HL. The median CD4 count at HL diagnosis was 240/μL. The complete remission rates for patients with early favorable, early unfavorable, and advanced-stage HL were 96%, 100%, and 86%, respectively. The 2-year progression-free survival of the entire study population was 91.7%. Eleven patients (11%) have died, and treatment-related mortality was 5.6%. The 2-year overall survival rate was 90.7% with no significant difference between early favorable (95.7%), early unfavorable (100%), and advanced-stage HL (86.8%)., Conclusion: In patients with HIV-HL, stage- and risk-adapted treatment is feasible and effective. The prognosis for patients with HIV-HL may approach that of HIV-negative patients with HL.

Purpose: Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population., Patients and Methods: Panobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed., Results: The 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 patients (27%), including 30 (23%) partial responses and five (4%) complete responses. The median TTR was 2.3 months, median DOR was 6.9 months, and median PFS was 6.1 months. The estimated 1-year overall survival rate was 78%. Common nonhematologic adverse events (AEs)-diarrhea, nausea, vomiting, and fatigue-were generally grade 1 and 2. Most common grade 3 and 4 hematologic AEs-thrombocytopenia, anemia, and neutropenia-were manageable. Early reductions in thymus and activation-regulated chemokine were observed in patients achieving complete or partial response., Conclusion: In the largest, prospective, multicenter, international trial conducted in heavily pretreated patients with HL who relapsed or were refractory to ASCT, panobinostat monotherapy demonstrated antitumor activity, resulting in durable responses.

Purpose: Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas., Patients and Methods: In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility., Results: The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea., Conclusion: The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.

Purpose: In patients with early unfavorable Hodgkin's lymphoma (HL), combined modality treatment with four cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and 30 Gy involved-field radiotherapy (IFRT) results in long-term tumor control of approximately 80%. We aimed to improve these results using more intensive chemotherapy., Patients and Methods: Patients with newly diagnosed early unfavorable HL were randomly assigned to either four cycles of ABVD or an intensified treatment consisting of two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (2 + 2). Chemotherapy was followed by 30 Gy IFRT in both arms. The primary end point was freedom from treatment failure (FFTF); secondary end points included progression-free survival (PFS) and treatment-related toxicity., Results: With a total of 1,528 qualified patients included, the 2 + 2 regimen demonstrated superior FFTF compared with four cycles of ABVD (P < .001; hazard ratio, 0.44; 95% CI, 0.30 to 0.66), with a difference of 7.2% at 5 years (95% CI, 3.8 to 10.5). The difference in 5-year PFS was 6.2% (95% CI, 3.0% to 9.5%). There was more acute toxicity associated with 2 + 2 than with ABVD, but there were no overall differences in treatment-related mortality or secondary malignancies., Conclusion: Intensified chemotherapy with two cycles of BEACOPP escalated followed by two cycles of ABVD followed by IFRT significantly improves tumor control in patients with early unfavorable HL.

Purpose: Eight cycles of BEACOPP(escalated) (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy., Patients and Methods: In this prospectively randomized multicenter trial, eight cycles of BEACOPP(escalated) was compared with four cycles of BEACOPP(escalated) followed by four cycles of the baseline dose of BEACOPP (BEACOPP(baseline); 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%., Results: Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPP(escalated) arm and 84.8% in the 4 + 4 arm (difference, -1.6%; 95% CI, -5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, -1.7%; 95% CI, -4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPP(escalated), n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, -3.4%; 95% CI, -6.6% to -0.1%), particularly in patients who had residual disease after chemotherapy (difference, -5.8%; 95% CI, -10.7% to -1.0%), but not in patients with bulk in complete response after chemotherapy (difference, -1.1%; 95% CI, -6.2% to 4%)., Conclusion: The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.

Purpose: To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-depleted classical Hodgkin's lymphoma (LDCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL)., Patients and Methods: From a total of 12,155 evaluable patients with biopsy-proven HL treated within the German Hodgkin Study Group trials HD4 to HD15, 10,019 patients underwent central expert pathology review. Eighty-four patients with LDCHL (< 1%) were identified and confirmed. The median follow-up time was 67 months., Results: Patients with LDCHL, compared with patients with other histologic subtypes, presented more often with advanced disease (74% v 42%, respectively; P < .001) and "B" symptoms (76% v 41%, respectively; P < .001). Other risk factors were also more frequent in patients with LDCHL. Complete remission or unconfirmed complete remission was achieved in 82% of patients with LDCHL compared with 93% of patients with other HL subtypes (P < .001), and more patients with LDCHL had progressive disease. At 5 years, progression-free survival (PFS) and overall survival (OS) were significantly lower in patients with LDCHL compared with patients with other HL subtypes (PFS, 71% v 85%, respectively; P < .001; OS, 83% v 92%, respectively; P = .0018). However, when analyzing the subgroup of patients who underwent treatment with intensified or dose-dense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, patients with LDCHL (n = 39) had similar outcomes when compared with patients with other subtypes of HL (n = 3,564; P = .61)., Conclusion: LDCHL has a different pattern from other HL subtypes with more clinical risk factors at initial diagnosis and significantly poorer prognosis. Patients with LDCHL should be treated with modern dose-intense treatment strategies.

Purpose: High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy., Patients and Methods: Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points., Results: From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001)., Conclusion: Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL.

Purpose: Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied., Patients and Methods: Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT., Results: With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy., Conclusion: Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

Purpose: To determine whether epoetin alfa reduces anemia-related fatigue, improves other aspects of health-related patient-recorded outcomes (PROs), reduces the number of RBC transfusions, and has an impact on freedom from treatment failure (FFTF) and overall survival (OS) in patients with advanced-stage Hodgkin's lymphoma (HL)., Patients and Methods: The prospectively randomized HD15EPO study performed by the German Hodgkin Study Group investigated epoetin alfa administered at doses of 40,000 U weekly during and after chemotherapy (six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) in a double-blind, placebo-controlled setting. The study accrued 1,379 patients, of whom 1,328 were assessable for safety, 1,303 were assessable for clinical outcome, and 930 were assessable for PROs., Results: PROs were not different in patients receiving placebo or epoetin alfa, both after the end of chemotherapy and 6 months thereafter. There was no difference between patients treated with epoetin alfa or placebo with respect to FFTF and OS. There were also no differences in the numbers of deaths, progressions, relapses, and thromboembolic events. The median number of RBC transfusions was reduced from four per patient in the placebo group to two per patient in the epoetin alfa group (P < .001), with 27.4% of patients needing no RBC transfusion in the placebo group compared with 36.7% of patients in the epoetin alfa group (P < .001)., Conclusion: Epoetin alfa administered at 40,000 U weekly parallel to BEACOPP chemotherapy was safe in patients with advanced-stage HL and reduced the number of RBC transfusions but had no impact on fatigue and other PRO domains.

PURPOSE The standard of care for adolescent patients with Hodgkin's lymphoma (HL) is undefined, particularly the choice between pediatric and adult protocols. Thus, we compared risk factors and outcome of adolescents and young adults treated within study protocols of the German Hodgkin Study Group (GHSG). PATIENTS AND METHODS Three thousand seven hundred eighty-five patients treated within the GHSG studies HD4 to HD9 were analyzed; 557 patients were adolescents age 15 to 20 years, and 3,228 patients were young adults age 21 to 45 years. Results Large mediastinal mass and involvement of three or more lymph node areas were more frequent in adolescents (P < .001). The incidence of other risk factors did not differ significantly between age groups. With a median observation time of 81 months for freedom from treatment failure (FFTF) and 85 months for overall survival (OS), log-rank test showed no significant differences between age groups regarding FFTF (P = .305) and a superior OS (P = .008) for adolescents. Six-year estimates for FFTF and OS were 80% and 94%, respectively, for adolescents and 80% and 91%, respectively, for young adults. After adjustment for other predictive factors, Cox regression analysis revealed age as a significant predictor for OS (P = .004), with a higher mortality risk for young adults. Secondary malignancies were more common in young adults (P = .037). CONCLUSION Outcome of adolescent and young adult patients treated within GHSG study protocols is comparable. These data suggest that adult treatment protocols exhibit a safe and effective treatment option for adolescent patients with HL. However, longer follow-up, including assessment of late toxicity, is necessary for final conclusions.

Purpose: The HD9 trial of the German Hodgkin Study Group compared two different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1,196 patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 5 years median follow-up had indicated improved tumor control with BEACOPP escalated. Since the long-term safety and efficacy of this regimen has been debated, we report the 10-year follow-up., Patients and Methods: Patients received one of three chemotherapy regimens: eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); eight cycles of BEACOPP baseline; or eight cycles of BEACOPP escalated., Results: Median follow-up was 111 months. At 10 years, freedom from treatment failure (FFTF) was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP escalated (arm C), respectively (P < .001). BEACOPP escalated was significantly better than BEACOPP baseline in terms of FFTF (P < .0001) and OS (P = .0053). A total of 74 second malignancies (6.2%) were documented, including acute myeloid leukemia (0.4%, 1.5%, and 3.0%), non-Hodgkin's lymphoma (2.7%, 1.7%, and 1.0%), and solid tumors (2.7%, 3.4%, and 1.9%). The corresponding overall secondary malignancy rates were 5.7%, 6.6%, and 6.0%, respectively., Conclusion: The 10-year follow-up of the HD9 trial demonstrates a stabilized significant improvement in long-term FFTF and OS for BEACOPP escalated in advanced-stage HL. These results challenge ABVD as standard of care for this patient population.

Purpose: Peripheral T-cell lymphomas (PTCLs) are rare malignancies with poor outcome after conventional chemotherapy. The role of myeloablative therapy and autologous stem-cell transplantation (autoSCT) is still unclear. Therefore, we initiated the first prospective multicenter study on upfront autoSCT in PTCL and recently reported good feasibility and efficacy of this approach. Here, we present the final analysis of the study., Patients and Methods: The treatment regimen consisted of four to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by mobilizing therapy with either the dexamethasone, carmustine, melphalan, etoposide, and cytarabine protocol or the etoposide, methylprednisolone, cytarabine, and cisplatin protocol and stem-cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemoradiotherapy (fractionated total-body irradiation and high-dose cyclophosphamide) and autoSCT., Results: From June 2000 to April 2006, 83 patients were enrolled onto the study. Main subgroups were PTCL not specified (n = 32) and angioimmunoblastic T-cell lymphoma (n = 27). Fifty-five (66%) of the 83 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the overall response rate after myeloablative therapy was 66% (56% CR and 8% PR). With a median follow-up time of 33 months, 43 patients are alive; the estimated 3-year overall and disease-free survival rates for patients in CR (calculated from CR to the date of relapse) and 3-year progression-free survival rate were 48%, 53%, and 36%, respectively., Conclusion: The results of this prospective study suggest a substantial impact on outcome for upfront autoSCT in PTCL and should be further evaluated in randomized trials. Pretransplantation treatment needs to be improved to increase the transplantation rate.

Purpose: Lymphocyte-predominant Hodgkin's lymphoma (LPHL) is rare and differs in histologic and clinical presentation from classical Hodgkin's lymphoma (cHL). To shed more light on the prognosis and outcome of LPHL, we reviewed all LPHL patients registered in the German Hodgkin Study Group (GHSG) database, comparing patient characteristics and treatment outcome with cHL patients., Patients and Methods: We analyzed retrospectively 8,298 HL patients treated within the GHSG trials HD4 to HD12, of whom 394 had LPHL and 7,904 had cHL., Results: Complete remission and unconfirmed complete remission after first-line treatment was achieved in 91.6% v 85.9% of patients in early favorable stages, 85.7% v 83.3% of patients in early unfavorable stages, and 76.8% v 77.8% of patients in advanced stages of LPHL compared with cHL, respectively. Tumor control (freedom from treatment failure [FFTF]) for LPHL and cHL patients at a median observation of 50 months was 88% and 82% (P = .0093) and overall survival (OS) was 96% and 92%, respectively (P = .0166). In LPHL patients, negative prognostic factors were advanced stage (P = .0092), Hb less than 10.5 g/dL (P = .0171), and lymphopenia (P = .010) for FFTF. Age >or= 45 years (P = .0125), advanced stage (P = .0153), and Hb less than 10.5 g/dL (P = .0014) were negative prognostic factors for OS., Conclusion: The better prognosis of LPHL as compared with cHL might allow different treatment strategies, particularly for early-stage LPHL patients.

Purpose: To investigate whether combined-modality treatment (CMT) with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by extended-field radiotherapy (EF-RT) is superior to EF-RT alone in patients with early favorable Hodgkin's lymphoma (HL)., Patients and Methods: Between 1993 and 1998, 650 patients with newly diagnosed, histology-proven HL in clinical stages IA to IIB without risk factors were enrolled onto this multicenter study and randomly assigned to receive 30 Gy EF-RT plus 10 Gy to the involved field (arm A) or two cycles of ABVD followed by the same radiotherapy (arm B). Results At a median observation time of 87 months, there was no difference between treatment arms in terms of complete response rate (arm A, 95%; arm B, 94%) and overall survival (at 7 years: arm A, 92%; arm B, 94%; P = .43). However, freedom from treatment failure was significantly different, with 7-year rates of 67% in arm A (95% CI, 61% to 73%) and 88% in arm B (95% CI, 84% to 92%; P

Purpose: MDX-060 is a human anti-CD30 immunoglobulin (Ig) G1kappa monoclonal antibody that inhibits growth of CD30-expressing tumor cells in preclinical models. To determine the safety, maximum-tolerated dose (MTD), and efficacy of MDX-060 in patients with relapsed or refractory CD30+ lymphomas, sequential phase I and II studies were performed., Patients and Methods: In the phase I portion, MDX-060 was administered intravenously at doses of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of three to six patients. Twenty-one patients--16 with Hodgkin's lymphoma (HL), three with anaplastic large-cell lymphoma (ALCL), and two with CD30+ T-cell lymphoma--were enrolled. Because of the lack of a defined MTD or dose-response correlation, the phase II portion was amended to include several dose levels. In the phase II portion, an additional 51 patients, 47 with HL and four with ALCL, were treated at doses of 1, 5, 10, and 15 mg/kg., Results: MDX-060 was well tolerated, and an MTD has not been identified. Only 7% of patients experienced grade 3 or 4 treatment-related adverse events. Among the 72 patients treated, clinical responses were observed in six. Twenty-five patients had stable disease, including five who remained free from progression 1 year after treatment., Conclusion: MDX-060 was well tolerated at doses up to 15 mg/kg. MDX-060 has limited activity as a single agent, but the minimal toxicity observed and the significant proportion of patients with stable disease suggests that further study of MDX-060 in combination with other therapies is warranted.

Purpose: A multicenter, single-arm study examining efficacy and toxicity of epratuzumab combined with rituximab was conducted in patients with recurrent or refractory non-Hodgkin's lymphoma., Patients and Methods: Sixty-five patients were enrolled; 34 patients with follicular lymphoma (FL), 15 patients with diffuse large B-cell lymphoma (DLBCL), and 16 patients with other lymphomas. The patients had received a median of two prior therapies (range, 1 to 4); 23% had received rituximab. Epratuzumab was given at 360 mg/m2 intravenously over 60 minutes followed by infusion of 375 mg/m2 rituximab, weekly for 4 consecutive weeks., Results: Combination therapy was well tolerated without greater toxicity than rituximab alone. The objective response (OR) rate was 47% (30 of 64) in assessable patients (46%; 30 of 65 in all patients), being highest in FL (64%; 21 of 33) and DLBCL (47%; seven of 15), and with 24% (eight of 33) and 33% (five of 15) achieving complete response (CR) or complete response unconfirmed (CRu) in these two groups, respectively. Two of six patients with marginal zone lymphoma responded to treatment (one CR). There was a trend for the response rates to be higher in patients with low prognostic index scores (statistically significant with respect to the Follicular Lymphoma International Prognostic Index score in FL patients), with 12 FL patients and three DLBCL patients in groups 0 to 1 having OR (CR/CRu) rates of 83% (33%) and 100% (100%), respectively. The median duration of response was 16 months for FL, with five patients currently progression free for 18 months to 30 months, and 6 months for DLBCL, with two patients currently progression free for 12 months and 18 months., Conclusion: Epratuzumab combined with rituximab was well tolerated, demonstrating promising antilymphoma activity that warrants additional study.

Purpose: Several scores have described sex as a prognostic factor in patients with Hodgkin's lymphoma (HL). However, little is known how sex-specific factors influence treatment outcome. We systematically investigated sex differences with regard to pretreatment characteristics and therapy-related variables, and examined their influence on the outcome of HL patients., Patients and Methods: This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed., Results: Male and female patients had similar prognostic factors. There was more acute chemotherapy-related hematotoxicity in women, especially more severe leucopenia (WHO grade 3/4, 69.9% female and 55.2% male; P < .0001). Importantly, this did not translate into more infections. Female patients had similar response rates but fewer relapses and deaths, leading to a significantly better freedom from treatment failure (FFTF; at 66 months, 81% female [95% CI, 79% to 82%] and 74% male [95% CI, 72% to 76%]). Severe leucopenia during chemotherapy was strongly associated with better FFTF, both for males and females. In addition, when only those patients who developed severe leucopenia within the first two cycles of chemotherapy were included, the factor maintained its protective role., Conclusion: The protective role of severe leucopenia suggests the testing of a more individualized therapy. In future trials, this therapy may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.

Purpose: Long-term survivors of successfully treated Hodgkin's lymphoma (HL) are at risk for late complications. Among these, infertility for female patients is of major importance. The subject of this analysis is to evaluate the menstrual status after HL therapy., Patients and Methods: From 1994 to 1998, the German Hodgkin's Lymphoma Study Group conducted clinical trials for early-, intermediate-, and advanced-stage HL (trials HD7 to HD9) involving a total of 3,186 patients. A survey was carried out to evaluate the menstrual status after therapy. The following factors were assessed concerning their influence on amenorrhea: age, treatment, stage, and the use of oral contraceptives during chemotherapy., Results: A total of 405 women aged younger than 40 years answered the study questions. After a median follow-up of 3.2 years, 51.4% of the women receiving eight cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had continuous amenorrhea. Amenorrhea was significantly more frequent after dose-escalated BEACOPP compared with doxorubicin, bleomycin, vinblastine, and dacarbazine; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; or standard BEACOPP (P = .0066). Amenorrhea after therapy was most pronounced in women with advanced-stage HL (P < .0001), in women older than 30 years at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002)., Conclusion: Most women who are treated for advanced-stage HL experience amenorrhea after therapy. Amenorrhea is significantly more frequent in women with advanced-stage HL receiving eight cycles of dose-escalated BEACOPP and in women older than 30 years at first treatment. Furthermore, the data show a statistical association between the use of oral contraceptives and return of menstrual cycle, which is subject to further investigation.

Purpose: To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL)., Patients and Methods: A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment., Results: The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred., Conclusion: The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.

Purpose: To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL)., Patients and Methods: From a total of 2,715 patients with biopsy-proven HL treated within the trials HD7 to HD12 of the German Hodgkin's Study Group, 100 patients (4%) with LRCHL, 145 patients (5%) with lymphocyte-predominant HL (LPHL), 1,688 patients (62%) with nodular sclerosis, 731 patients (27%) with mixed cellularity, and 23 patients (1%) with lymphocyte depletion were identified. Patients with LRCHL had a median age of 38 years (range, 16 to 74 years)., Results: Compared with other histologic subtypes, patients with LRCHL are, on average, older and usually present with early stages of disease (stage I, 34%; stage II, 46%). The median time of follow-up was 32.2 months (95% CI, 28.2 to 37.0 months). Complete and partial remission was achieved in 96 patients (96%) and four patients (4%), respectively, with LRCHL. The event-free and overall survival rates were 97% (95% CI, 93% [corrected] to 100% [corrected]) and 97% (95% CI, 93% [corrected] to 100% [corrected]), respectively, at 30 months. Only three patients died; all of the deaths were caused by treatment-related toxicities., Conclusion: LRCHL is a distinct subtype of CHL, with features of CHL and LPHL, and is a rare entity accounting for only 4% of HLs. LRCHL has a different pattern of clinical presentation and age and sex distribution than other CHLs. It is associated with an excellent prognosis if treated with current treatment regimens. When treating patients with LRCHL, great attention should be paid to avoid acute toxicities.

Purpose: With improved prognosis for patients with Hodgkin's lymphoma (HL), interest increasingly focuses on high-risk groups such as elderly patients. We thus performed a retrospective analysis using the German Hodgkin's Study Group (GHSG) database to determine clinical risk factors, course of treatment, and outcome in elderly HL patients in comparison with younger adults., Patients and Methods: A total of 4,251 patients included in the GHSG studies HD5 to HD9 were analyzed, of whom 372 (8.8%) were 60 years or older and 3,879 (91.2%) were younger than 60 years. Patient characteristics, treatment results, toxicity, freedom from treatment failure (FFTF), and overall survival (OS) were compared., Results: Elderly patients more often had mixed cellularity subtype, "B" symptoms, elevated erythrocyte sedimentation rate, and poorer performance status. Less frequently observed were nodular sclerosis subtype, large mediastinal mass, and bulky disease. Acute toxicity during chemotherapy was generally higher in elderly patients. This was most obvious for severe infections (grade 3 or 4; 15% v 6%) correlating with more severe leukopenia in elderly patients (grade 4; 38% v 23%). As a result, significantly fewer elderly patients received the intended full chemotherapy dose (75% v 91%). The survival analysis showed a significantly poorer treatment outcome for elderly patients in terms of 5-year OS (65% v 90%), FFTF (60% v 80%), and HL-specific FFTF (73% v 82%)., Conclusion: Elderly patients have a poorer risk profile compared with younger HL patients and experience more severe treatment-associated toxicity. Higher mortality during treatment as well as lower dose-intensity are the major factors explaining the poorer overall outcome of elderly HL patients.

Purpose: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I)., Patients and Methods: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4., Results: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses., Conclusion: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.

Purpose: To evaluate treatment outcome and prognostic factors in patients with refractory or first relapsed Hodgkin's disease (HD) treated with salvage radiotherapy (SRT) alone., Patients and Methods: From 4,754 patients registered in the database of the German Hodgkin Study Group from 1988 to 1999, 624 patients were identified with progressive disease (n = 202), or with early (n = 170) or late (n = 252) relapsed HD. At first treatment failure, SRT alone was given to 100 patients. Patient characteristics were: median age, 36 years; progressive disease, 47%; early relapse, 23%; late relapse, 30%; and "B" symptoms, 14%. Eighty-five percent of the patients relapsed after cyclophosphamide, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) -like regimens; 8% after bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimens, 7% after first-line radiotherapy alone., Results: The volume irradiated was mantle field in 43% of patients, inverted-Y in 8%, total nodal irradiation in 12%, and involved-field in 37%. The median SRT dose was 40 Gy (range, 15 to 50 Gy). Seventy-seven patients achieved a complete remission and four patients achieved a partial remission. The 5-year freedom from treatment failure and overall survival (OS) rates were 28% and 51%, respectively. In multivariate analysis, significant prognostic factors for OS were B symptoms (P = .018) and stage at relapse (P = .014). For freedom from second failure (FF2F) Karnofsky performance status (P = .0001) was significant. In patients with limited stage at progression/relapse, duration of first remission was significant (P = .04) for FF2F., Conclusion: SRT offers an effective treatment for selected subsets of patients with relapsed or refractory HD.