German Hodgkin Study Group Research Articles

Lymphocyte-Depleted Classical Hodgkin's Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group

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). 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. 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). 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.

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

D. A. Eichenauer1, A. Engert1, M. Andre2, M. Federico3, T. Illidge4, M. Hutchings5, & M. Ladetto6 on behalf of the ESMO Guidelines Working Group* First Department of Internal Medicine, University Hospital Cologne and German Hodgkin Study Group (GHSG), Cologne, Germany; CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium; Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy; Institute of Cancer Sciences, University of Manchester, Manchester, UK; Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Divisione di Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

Evolution of Radiation Therapy Within the German Hodgkin Study Group Trials

Since its beginning, more than 16,000 patients have been enrolled in the multicentric randomized trials of the German Hodgkin Study Group (GHSG) for adult patients. Within 6 study generations, the treatment of Hodgkin lymphoma has been developed stepwise by using the results of the completed protocols. Now the sixth generation is active. According to the role of radiotherapy, the study group successfully evaluated different dose-effect relationships and could also prove the efficacy of involved-field radiotherapy in early stages in combination with effective chemotherapy. Currently, a radiation dose of 20 Gy to the involved field after a mildly aggressive chemotherapy (2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine [ABVD]) should be the standard for early-favorable stages according to the GHSG classification. In early-unfavorable or intermediate-risk stages, involved-field radiation therapy with 30 Gy is sufficient; the optimal chemotherapy has to be fixed. For the advanced stages, the question of radiotherapy is still unclear. Preliminary results of the GHSG and others show that additive radiotherapy after intensive chemotherapy might be useful for elective subgroups of patients. The extensive radiotherapy quality assurance program, performed by the GHSG and its radiotherapy reference center, has proven to be successful and necessary to ensure that, with reduced radiation doses and reduced radiation volumes, precise radiotherapy, as defined by the protocol, will be performed by the participating radiotherapy departments.

Abbreviated 8-week chemotherapy (CT) plus involved node radiotherapy (INRT) for nonbulky stage I-II Hodgkin lymphoma: Preliminary results of the Stanford G5 Study.

8064 Background: Combined modality therapy is the standard of care for non-bulky Stage I-II HL. Currently, brief CT +30 Gy involved field (IF) radiotherapy (RT) is associated with a high cure rate. To further limit treatment risk, we tested brief CT (Stanford V–C x 8 weeks) + 20 Gy INRT (G5 study). Methods: Pts with stage I-IIA supra-diaphragmatic non-bulky disease (mediastinal mass ratio <1/3 and no disease >10 cm) were eligible. Stanford V-C (cyclophosphamide substituted for nitrogen mustard) was administered x 8 weeks. G-CSF was permitted for gr ≥3 neutropenia. Two wks after completion of CT, pts received INRT (20 Gy) to initially involved nodes with 1-1.5 cm margins axially and 2-5 cm cephalo-caudad. All pts were treated and followed at Stanford. Endpoints were toxicity and efficacy (PFS and OS). Results: 43 pts (16% stage I and 84% stage II) were accrued with median age 31 yrs (19-66). 20 pts (47%) were “unfavorable” according to German Hodgkin Study Group (GHSG) criteria: >2 nodal sites (n=20) or elevated ESR (≥ 50 mm/hr) (n=3). G-CSF was required in 60% of pts due to gr 3 (n=10) or 4 (n=16) neutropenia. Other gr 3 toxicities reported: fever (n=1), pain (n=3), acute pulmonary embolism (n=1) and epigastric pain (n=2). At median follow-up of 4.8 yrs (0.8-9.6), the overall PFS and OS are 94.6% and 100%, respectively. For pts with unfavorable risk factors the PFS and OS are 88.5% and 100%, respectively. Therapy failed in 2 pts considered “unfavorable” by GHSG criteria with >2 nodal sites. The mean time to relapse was 23 mths (16-30). One pt failed in RT field and the second in-field and distant. Both were salvaged with secondary therapy and stem cell support. No bleomycin lung toxicity or radiation pneumonitis have been noted and to date there have been no second malignancies, AML or cardiac events. Conclusions: The G5 regimen (8 wks Stanford V-C and 20 Gy INRT) has excellent results with minimal toxicity in pts with non-bulky stage I-II HL, including those defined as “unfavorable” by the GHSG criteria. The outcome is comparable to studies using more intense CT and IFRT. Longer follow up is required to assess the impact of this reduced intensity approach on CT and RT related late effects.

Secondary MDS/AML In Hodgkin Lymphoma Patients Treated within German Hodgkin Study Group (GHSG) Clinical Trials After Introduction of the BEACOPP Protocol

AbstractAbstract 2682 Background:With modern multi-agent chemotherapy regimens optionally combined with radiotherapy, even patients with advanced Hodgkin lymphoma (HL) are cured in over 80% of cases. Since there is only little room for further therapeutic improvements, one major focus of current clinical research in HL consists in reducing treatment-related late effects such as secondary malignancies. Secondary MDS/AML represents a relevant problem since it was reported to be associated with a very poor prognosis. To shed some more light on incidence, course and outcome of patients with secondary MDS/AML after HL treatment, we performed an analysis addressing this issue. Patients treated within German Hodgkin Study Group (GHSG) clinical trials after introduction of the BEACOPP protocol were included. Methods and patients:11891 HL patients of all stages aged 16 to 75 and treated within the third (HD7-HD9, 1993–1998), fourth (HD10-HD12, 1998–2003) and fifth (HD13-HD15, 2003–2009) GHSG trial generation, the BEACOPP14 pilot study (1997-2000) and a phase II trial evaluating the role of GnRH analogues and oral contraceptives in female patients receiving BEACOPPescalated were retrospectively analyzed. Treatment consisted of radiotherapy alone, chemotherapy alone or combined-modality approaches. Results:With a median follow-up of 70 months, overall secondary MDS/AML rate was 0.8% (99 patients). However, 13 patients had a concurrent event (i.e. progress/relapse of HL or another secondary malignancy requiring salvage treatment) prior to MDS/AML diagnosis so that 86 patients were included in the present analyses. Median time from HL treatment to MDS/AML diagnosis was 28.3 months. The median age of patients developing secondary MDS/AML was significantly higher than the median age in the whole patient group (41 vs 34 years, p=.0002). To determine the impact of treatment intensity on the risk to develop secondary MDS/AML, patients were assigned into three groups. Groups consisted of patients who had received no BEACOPP-containing treatment, less than four cycles of BEACOPPescalated and four or more cycles of BEACOPPesclated, respectively. As a result, patients receiving four or more cycles of BEACOPPescalated had a significantly increased risk to develop secondary MDS/AML when compared to the other groups (5-year cumulative incidence 1.5% vs 0.5% and 0.3%, respectively, log-rank p<.0001). In 36 patients included in this analysis, allogeneic stem cell transplantation (aSCT) was applied to treat secondary MDS/AML. Patients who received aSCT had a significantly lower median age than those treated with conventional chemotherapy or supportive care only (35 vs 50 years, p=.0016) and showed an improved outcome. However, median overall survival (OS) after MDS/AML diagnosis was only 7.2 months. Conclusions:Secondary MDS/AML is a relevant problem after HL therapy particularly in patients diagnosed with advanced stages treated with intensive first-line protocols. However, the clinical benefit achieved by the use of these more intensive protocols clearly outweighs the risk of developing secondary MDS/AML. To reduce the risk of developing secondary MDS/AML, novel treatment strategies should include risk-adapted early treatment stratification based on modern tools such as positron emission tomography (PET) to prevent overtreatment whenever possible. Disclosures:No relevant conflicts of interest to declare.

Longitudinal Evaluation of Quality of Life and Fatigue In Hodgkin Lymphoma Patients

AbstractAbstract 935 Background:Long term impairment of quality of life (QoL) and elevated fatigue levels in Hodgkin Lymphoma (HL) survivors have been reported. However, few longitudinal data and no conclusive knowledge on components and determinants of QoL exist so far. Therefore, the German Hodgkin Study Group (GHSG) assessed the patients' QoL within the prospectively randomized studies HD10-12 for a detailed longitudinal evaluation of QoL and fatigue. Methods:QoL was assessed with a psychometrically proven questionnaire (QLQ-S) which contains the EORTC QLQ-C30 among other scales and items. Patients answered the questionnaires before, during, and at the end of therapy and at regular follow-up visits. For all QLQ-C30 functional scales and fatigue, longitudinal courses up to 27 months from diagnosis are given with means and 95%-confidence intervals. Reference values from a German control population were used for interpretation of the results. Components and determinants of QoL were analyzed with special modeling software (MPlus) which allows for full information maximum likelihood estimation of multivariate longitudinal models in the presence of missing data. The predictive value of fatigue at baseline for progression free survival and overall survival was tested in Cox proportional hazards analyses together with other known risk factors. Results:4,160 patients were included in HD10-12, and 3,208 are evaluable for this analysis (total of 15,722 assessments). Before therapy, HL patients had clearly poorer mean scores in each QoL scale when compared to the German reference population. All scales at baseline were negatively influenced by gender (females) and more advanced disease. Before therapy age ≥50 years was negatively related to physical functioning and cognitive functioning, but positively to social functioning. After a decrease of QoL during chemotherapy, all scales showed considerable improvement. However, usually long term QoL remained below normal reference values and this was most pronounced in patients ≥50 years of age and advanced stages. A QoL model with three factors (physical, mental, and social) showed very good fit (RMSEA<.05) and high stability of QoL already 12 months after diagnosis. No relevant effect of the type of treatment could be detected. Overall, 44.7% of patients never experienced severe fatigue ≥50 (relative scale from 0–100), and 17.4% had fatigue only temporarily during treatment, and 15.1% had severe fatigue before therapy which vanished after therapy. In addition, 6.8% of patients developed severe long term fatigue without being severely fatigued before, and 6% had permanently severe fatigue. Cox regression for overall survival revealed that severe fatigue at baseline is a significant, strong and independent risk factor for death from any cause (p<.05, HR= 1.5). Other significant risk factors for OS included age, infradiaphragmatic nodes, and large mediastinal mass. In contrast, gender, high ESR, extranodal involvement, B-symptoms, intermediate stages, advanced stages were not significant. Conclusion:This is the first detailed QoL and fatigue analysis in HL patients covering all stages of the disease before, during, and after therapy. QoL domains are clearly impaired before the onset of chemotherapy, but improve over time substantially. Baseline QoL is affected in considerable degree by tumor- and patient-specific characteristics. Importantly, type and intensity of HL treatment have no relevant negative impact on long term QoL or fatigue. The strong impact of severe fatigue at baseline on overall survival is currently analyzed in more detail and results will be presented. Disclosures:No relevant conflicts of interest to declare.

Assessment of Residual Bulky Tumor Using FDG-PET In Patients with Advanced-Stage Hodgkin Lymphoma After Completion of Chemotherapy: Final Report of the GHSG HD15 Trial

AbstractAbstract 764 IntroductionThe role of additional radiotherapy after chemotherapy for advanced-stage Hodgkin lymphoma is unclear. The German Hodgkin Study Group (GHSG) thus performed the HD15 trial in which advanced-stage Hodgkin lymphoma patients having residual disease after 6–8 cycles of BEACOPP were evaluated by 18F-fluorodesoxyglucose positron emission tomography (PET) following chemotherapy. MethodsEntry criteria for the PET question in HD15 were partial remission (PR) after the end of chemotherapy with at least one involved nodal site measuring more than 2.5 cm in diameter by computed tomography (CT). Exclusion criteria included diabetes, elevated blood sugar levels and skeletal involvement with risk of instability. Calculations were restricted to those cases with either progressive disease (PD) or relapse within 12 months after PET or at least 12 months of follow-up. A total of 2,137 patients with de novo HL were included in HD15 of whom 728 had a tumor bulk ≥ 2.5 cm after BEACOPP chemotherapy and were qualified for the PET question. An expert panel performed the assessment of response and PET. Only PET-positive patients were scheduled for radiotherapy of residual disease. The negative prognostic value (NPV) of PET was defined as the proportion of PET-negative patients without progression, relapse or radiotherapy despite being PET-negative within 12 months. ResultsThe full analysis set included 728 patients of whom 699 had at least 12 months of follow-up. Median age was 30 years, 57% were males and 66% had NS histology. Of the 728 qualified patients with residual disease ≥ 2.5 cm after BEACOPP, 74.2% were PET-negative and 25.8% PET-positive. In the PET-negative group, a total of 28 patients relapsed or had radiotherapy despite being PET-negative (8 patients including 1 relapsing patient) resulting in a negative prognostic value of 94.6% (95% CI 92.7% to 96.6%). With a median follow-up of 38 months, the time-to-progression after PET at 3 years was 92.1% for PET-negative patients counting radiotherapy as failure and 86.1% for PET-positive patients (95%-CI for difference -11.9% to -0.1%). Overall, only 11% of patients had additional radiotherapy as compared to 71% after BEACOPPescalated in our prior HD9 trial. In addition, there was no difference in PFS or overall survival as compared to our earlier trials in advanced-stage HL. DiscussionThe NPV of PET of 0.95 suggests that indeed only patients with residual disease after chemotherapy who are PET-positive need additional radiotherapy. PET-negative patients at least after BEACOPP can be spared from additional radiotherapy. Disclosures:No relevant conflicts of interest to declare.

PVAG (Prednisone, Vinblastine, Doxorubicin and Gemcitabine) In Elderly Patients with Intermediate or Advanced Stage Hodgkin Lymphoma: Final Results of a Phase II Study of the German Hodgkin Study Group (GHSG).

AbstractAbstract 2827About 20% of all patients diagnosed with Hodgkin lymphoma (HL) are older than 60 years. These patients have a rather poor prognosis, particularly when presenting in intermediate or advanced stages. Besides a biologically more aggressive disease, the main reason is a drastically increased toxicity of chemo- and radiotherapy resulting in a higher treatment-related mortality and insufficient dosing of the applied treatment. In the GHSG-HD9 trial, elderly patients did not benefit from the BEACOPP regimen in terms of overall survival due to a high toxicity related death rate. In order to improve tolerability, the PVAG regimen (prednisone, vinblastine, doxorubicin, and gemcitabine) was developed. This is a modification of the ABVD regimen in which bleomycin and dacarbazine were replaced by prednisone and gemcitabine. Here we report for the first time on the final analysis of this multi-center phase II study for elderly HL patients.61 patients were recruited between 2004 and 2007. 2 patients were excluded due to histology review not confirming HL, resulting in 59 patients with intermediate- or advanced-stage HL aged between 60 and 75 years. Treatment consisted of 6 cycles PVAG in patients achieving a complete remission (CR) after 4 cycles or 8 cycles PVAG in case of partial remission (PR) after 4 cycles. Patients who did not achieve CR after the end of chemotherapy received additional radiotherapy. Primary endpoints were administration of adequate dose without excessive delays, and response rate 3 months after end of treatment. Secondary endpoints included WHO grade III/IV toxicities, and occurrence of early progression.59 patients with a median age of 68 years were evaluated, of which 59% were male and 93% had advanced stage disease.The relative dose intensity (relative dose divided by relative chemotherapy duration) was at least 80% in 44 patients (76%). Regarding the single cycles, of which 85% started without major delay (max. 1 day), the mean relative dose of all agents was slightly decreasing over time but always exceeded 90%.WHO grade III/IV toxicities were documented in 43 patients (75%). Only 3 patients terminated CT because of excessive toxicity. 10 Patients (17%) received consolidating radiotherapy.In total, 46 patients responded with CR/CRu (78%; 95% CI: 65% to 88%), 2 with PR (3%), 2 with no change (3%) and 4 with progressive disease (7%). 3 patients died before restaging with unknown response and in 2 patients treatment outcome is unknown. With a median observation time of 37 months, 6 patients (10%) had progressive disease and 9 patients (15%) relapsed. In total, 10 patients died from relapsing or progressing HL, 2 from second malignancies (one of lung cancer after 23 months, and one of AML after 25 months) and 5 patients due to other reasons. Overall 17 patients (29%, 95% CI: 18% to 42%) have died so far.In conclusion, PVAG is safe and feasible in Hodgkin patients older than 60. The PFS indicates activity of this regimen in this poor prognosis patient cohort. However, a controlled randomized trial to determine the best treatment in this patient population is warranted.This trial was registered at www.clinicaltrials.gov as #NCT00147875. Disclosures:No relevant conflicts of interest to declare.

Dose-Escalation with BEACOPP Escalated Is Superior to ABVD In the Combined-Modality Treatment of Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) HD14 Trial

AbstractAbstract 765 Purpose:Combined modality treatment consisting of 4 cycles of chemotherapy and IF-RT is the standard treatment for early unfavorable HL. Overall survival (OS) and freedom from treatment failure (FFTF) at 5 years in this group of patients was 91% and 83%, respectively, in our prior HD8 study. Thus, the rationale for HD14 was to improve on these results by increasing dose intensity using BEACOPP escalated. Methods:Between January 2003 and July 2008, 1655 patients with histologically confirmed diagnosis of Hodgkin lymphoma in early unfavorable stages were randomized. Patients had to be 16–60 years old and have CS I, IIA with one of the following risk factors: large mediastinal mass (a), extranodal disease (b), elevated ESR (c), or ≥ 3 nodal areas (d), IIB with risk factors c or d). Patients were randomized to either 4 cycles of ABVD (arm A) or 2 cycles BEACOPP escalated followed by 2 cycles ABVD (arm B). All patients received 30Gy IF-RT after chemotherapy. Primary objective was the improvement of FFTF. Results:The full analysis set comprised 1623 patients (98.1%) who were documented and followed for treatment effects; 818 were in arm A and 805 in arm B. Patient characteristics were well balanced between the two arms with a median age of 33.6 years and most patients in stage IIA (67%). The overall response rate to treatment was 95% in each arm. With a median follow-up of 42.4 months, 20 patients had died in each arm; 19 patients in arm A had secondary neoplasia compared to 16 patients in arm B. Progressive disease was observed in 2.9% versus 0.9% of patients in arms A and B, respectively; early relapse rates were 2.8% versus 0.9%, and late relapse rates were 2.3% versus 0.9%. The estimated 4-year FFTF rate was 89.3% in arm A and 94.7% in arm B (p=0,0001, hazard ratio HR=2.04, 95%-CI: 1.39–2.94). There was no significant difference in overall survival yet (p=0.95). Acute grade III-IV toxicity rates of chemotherapy were higher in arm B (87.1%) than in arm A (50.7%) with leucopenia rates of 79% versus 24%, hair loss 48% versus 24%, thrombocytopenia 22% versus 0.1% and anemia 9% versus 1% in arms B and A respectively. 7.3% of patients had grade III/IV infections in arm B as compared to 3.4% in arm A. However, we observed no differences in treatment-related death or secondary neoplasia rates between treatment arms. Conclusion:Intensifying treatment for patients with early unfavorable HL using 2 cycles of BEACOPP escalated followed by 2 × ABVD and IFRT results in a significant improvement in tumor control as compared to our prior standard of 4 × ABVD plus IFRT. As defined in the study protocol, this more aggressive treatment was implemented as new standard of care for early unfavorable HL in our follow-up study (GHSG HD17). Disclosures:Greil:Cephalon: Research Funding.

Feasibility and Efficacy of ABVD In Elderly Hodgkin Lymphoma Patients: Analysis of Two Randomized Prospective Multicenter Trials of the German Hodgkin Study Group (HD10 and HD11)

AbstractAbstract 418About 20% of all patients with first diagnosis of Hodgkin Lymphoma (HL) are older than 60 years. They have a poor prognosis mainly due to an increased toxicity of chemo- and radiotherapy. Although resulting in better disease control, aggressive regimens as BEACOPP are not feasible in this cohort of patients due to a treatment related mortality of up to 20%. Therefore, ABVD is considered treatment of choice for elderly HL patients, although prospective studies are lacking and current concepts mostly rely on cohort analyses. We therefore analyzed feasibility, safety and outcome of patients older than 60 years with early favorable- or early unfavorable-stage HL treated with 4 cycles of ABVD within the HD10 and HD11 trials of the GHSG. Sixty-eight and 49 elderly patients with a median age of 65 and 64 years were treated in HD10 and HD11, respectively. Early termination of protocol therapy was documented in 18% of HD10 patients, but only in 8% of HD11 patients, resulting in a lower relative total chemotherapy dose (RCD) in HD10. The relative dose intensity (RCD divided by total relative chemotherapy duration) was much lower in both studies compared to younger patients, due to more toxicity-related therapy delays and dose reductions, as 4 cycles of ABVD caused WHO grade III/IV toxicities in 67% (HD10) and 69% (HD11). Overall efficacy was significantly lower than in younger patients with an overall response rate of 90% in HD10 and 92% in HD11. The rate of relapsing patients was the same as in younger patients in HD11 (14%), whereas in HD10 it was much higher in the elderly (12%) which was mainly due to late relapses. Overall 22% and 37% of the patients died in HD10 and HD11, respectively (median observation time: 92 months). Besides other causes as cardiovascular disease (7%) or secondary neoplasia (5%), there was a high rate of deaths due to insufficient HL-control (5%) and treatment-related toxicities (5%). The 5-year PFS estimates for elderly patients were 79% (95% CI, 67% to 87%) in HD10 and 69% (95% CI, 54% to 80%) in HD11 compared to 96% (95% CI, 93% to 97%) and 86% (95% CI, 83% to 88%) for younger patients in HD10 and HD11, respectively. In conclusion, 4 cycles of ABVD are effective in elderly HL patients; however, treatment-related toxicity is high. Disclosures:No relevant conflicts of interest to declare.

Tailored Therapy In Hodgkin Lymphoma, Based on Predefined Risk Factors and Early Interim PET/CT, Can Lead to Modification and Safe Reduction In Therapy: Results of 134 Patients on the Israel National Hodgkin Study.

AbstractAbstract 2809The current aim of treatment for Hodgkin lymphoma (HL) is to maximize response and minimize long term toxicity. This study prospectively evaluates the outcome of patients with HL whose therapy is chosen based on baseline prognostic factors and is tailored based on results of PET/CT imaging performed after 2 cycles of chemotherapy. In this multicenter study, initiated in 2006, we reduce the intensity of therapy for early responders and escalate the intensity for those with suboptimal early response. Patients with classic HL aged 18–60 years, I-IV are eligible. Those with early disease are categorized according to the German Hodgkin study group criteria for early favorable and unfavorable disease. Following 2 cycles of ABVD, patients with early favorable disease and a negative PET/CT undergo involved nodal radiation therapy (INRT) and those with early unfavorable disease receive 2 more cycles of ABVD (total of 4 cycles) followed by INRT. Patients whose interim PET/CT remains positive are given 2 additional cycles of ABVD for a total of 4 or 6 cycles followed by radiation therapy. Patients with advanced disease including all those with B symptoms or stages III and IV are assigned treatment according to the International Prognostic Score (IPS). Standard risk patients (IPS score 0–2) are initially treated with 2 cycles of ABVD and those with IPS score of ≥ 3 receive 2 cycles of escalated BEACOPP (EB). If interim PET/CT is negative or shows minimal residual uptake in no more than a single site then further therapy with 4 cycles of ABVD is administered and radiation therapy to bulky mediastinal mass is omitted. If interim PET/CT is positive but there no evidence of disease progression then therapy is escalated to EB with radiation therapy given to bulky mediastinal mass. 153 patients enrolled, of which 134 reached their interim imaging. Table 1 shows the number of patients in each risk group, positive predictive value of interim positive PET/CT and negative predictive value of negative study. Six patients had disease progression, two of them had primary refractory disease. One patient succumbed during autologous bone marrow transplantation. After a short follow up, median 20 month (6-50), the current study appears to demonstrate progression free survival (PFS) of 95%. The negative predictive value for the patient with negative interim study was 96% demonstrating that de-escalation is feasible and safe for patients with interim negative imaging. Further follow up and a larger cohort is needed to draw conclusions regarding the PFS of patients with interim positive PET/CT study as well as the long term toxicity.Table 1Risk group scorenPositive interim PET/CTNegative interim PET/CTProgressionTotalProgressionTotalNo ProgressionAll patients1521821181146 (4%)Early favorable1520660Early unfavorable702155533 (4%)Advanced disease67Score 0–2382031292 (5%)Score ≥3296120201 (3%) Disclosures:No relevant conflicts of interest to declare.

Stage I-IIA Non-Bulky Hodgkin's Lymphoma. Is Further Distinction Based on Prognostic Factors Useful? The Stanford Experience

In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center. This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n=84 patients) or 20-Gy (n=17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors. At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n=55%; European Organization for Research and Treatment of Cancer, n=33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n=61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p=0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged. The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL).Patients and methods: Women (18–40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up.Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women’s median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%).Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

Two Cycles of ABVD Followed by Involved Field Radiotherapy with 20 Gray (Gy) is the New Standard of Care in the Treatment of Patients with Early Stage Hodgkin Lymphoma: Final Analysis of the Randomized German Hodgkin Study Group (GHSG) Trial HD10

There has been continuous discussion about the best treatment for patients with early favorable Hodgkin lymphoma (HL). Open questions included the choice between combined modality treatment and chemotherapy only, the number of chemotherapy cycles needed and the optimal radiation dose. The GHSG thus conducted a randomized study for patients with early-stage favorable Hodgkin lymphoma (HD10) which addressed these questions were.

Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) Randomized HD11 Trial

Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) Randomized HD11 Trial

Quality Control of Involved Field (IF)-radiotherapy for Patients with Early-stage Hodgkin Lymphoma Based on a Central Prospective Review: Comparison of the Results between Two Study Generations of the German Hodgkin Study Group (GHSG)

Quality Control of Involved Field (IF)-radiotherapy for Patients with Early-stage Hodgkin Lymphoma Based on a Central Prospective Review: Comparison of the Results between Two Study Generations of the German Hodgkin Study Group (GHSG)

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

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

Radiotherapy in Early-Stage Favourable Hodgkin`s Lymphom: Experiences of the German Hodgkin Study Group~!2010-04-12~!2010-07-09~!2010-08-13~!

Radiotherapy in Early-Stage Favourable Hodgkin`s Lymphom: Experiences of the German Hodgkin Study Group~!2010-04-12~!2010-07-09~!2010-08-13~!

Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial

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 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. 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. 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.

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up