German Hodgkin Study Group HD10 Research Articles

Relapse After Early-Stage, Favorable Hodgkin Lymphoma: Disease Characteristics and Outcomes With Conventional or High-Dose Chemotherapy.

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). 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. 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. 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.

Radiation Dose Reduction in Early-Stage Hodgkin Lymphoma

IntroductionTreatment for early-stage Hodgkin lymphoma (HL) involves radiotherapy (RT), chemotherapy, or combined modality therapy (CMT). We analyzed reduction of RT dose in CMT, particularly in the context of German Hodgkin Study Group (GHSG) HD10 randomized trial results of 2010. Patients and MethodsThe National Cancer Data Base was queried for patients with stage I-II HL receiving CMT. RT dose and associated characteristics were analyzed. Stage I and absence of B symptoms were used as a surrogate for early-stage favorable disease. ResultsOf 31,301 patients with stage I-II HL, 11,457 received CMT between 2004 and 2015. Using the surrogate defined above, 1955 patients (17.1%) were classified as having favorable disease. The majority (61.6%) received 30-36 Gy, while 7.0% received 20 Gy. The provision of 20 Gy was more common in stage I patients (12.3% vs. 5.4% in stage II) and at academic facilities (10.8% vs. 6.3%-8.9% at other facilities). Use of 20 Gy (vs. 30-36 Gy) was less likely with thorax site (odds ratio [OR] 0.43 vs. head and neck), stage II disease (OR 0.41), and B symptoms (OR 0.33). Notably, the use of 20 Gy increased dramatically after 2010 (the year of publication of GHSG HD10 trial results), with rates of 12.3% in 2010-2015 versus 0.1% in 2004-2009 (OR 6.3, P < .001). This was even more pronounced in cases of favorable early-stage disease, with 25.5% after 2010 versus 2.8% before 2010 (OR 13.2, P < .001). The use of doses > 36 Gy decreased over a corresponding time period (OR 0.44, P < .001). ConclusionAnalysis of CMT for patients with early-stage HL demonstrates variability in RT dose, including increasing use of 20 Gy and decreasing use of high doses > 36 Gy.

Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials

AbstractDoxorubicin, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) is associated with severe toxicity in older patients, particularly from bleomycin-induced lung toxicity (BLT). Therefore, using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients, especially in early-stage HL. We therefore analyzed feasibility, toxicity, and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients. We included patients ≥60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2×ABVD; n = 137) or AVD (2×AVD; n = 82), each followed by involved-field radiotherapy (IF-RT), with patients randomized to 4×ABVD+IF-RT (n = 68). Patients' median age was 65 years (range, 60-75) with comparable patient and disease characteristics. Grade III-IV adverse event rates were similar in patients receiving 2×AVD and 2×ABVD (40% and 39%, respectively), but considerably higher in patients receiving 4×ABVD (65%). Similarly, BLT was rare in patients receiving 2×ABVD/AVD, but occurred in 7/69 (10%) of patients randomized to 4×ABVD, with 3 lethal events. In conclusion, no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy. However, we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD. These trials are registered at www.clinicaltrials.gov and www.isrctn.com as #NCT00265018 (HD10) and #ISRCTN63474366 (HD13).

Guidelines for the first line management of classical Hodgkin lymphoma

The guideline group was selected to be representative of UK-based medical experts and patients’ representatives. MEDLINE and EMBASE were searched systematically for publications in English from January 1990 to June 2013 using the key words Hodgkin, Lymphoma, Treatment, Chemotherapy and Radiotherapy. References from relevant publications were also searched. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and the BCSH and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with classical Hodgkin Lymphoma (HL). The guidance may not be appropriate for all patients with HL and in all cases individual patient circumstances may dictate an alternative approach.

Infradiaphragmatic Hodgkin Lymphoma In Patients Treated With State-Of-The-Art Therapies: A Risk Factor Analysis From The German Hodgkin Study Group (GHSG) HD13 and HD14 Trials

IntroductionThe prognostic impact of isolated infradiaphragmatic Hodgkin Lymphoma (HL) is controversial and no large risk factor analysis in patients treated with state-of-the-art therapies exists. Therefore, we performed a risk factor analysis focusing on isolated infradiaphragmatic nodal disease in patients treated within the German Hodgkin Study Group (GHSG) HD13 (2xABVD vs 2xABV, 2xAVD and 2xAV; followed by 30Gy IFRT each) and HD14 (4xABVD vs 2xBEACOPPescalated plus 2xABVD; followed by 30 Gy IFRT each) trials. MethodsThe characteristics and outcomes of patients with isolated infradiaphragmatic nodal disease qualified for and treated within the HD13 and HD14 trials were compared to patients with supradiaphragmatic nodal disease. Patients with extranodal disease were excluded. Progression-free survival (PFS) and overall survival (OS) were estimated according to the Kaplan-Meier method and compared between groups using the log-rank test. The Cox proportional hazards regression model was applied for multivariate analyses. To assess whether the prognostic impact of infradiaphragmatic disease depends on treatment intensity, patients were divided into groups of less intensive (HD13 arms 2xABV/2xAVD/2xAV and HD14 arm 4xABVD) and more intensive (HD13 arm 2xABVD and HD14 arm 2xBEACOPPescalated plus 2xABVD) chemotherapy, and groups were analyzed separately. All Hazard Ratios (HR) reported for these subgroup analyses were obtained from Cox proportional hazards regression models adjusted for age (HRa). Results1500 and 1403 patients with nodal disease from the HD13 and HD14 trials, respectively, qualified for the analysis. Of those, 139 patients from HD13 (9.3%) and 84 patients from HD14 (6.0%) had isolated infradiaphragmatic disease. Compared to patients with supradiaphragmatic disease, these patients were older (median age 47 vs 35 years, p<0.001), had a WHO index >0 more frequently (22.4 vs 15.2%, p<0.01), and had the subtype of nodular sclerosis less frequently (29.7 vs 55.3%, p<0.001). More patients with infradiaphragmatic disease were male (69.5 vs 52.1%, p<0.001). After a median follow-up of 51 months, PFS was significantly worse in patients with infradiaphragmatic disease (5-year PFS 80.1% vs 91.2%, p<0.001). In a multivariate model adjusted for age and sex, infradiaphragmatic HL remained a significant risk factor in terms of PFS (HR 1.6, 95%-CI [1.2-2.3], p<0.01). However, the inferior PFS could only be observed in the group receiving less intensive chemotherapy (HRa 2.1 [1.4-3.0], p<0.001, figure 1A) whereas there was no difference in patients treated within the more intensive arms (HRa 1.1 [0.5-2.3], p=0.8, figure 1B). Similarly, infradiaphragmatic disease was a significant risk factor for OS when analyzed univariately (5-year OS 91.5 vs 97.6%, p<0.001) and in a multivariate model adjusted for age, trial and WHO index (HR 2.2 [1.3-3.7], p=0.002), but this difference was also restricted to the arms with less intensive chemotherapy (HRa 3.0 [1.7-5.5], p<0.001; more intensive chemotherapy: HRa 1.3 [0.5-3.5], p=0.6). To assess if the current GHSG standard for early favorable HL is sufficient to treat patients with infradiaphragmatic disease, 299 patients who received 2xABVD and 20Gy IFRT within the GHSG HD10 trial were additionally analyzed. The rate of infradiaphragmatic disease was 8.4% (25 patients). In this limited number of patients, there was no PFS or OS difference (HRa 1.0 [0.3-3.2], p=0.95 for PFS; HRa 0.8 [0.1-6.0], p=0.8 for OS). [Display omitted] ConclusionIsolated infradiaphragmatic disease is a risk factor for PFS and OS in HL patients that can be overcome with the current GHSG standard therapies for early favorable (2xABVD followed by 20Gy IFRT) and early unfavorable (2xBEACOPPescalated plus 2xABVD followed by 30Gy IFRT) disease. Disclosures:von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Böll:Celgene: Travel Grant Other. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other.

XVII. Radiotherapy in early stage Hodgkin lymphoma

The treatment of patients with Hodgkin lymphoma (HL) is one of the major success stories in oncology and 60–90% of patients are cured of their malignancy depending on clinical stage and risk factors. Radiotherapy was used to cure patients with HL as early as the 1940s, but more widespread successes came in the 1960s for early stage diseases I A and II A with the use of extended field radiotherapy (RT) techniques to include all nodal stations above the diaphragm such as the ‘mantle’ field [1]. Recurrence of disease outside the radiation field in some patients led to studies of adjuvant chemotherapy as part of a combined modality approach. These studies led to improved progression free survival (PFS) but no overall survival (OS) advantage was seen over RT alone because patients developing recurrent disease after RT were very efficiently salvaged by chemotherapy [2]. A sequential and thorough approach in large randomized trials exemplified by the German Hodgkin Study Group (GHSG) has led to substantial treatment reduction and established a standard of care based on minimal highly effective combined modality treatment (CMT). With a median follow-up of 7.5 years, 8-year results of the GHSG HD10 trial involving 1370 patients with early stage favourable HL showed that two cycles of chemotherapy regimen consisting of Adriamycin, Cyclophosphamide, Oncovin, Procarbazine, Prednisolone (ABVD) and 20Gy of involved field radiotherapy (IFRT) were as effective as four cycles ABVD and 30 Gy, produced less immediate toxicity and resulted in an OS of 95% and freedom from treatment failure and event-free survival of 86% [3]. For early stage unfavourable HL, moderate dose escalation using a chemotherapy regimen consisting of Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin, Procarbazine and Prednisone (BEACOPP) did not significantly improve outcome over four cycles of ABVD and 30 Gy IFRT, which the GHSG HD11 concluded remains the standard of care [4] Whilst efforts to improve a 5-year Failure From Treatment Failure (FFTF) of 85% and OS of 94.5% are ongoing in unfavourable disease, it will be difficult to improve the results of two cycles of ABVD and 20 Gy for the favourable

ABVD in Older Patients With Early-Stage Hodgkin Lymphoma Treated Within the German Hodgkin Study Group HD10 and HD11 Trials

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. 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. 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%). In patients age ≥ 60 years with HL, four cycles of ABVD is associated with substantial dose reduction, treatment delay, toxicity, and treatment-related mortality.

Treatment of Stage I-II A Non-Bulky Hodgkin's Lymphoma (HL): An Individual Patient-Data Comparison of German Hodgkin Study Group (GHSG) HD10 and HD11 Combined-Modality Therapy (CMT) and NCIC Clinical Trials Group (NCIC CTG) HD.6 ABVD Alone

AbstractAbstract 548 Background:Excellent results are seen in HL patients with stage I-IIA disease treated with CMT that includes involved field radiation therapy (IFRT), as per GHSG HD10 [Engert NEJM 2010] and HD11 [Eich JCO 2010] or with ABVD alone, as per NCIC CTG/ECOG HD.6 [Meyer NEJM 2012]. Comparing these reports is complicated by differences in eligibility, staging, endpoints and follow-up duration. Our objectives were to use individual patient data from these 3 trials to compare outcomes after standardizing patient eligibility. Methods:Potentially eligible patients were those treated with 2 cycles of ABVD/20 Gy IFRT on GHSG HD10, 4 cycles of ABVD/30 Gy IFRT on GHSG HD11 and 4–6 cycles of ABVD alone on NCIC CTG HD.6. To be included in analysis, patients were required to be eligible for GHSG HD10 or HD11 and NCIC CTG HD.6. Eligibility of HD10/11 patients for HD.6 was determined by the GHSG by applying HD.6 protocol criteria. Anonymized individual patient data of eligible patients was forwarded to NCIC CTG along with reasons for ineligibility of other patients. Eligibility of HD.6 patients for HD10/11 was determined by NCIC CTG by applying HD10/11 protocol criteria with listing of reasons for ineligibility. Eligibility questions were resolved through consensus. Patients meeting mutually inclusive eligibility criteria were stratified by a propensity score (PSc) based on age, gender, stage, ESR and number of disease sites. Outcomes were based on Revised Response Criteria for Malignant Lymphoma [Cheson JCO 2007]; no trial incorporated PET scanning. The primary outcome measure was progression-free survival (PFS), which includes disease progression and death from any cause as events. Secondary outcomes included overall survival (OS) and time to progression (TTP), which includes disease progression and death from HL as events. A priori subsets for analysis included eligibility for HD10 vs. HD11 and CR/CRu status after 2 cycles of ABVD among those eligible for both HD10 and HD.6. Cox models stratified by PSc were used to obtain hazard ratios (HR) for PFS, OS and TTP; HRs are expressed as GHSG HD10/11 relative to NCIC CTG HD.6. Results:Of 655 patients eligible for selected arms of HD10/HD11, 406 were eligible when applying the inclusion criteria for HD.6 (HD10 = 254; HD11 = 152). Most common reasons for ineligibility were B symptoms (n=127) and large mediastinal mass (n=80). Of 196 HD.6 patients, 182 were eligible for HD10 (n=110) or HD11 (n=71; 1 patient not assignable). Median follow-up for both HD10 and HD11 was 91 months and for HD.6 was 134 months. Results that include all eligible patients are shown in table; TTP was superior in GHSG trials.EndpointGHSG HD10/11NCIC CTG HD.6HR95% CI8-yr PFS89%86%0.710.42-1.188-yr OS95%95%1.090.49-2.408-yr TTP93%87%0.440.24-0.78In the HD10/HD.6 subset, 8-yr PFS was 87% vs 82% (HR=0.58; 95% CI=0.32–1.05) and OS was 96% vs 94% (HR=0.65; 95% CI=0.25–1.72). Among those with CR/CRu after 2 cycles of ABVD, 8-yr PFS was 87% vs 95% (HR=2.8; 95% CI=0.64–12.5) and OS was 96% vs 100%. Among those without CR/CRu after 2 cycles of ABVD, 8-yr PFS was 88% vs 74% (HR=0.35; 95% CI=0.16–0.79) and OS was 95% vs 91% (HR=0.42; 95% CI=0.12–1.44). In the HD11/HD.6 subset, 8-yr PFS was 91% vs 91% (HR=1.15; 95% CI=0.45–2.97) and OS was 95% vs 97% (HR=2.03; 95% CI=0.53–7.79). Among 406 HD10/11 patients, there have been 19 deaths; 7 were attributed to HL or immediate treatment toxicity and 12 to other causes. Among 182 HD.6 patients, there have been 10 deaths; 5 were attributed to HL or immediate treatment toxicity and 5 to other causes. Conclusions:In this non-randomized cohort comparison, TTP was superior and PFS trended to being superior in patients treated with CMT on HD10/11. No differences in OS are evident; longer follow-up is needed to assess trade-offs between disease control and risks of late treatment effects. The role of IFRT in attaining long-term disease control appears to be especially important in those who do not attain CR/CRu status after 2 cycles of ABVD. As outcomes of those eligible for HD10/HD.6 and treated with 4–6 cycles of ABVD alone were excellent if CR/CRu was attained after 2 cycles of ABVD, these data support more recent strategies evaluating response-adapted approaches for use of IFRT. Disclosures:Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Horning:Genentech: Employment; Roche: Equity Ownership. Engert:Millenium The Takeda Oncology Company: Honoraria. Meyer:Lilly: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen Canada: Research Funding; Ariad Pharma: Research Funding; Astex Therapeutics: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; GlaxoSmithKline: Research Funding; Janssen Ortho: Research Funding; Novartis: Research Funding; Oncothyreon: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sanofi-Aventis: Research Funding; Schering Canada: Research Funding.