German Hodgkin Lymphoma Study Group Research Articles

Learning from Lymphocytes: A Career Studying Lymphoid Cancer

Joseph M Connors speaks to Adam Born, Assistant Commissioning Editor: Joseph M Connors, MD is a clinical professor in the Department of Medicine, Division of Medical Oncology, at the University of British Columbia (BC, Canada) and the Clinical Director of the British Columbia Cancer Agency Centre for Lymphoid Cancer (BC, Canada). Dr Connors obtained his medical degree at Yale University (CT, USA), trained in internal medicine at the University of North Carolina in Chapel Hill (NC, USA), and completed his medical oncology fellowship with Dr Saul Rosenberg at the Stanford University Medical Center (CA, USA) between 1979 and 1981. He then joined the staff and faculty at the BC Cancer Agency and University of British Columbia and has focused his clinical activities and research efforts in the area of understanding lymphoid cancers. Dr Connors is best known for his research into the biology and treatment of Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemias and multiple myeloma. He serves as a member of the executive committee of the Hematology Site Group for the National Cancer Institute of Canada Clinical Trials Group, as a Councilor for the American Society of Hematology and on the scientific advisory board of the Lymphoma Foundation Canada. Dr Connors has published over 300 peer-reviewed scientific articles addressing various aspects of research into lymphoid cancers. He has been awarded the Terry Fox Cancer Research Award by the British Columbia Medical Association, the Bernard L Schwartz Memorial Award by the Scripps health system in San Diego, California, the Canadian Cancer Society John W Whittick Memorial Award by the Saskatchewan Medical Association, the Karl Musshoff Lifetime Achievement Award of the German Hodgkin Lymphoma Study Group, the 2013 Dr Don Rix Award for Lifetime Achievement by Life Sciences BC and a Lifetime Achievement Award and Honorary Membership by the Canadian Medical Association in 2013.

Guideline on the management of primary resistant and relapsed classical Hodgkin lymphoma

Summary of key recommendations ● Repeat biopsy is generally recommended in Hodgkinlymphoma (HL) patients thought to have relapsed, andshould be considered in those who have residual fluoro-deoxyglucose (FDG)-avid lesions post-therapy (1C).● Positron-emission tomography/computerized tomogra-phy (PET-CT) is the preferred restaging modality aftersalvage therapy (1B).● The aim of salvage treatment should be to achieve anFDG-PET-negative remission (1B).● The choice of a first-line salvage regimen in patients eli-gible for autologous stem cell transplantation (ASCT)should be based on patient factors and familiarity ofthe treatment centre with the regimen (2C).● Regimens containing stem cell toxic agents (such as car-mustine and melphalan) should be avoided if possibleuntil stem cells have been successfully collected andcryopreserved if ASCT is planned (1B).● There is currently no evidence to support intensivesequential induction/consolidation strategies prior toASCT (1B).● Consider switching to an alternative non-cross-resistantsalvage regimen if there are residual FDG-avid lesionsafter first line salvage treatment and the intent is toproceed to ASCT (2B).● In patients not eligible for ASCT, combined modalitytherapy should be considered especially in early stagerelapse and in patients who have not received priorradiotherapy or who have relapsed outside of the initialradiotherapy field (2B).● In patients unlikely to tolerate the toxicities associatedwith more intensive regimens, palliation with either a sin-gle agent or with a multi-agent oral regimen with or with-out intravenous vinblastine should be considered (2C).● Early consideration of involvement of palliative care ser-vices is recommended, particularly in those not eligiblefor high dose therapy (1C).● ASCT is the standard treatment for patients withrelapsed disease who achieve an adequate response tosalvage therapy (1A).● ASCT is also the standard treatment for patients withprimary resistant disease who achieve an adequateresponse to salvage therapy (1B).● ASCT is not recommended in those failing to achievean adequate response (1B).Guideline

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

Hematopoietic stem cell transplantation for Hodgkin's disease

Autologous stem cell transplantation (aHSCT) has been considered the gold treatment following salvage chemotherapy for relapsed or refractory Hodgkin's lymphoma. The first randomized trial comparing conventional chemotherapy and aHSCT was published in 1993.(1) Forty patients received BCNU, etoposide, cytarabine, and melphalan (BEAM) as conditioning regimen followed by aHSCT or mini-BEAM in the chemotherapy arm. The results indicated the superiority of transplantation. The European Group for Blood and Marrow Transplantation published a confirmatory randomized study (n = 161 patients), in which dexa-BEAM was chosen for the chemotherapy control arm.(2) With a median follow-up of 3 years, event-free survival (EFS) was 55% versus 34% for the transplant and chemotherapy arms, respectively, reinforcing the recommendation that high-dose chemotherapy with aHSCT rescue should be the treatment of choice for relapsed or refractory disease. Several models have been employed to predict outcomes in patients with relapsed/refractory Hodgkin's lymphoma who undergo high-dose chemotherapy followed by aHSCT. Moskowitz et al. proposed the use of three factors: complete remission < 1 year, presence of B-symptoms and extranodal disease at the time of relapse. Patients with 0-1 risk factors had an EFS of 83%, while patients with 2 and 3 factors had EFS of 27% and 10%, respectively.(3) More recently, functional studies to assess chemosensitivity (FI; PET scan, Ga67 scan) performed before transplant have become excellent prognostic tools.(4,5) Persistence of positive FI before aHSCT identifies a group of patients who will have a worse outcome than those with negative FI after finishing salvage chemotherapy. Chemosensitive disease has better outcomes with autologous transplants, given the higher relapse and toxicity rates among chemorefractory patients. Several approaches have been proposed to overcome this barrier, including tandem transplants. In this approach, patients are submitted to two sequential autologous transplants, usually within one to three months. An investigation by the German Hodgkin Lymphoma Study Group enrolled 43 primary refractory or very unfavorable relapse patients. Patients received salvage chemotherapy with ifosfamide, etoposide and woxorubicin (IVA), underwent stem cell collection and two tandem transplants.(6) Conditioning regimen for the first aHSCT consisted of CBV plus mitoxantrone, while the second transplant was with cytarabine 6 g/m2, melphalan 140 mg/m2 and total body irradiation of 12 Gy, or busulfan 12 mg/kg. Four patients had no response to salvage therapy, seven patients received only one transplant and 32 patients completed the initially planned treatment. Among the 24 patients with unfavorable relapses, 20 achieved complete remission and among the 19 patients with induction failure, ten were in remission. The 2-year survival from the date of progression was 65% for the whole study population, while it was 74% for the 32 patients who completed the treatment. The Groupe d'Etude des Lymphomes de l'Adulte (GELA) treated 245 patients with relapsed disease - 150 of which had primary refractory or very high-risk disease - with a protocol including IVA or MINE for salvage, and single or tandem autologous transplants.(7) Patients with standard risk received the first transplant only, while primary refractory or very high-risk patients proceeded to tandem transplants. The first conditioning regimen included cyclophosphamide, carmustine, etoposide and mitoxantrone, while the second transplant, performed 45 to 90 days after the first, used total body irradiation at 12 Gy, cytarabine and melphalan, or busulfan-based preparative regimen, similar to the German study. With a median follow-up of 51 months, in an intention to treat analysis, 5-year progression-free and overall survival were 46% and 57% for high-risk patients, and 73% and 85% for the standard risk group, respectively. In addition, the 5-year overall survival for patients with chemotherapy-resistant disease was 46% (as opposed to an expected rate of 30% observed in previous studies). These results would suggest that patients who do not respond well to salvage chemotherapy or for early (occurring less than 1 year after achievement of remission), unfavorable relapses, tandem transplants may be superior to standard single aHSCT. There are several unresolved controversies surrounding this issue, however, and this recommendation is not universally accepted. Allogeneic transplants have been explored in younger patients who relapse following aHSCT, but are still considered experimental and should be performed within a clinical trial. There is still controversy as to whether a graft-versus Hodgkin's disease effect exists. However, long-term survival rates of 10-40% have been reported for selected patients. For those without matched related or unrelated donors, several centers are investigating haploidentical (mismatched related) or unrelated cord blood transplantation. Outcomes are better for chemosensitive patients, especially for those that achieve complete remission prior to transplant.(8-10) Non-transplant options include everolimus, and the immunotoxin, brentuximab vedotin drugs that have recently been shown to have activity in relapsing/refractory Hodgkin's lymphoma. In summary, patients with relapsed disease should be referred for transplantation. Hodgkin's lymphoma, however, remains a challenging disease for the minority of patients that are not cured after initial chemotherapy.

Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG)

Because nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) express CD20, rituximab may be used as a nonmutagenic treatment option to avoid late toxicities in this rather indolent entity. Between 1999 and 2004, the German Hodgkin Study Group (GHSG) investigated the activity of rituximab (375 mg/m(2) in 4 doses) in a phase 2 trial in 21 relapsed or refractory NLPHL patients. The initial diagnosis of NLPHL was confirmed in 15 of the 21 enrolled patients by reference pathology. The remaining cases were reclassified as Hodgkin lymphoma transformed to T-cell rich B-cell lymphoma (TCRBCL; n = 2) or CD20(+) classical Hodgkin lymphoma (cHL; n = 4). In NLPHL patients the overall response rate was 94%, including 8 complete remission (CR) and 6 partial remission (PR). With a median follow-up of 63 months (range, 3-84), the median time to progression was 33 months, with the median overall survival (OS) not reached. Thus, rituximab is highly effective in relapsed and refractory NLPHL. This study is registered at http://www.klinisches-studienzentrum.de/trial/285.

HD12 Randomised Trial Comparing 8 Dose-Escalated Cycles of BEACOPP with 4 Escalated and 4 Baseline Cycles in Patients with Advanced Stage Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Lymphoma Study Group (GHSG), University of Cologne, D-50924 Cologne, Germany.

The preceding trial HD9 had shown a significant superiority for escalated BEACOPP (EB) for failure-free survival (FFTF) and overall survival (OS) over COPP/ABVD or baseline BEACOPP (BB) (each 8 cycles). HD12 aimed to de-escalate chemotherapy by comparing 8 cycles EB with 4 cycles EB plus 4 cycles BB, with or without consolidatory 30 Gy radiation (RT) to initial bulky and residual disease. A total of 1661 patients aged 16–65 with HL in stage IIB (large mediastinal mass and/or E-lesions) or stage III-IV were randomised from 9/1999-1/2003 according to a factorial design between: 8EB + RT, 8EB no RT, 4EB+4BB + RT, 4EB+4BB no RT. A central diagnostic panel reviewed CT images after completion of chemotherapy independent of randomisation arm, and prescribed RT in selected cases. In the fifth analysis of HD12 (5/2006), 94% of all 1593 eligible randomised patients were evaluable, including 1498 for the chemotherapy comparison and 1449 for the radiotherapy comparison. Patient characteristics were very similar for all 4 arms. Radiation was given in arms with planned RT in 65%, in arms with no planned RT in 10%. 93% of all patients reached a complete remission, 2.2% suffered early progression, 4.6% relapsed and 8.2% died with a median folllow-up time of 48 months. Death due to acute toxicity was 3.2% (sepsis, cardiac, pulmonary, infection), with 21 such deaths in the 8EB arms and 27 in the 4EB+4BB arms. Secondary neoplasias were observed in 55 patients (3.7%): 14 AML/MDS, 12 NHL and 29 solid tumors/others. Four-year Kaplan-Meier estimates for arm pairs according to the factorial design were:4 year rates, %(95% CI)8EB vs. 4EB+4BBwith RT vs. without RTFFTF88(86–91) 86(83–89)91(89–93) 88(86–91)OS93(91–95) 91(89–93)No significant differences were observed when comparing treatments according to the sequential analysis plan (N.B. 10% received RT in arms ‘without RT'). The final analysis, scheduled when 80% of patients have 5 years follow-up, must be awaited before final conclusions can be drawn.

Sekundärneoplasien nach erfolgreicher Primärtherapie des malignen Hodgkin-Lymphoms

Malignant Hodgkin's lymphoma (HL) has become a curable disease through the increasing intensity of the treatment strategies applied. These regimens are aggressive, including radiotherapy and chemotherapy leading to the possibility of secondary malignancies. The German Hodgkin Lymphoma Study Group considered three cohorts including 5,411 patients with all stages of HL. In 127 patients a secondary solid tumor was diagnosed (cumulative risk 2%, median follow-up 72 months), with bronchial carcinomas (23.6%) and colorectal adenocarcinomas (20.5%) being the most frequent neoplasms. Secondary acute myeloid leukemia was found in 36 patients, another ten developed myeloid dysplasia (cumulative risk 1%, median follow-up 55 months). A total of 52 patients revealed a non-Hodgkin's lymphoma (NHL; cumulative risk 0.9%, median follow-up 46 months). The overall incidence of secondary malignancies was 3.9% in patients who had been treated successfully for their HL with radio- and/or chemotherapy.A secondary NHL can be particularly difficult to be distinguished from the preceding HL. Therefore, in case of a suspected relapse, a complete histopathological work-up must be performed.

Rituximab in Relapsed Lymphocyte Predominant Hodgkin's Disease (LPHD). Long-Term Results of a Phase-II Study from the German Hodgkin Lymphoma Study Group (GHSG).

Introduction: LPHD is a rare disease which accounts for 3–8% of all Hodgkin cases. Patients with LPHD relapse frequently and freedom from treatment failure is not significantly improved by intensification of polychemotherapy or radiotherapy. The malignant cells of LPHD are CD20+ and therefore the anti-CD20 antibody rituximab (R) may have activity with fewer adverse late effects.Methods: This phase-II trial was initiated by the German Hodgkin Lymphoma Study Group (GHSG) to evaluate rituximab in patients with LPHD at first or higher relapse or progressive disease after at least one standard treatment. Histological slides were reviewed by a reference panel. Pts received 375mg/m2 of the anti-CD20 antibody rituximab once weekly for four weeks given as intravenous infusion in saline solution.Results: Between 1999 and 2004 we treated twenty-one pts. with CD20-positive Hodgkin's lymphoma according to the study protocol. Fourteen patients had stage I/II disease at the time of study entry and all patients were in their first to third relapse (median 2). The initial diagnosis of LPHD was confirmed in 17/21 cases. The remaining cases were reclassified as HD transformed to T-cell rich B-cell lymphoma (2) or CD20-positive classical HD (2). The overall response rate was 90%. Time to progression was 31 months (ms). The median follow-up 58 ms. Both T-cell rich B-cell lymphoma are in continous remission (PR 51ms+, CR 61ms+).Conclusion: Single-agent therapy with rituximab is safe and showed high efficacy in relapsed LPHD. Therefore rituximab might be a non-toxic and efficient alternative treatment strategy compared to intensified chemo-and/or radiotherapeutic protocols in this young group of patients.

Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG)

BackgroundWe designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD). Patients and methodsEligibility criteria included age 18–65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, high-dose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT). ResultsA total of 102 patients (median age 34 years, range 18–64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3–61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P<0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P<0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were significant for OS. ConclusionBased on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol).

Case of relapsed CD20(+) mixed‐cellularity Hodgkin disease treated with sequential rituximab and radiotherapy

American Journal of HematologyVolume 77, Issue 4 p. 418-419 Letters and CorrespondenceFree Access Case of relapsed CD20(+) mixed-cellularity Hodgkin disease treated with sequential rituximab and radiotherapy Michalis V. Karamouzis, Michalis V. Karamouzis 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorNikiforos Apostolikas, Nikiforos Apostolikas Department of Pathology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorChara Georganta, Chara Georganta 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorGiorgos Lainakis, Giorgos Lainakis 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorKostas Kandylis, Kostas Kandylis 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorGerasimos Rigatos, Gerasimos Rigatos 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this author Michalis V. Karamouzis, Michalis V. Karamouzis 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorNikiforos Apostolikas, Nikiforos Apostolikas Department of Pathology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorChara Georganta, Chara Georganta 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorGiorgos Lainakis, Giorgos Lainakis 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorKostas Kandylis, Kostas Kandylis 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this authorGerasimos Rigatos, Gerasimos Rigatos 1st Department of Medical Oncology, St. Savvas Anticancer-Oncologic Hospital, Athens, GreeceSearch for more papers by this author First published: 18 November 2004 https://doi.org/10.1002/ajh.20224Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES 1Ekstrand BC, Lucas JB, Horwitz SM, et al. Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial. Blood 2003; 101: 4285– 4289. 2Rehwald U, Schulz H, Reiser M, et al. German Hodgkin Lymphoma Study Group (GHSG). Treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood 2003; 101: 420– 424. 3Ibom VK, Prosnitz RG, Gong JZ, et al. Rituximab in lymphocyte predominance Hodgkin's disease: a case series. Clin Lymphoma 2003; 4: 115– 118. 4DeVita VT Jr. Hodgkin's disease—clinical trials and travails. N Engl J Med 2003; 348: 2375– 2376. 5Aleman BMP, Raemaekers JMM, Tirelli U, et al. European Organization for Research and Treatment of Cancer Lymphoma Group. Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med 2003; 348: 2396– 2406. Citing Literature Volume77, Issue4December 2004Pages 418-419 ReferencesRelatedInformation

Secondary Amenorrhoea after Hodgkin's Lymphoma Is Influenced by Age at Treatment, Stage of Disease, Chemotherapy Regimen, and the Use of Oral Contraceptives during Therapy: A Report from the German Hodgkin Lymphoma Study Group (GHSG).

Purpose: Long term survivors of successfully treated Hodgkin's disease (HD) are at risk for late complications. Among these, infertility for female patients is of major importance affecting many young women. The subject of this analysis is to evaluate the menstrual status in young women after HD therapy.Patients and methods: From 1994–1998, the German Hodgkin Lymphoma Study Group (GHSG) conducted clinical trials for early, intermediate and advanced-stage HD (HD7-HD9) involving a total of 3186 patients. A questionnaire was used to evaluate the menstrual status of young female patients after therapy. The following factors were assessed by multivariate analysis for their influence on amenorrhoea: age, treatment, stage, and the use of oral contraceptives during chemotherapy.Results: The data presented were last updated in May 2004. A total of 405 women aged <40 years answered the questionnaire referring the menstrual status after HD therapy. For most women (89.6%), menstruation before the beginning of therapy was regular. After a median follow-up of 3.2 years, 51.6% of the women receiving 8 cycles of dose-escalated BEACOPP had continuous amenorrhoea. Amenorrhoea was significantly more frequent in women receiving 8 cycles of dose-escalated BEACOPP compared to women treated with ABVD alone, COPP/ABVD or standard BEACOPP (p=0.0066). Moreover, amenorrhoea after therapy was most pronounced in women with advanced-stage HD (p<0.0001), in those older than 30 years at treatment (p= 0.0065), and in women who did not take oral contraceptives during chemotherapy (p=0.0002).Conclusion: Most women who are treated for advanced-stage HD experience amenorrhoea after therapy. Amenorrhoea is significantly more frequent in women with advanced-stage HD receiving 8 cycles of dose-escalated BEACOPP and in women older than 30 years at treatment. Furthermore, the present data suggest a possible protection of oral contraceptives against amenorrhoea.

Hodgin's Lymphoma in Elderly Patients: A Comprehensive Analysis of the German Hodgkin Lymphoma Study Group (GHSG).

Background: With improved prognosis of patients with Hodgkin's lymphoma (HL), interest increasingly focuses on high-risk groups such as elderly patients. We thus performed a retrospective analysis of the German Hodgkin Lymphoma Study Group (GHSG) database to determine clinical presentation, toxicity of treatment and outcome of elderly HL patients.Methods: A total of 4251 patients included in the GHSG studies HD5-9 were analysed of whom 372 (8.8%) were 60 years or older and 3879 (91.2%) were younger than 60 years. Patient characteristics, treatment results, toxicity, failure free survival (FFTF) and overall survival (OS) were compared.Results: The median age of the two cohorts was 65 and 31 years, respectively. Statistically significant differences in patient characteristics were as follows: elderly patients had more frequently mixed cellularity subtype (35% vs. 19%), B-symptoms (50% vs. 43%) and elevated ESR (59% vs. 51%). Less frequently observed in elderly patients were nodular sclerosis subtype (41% vs. 66%), large mediastinal mass (9% vs. 20%), bulky disease (49% vs. 60%) and Karnofski index <8, (11% vs. 3%). Acute toxicity during chemotherapy was higher in elderly patients (87% vs 79%). The most obvious differences were observed for infections (17% vs 6%). The significantly higher rate of infections was due to more severe leukopenia in elderly patients (grade IV: 41% vs 25%). As a result, significantly fewer elderly patients received at least 85% of intended chemotherapy dose (74% vs. 90%). At a median follow-up of 65 months, 38% and 11% of patients respectively died. The survival analysis showed a statistically significant poorer prognosis for elderly patients in terms of 5-year OS (65% vs. 90%), FFTF (60% vs. 79%) and Hodgkin-specific FFTF (73% vs. 82%).Conclusion: Elderly patients have a poorer risk profile compared to 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 Hodgkin lymphoma patients.

Comparison of Patients (Pts) Characteristic and Treatment Outcomes in Lymphocyte-Predominant (LPHD) and Classical Hodgkin's Disease (cHD): A Report from the German Hodgkin Lymphoma Study Group (GHSG).

Introduction: LPHD differs in histological and clinical presentation from cHD. Treatment of LPHD patients (pts) using standard Hodgkin disease (HD) protocols leads to complete remission (CR) in more than 95% of pts. However, differences in terms of relapse rates, survival and freedom from treatment failure (FFTF) between clinical stages of LPHD and cHD pts were suggested by a recent intergroup analysis. To obtain a more comprehensive picture, we reviewed all LPHD-cases registered in the GHSG database and compared patient characteristics and treatment outcome with cHD pts.Patients and methods: We retrospectively analysed 8298 HD pts treated within the GHSG trials (HD4 to HD12): 394 LPHD pts and 7904 cHD pts. From 394 LPHD pts 63% were in early stage, 16% in intermediate and 21% in advanced stage of disease. Of the 7904 cHD pts analysed, 22% were in early, 39% in intermediate and 39% in advanced stages. 9% of LPHD pts had B symptoms compared to 40% in cHD pts.Results: 87.5% LPHD pts reached CR/CRu compared to 81.1% cHD pts. 0.3% LPHD pts developed progressive disease (PD) compared to 3.7% cHD. The relapse rate of LPHD pts was very similar to cHD (6.9%). 0.8% LPHD pts and 3.1% cHD had early relapse, 6.9% LPHD pts and 4.2% cHD pts suffered from late relapse. LPHD pts with late relapse were in intermediate stages (12.5%). In contrast, only 3.9% of cHD pts in intermediate stages had late relapses. There were 2.5% secondary malignancies in LPHD and 3.7% in cHD pts. 4.3% LPHD pts and 8.8% cHD pts died. The FFTF rates for LPHD or cHD pts at a median observation of 41 or 48 months, respectively were as follows: early stages 93% vs. 87%, in intermediate stages 87% vs. 85% and in advanced stages 77% vs. 75%. The OS rates for LPHD or cHD pts were 98% vs. 96% for early stages, 94% vs. 93% for intermediate stages and 91% vs. 87% for advanced stages. The multivariate analysis of prognostic and risk factors will be presented.Conclusion: cHD pts present more frequently with advanced stages and B symptoms compared to LPHD pts. Comparing LPHD and cHD pts we found differences in treatment outcome in respect of CR/CRu, progressive disease and mortality. Surprisingly, there were no differences in terms of relapses. The majority of late relapses in LPHD pts were in intermediate stages. In contrast to previous reports, our data suggest that relapses in LPHD and cHD pts seem to be comparable and not more frequent. Thus new treatment strategy for LPHD pts in intermediate stages should be considered.

Cologne High-Dose Sequential Chemotherapy in Relapsed and Refractory Hodgkin Lymphoma - Results of a Large Multicenter Study of the German Hodgkin Lymphoma Study Group (GHSG).

Purpose: Combination chemotherapy can cure patients (pts) with Hodgkin lymphoma (HD), but those with treatment failure or relapse still have a poor prognosis. We thus, designed a dose- and time-intensified high-dose sequential chemotherapy regimen with a final myeloablative course.Patients and Methods: Eligibility criteria included age 18–65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consists of two cycles DHAP (dexamethasone 40mg d1-4, high-dose cytarabin 2g/m2 12q d2, cisplatinum 100mg/m2 d1); pts with partial (PR) or complete remission (CR) received cyclophosphamide 4g/m2, followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8g/m2 plus vincristine 1,4mg/m2; and etoposide 2g/m2. The final myeloblative course was BEAM followed by PBSCT.Results: 102 pts (median age 34 years, range 18–64) were enrolled. The response rate (RR) at the final evaluation (100 days posttransplantation) was 80% (72% CR, 8% PR). PBSC harvest was succesful in 96% of pts. Toxicity was tolerable. With a median follow-up of 30 months (range 3–61 months) freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD: 41% and 48% and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after 2 cycles of DHAP (p < 0.0001) and duration of first remission (PD and multiple relapse vs. early and late relapse; p = 0.0127) were prognostic factors for FF2F. Response after DHAP (p < 0.0081), duration of first remission (p = 0.0017) and anemia (p = 0.019) were identified as prognostic factors for OS.Conclusion: We conclude that this regimen is feasible, tolerable and highly effective in poor risk patients with relapsed and refractory HD. Based on these results a prospective randomized european intergoup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol). First results of the second interim analysis of this study will be presented.

Fertility in Male Patients with Hodgkin's Disease - Results from the German Hodgkin Lymphoma Study Group (GHSG).

Background:Treatment results in Hodgkin Disease (HD) have improved tremendously over the last two decades. Therefore long term sides effects of therapy as infertility are of growing importance. However, patients (pts) with HD have increased risk for inadequate semen quality even prior to treatment. To investigate the influence of disease and therapy on the fertility status in pts with HD we performed semen and hormone analysis before and after treatment.Patients and Methods:All analysis were evaluated in pts with first diagnosis of HD enrolled into trials of the GHSG between 1988 and 2002, in 40 centers in Europe. Pts had no history of chemotherapy or radiotherapy. All analysis were evaluated according to WHO-guidelines.Results:We included 243 male pts with a median age of 26,5 years (range 16–57,5 years). At first diagnosis 138 pts were in clinical stage (CS) I/II, 105 in CS III/IV, and systemic symptoms were present in 106 pts. 202 pts underwent fertility screening before therapy: normospermia was diagnosed in 40 (20%) pts and 162 (80%) had inadequate semen quality. Normal values of FSH, LH, and testosterone were found in 140/151 (93%), 99/125 (79%), and 84/101 (83%) of pts respectively. 112 pts underwent at last one fertility screening after therapy. Treatment consisted of chemotherapy alone in 10 pts, in 9 pts of radiotherapy alone and in 93 pts of combined modality. In 40 (36%) pts a recovery of spermatogenesis was observed. Normal values of FSH, LH, and testosterone after treatment were found in 32/63, 40/51, and 36/40 pts respectively. Table 1 shows time of onset of spermatogenesis and normal values of fertility hormones after the end of therapy.Table 11st year2nd year3rd yearafter 3rd yearSpermatogenesis (40/112)7 (18%)9 (24%)10 (26%)14 (32%)Normal FSH (32/63)8 (25%)12 (38%)6 (19%)6 (19%)Normal LH (40/51)13 (33%)16 (40%)6 (15%)5 (13%)Normal testosterone (36/40)17 (47%)12 (33%)1 (3%)6 (17%)Recovery from azoospermia was observed in 8 (89%) pts treated with radiotherapy, in 1 (10%) pt treated with chemotherapy alone and in 31 (33%) pts treated with combined modality. Recovery rate from azoospermia was lower in pts treated with alkylating agents, BEACOPP chemotherapy, with systemic symptoms and elevated BSG.Conclusions:We confirmed that HD pts had inadequate semen quality even prior to treatment. The majority of pts had azoospermia after treatment, but recovery of spermatogenesis was observed, in general 2 years after the end of therapy. Hormone values usually recovered in the first two years. Patient treated with radiotherapy alone recovered in higher frequency. A detailed analysis (including multivariate analyses) will be presented at the annual meeting.

460 oral Comparison of 30 Gy versus 20 Gy involved field radiotherapy after two versus four cycles ABVD in early stage Hodgkin's disease: interim results of the German Hodgkin's Lymphoma Study Group (GHSG) trial hd10

460 oral Comparison of 30 Gy versus 20 Gy involved field radiotherapy after two versus four cycles ABVD in early stage Hodgkin's disease: interim results of the German Hodgkin's Lymphoma Study Group (GHSG) trial hd10

Biophysical analysis of acute toxicity of radiotherapy in Hodgkin’s lymphoma — a comparison between extended field and involved field radiotherapy based on the data of the german hodgkin study group (GHSG)

The correlation between complication probability and dose-volume histograms (DVHs) can be described with the linear-quadratic (LQ) model. The HD8 trial of the German Hodgkin Lymphoma Study Group (GHSG) for early-stage unfavourable Hodgkin’s lymphoma (HL) was designed to test whether radiotherapy (RT) can be reduced without loss of efficacy from extended field (EF) to involved field (IF) after two cycles of COPP alternating with two cycles of ABVD chemotherapy. Considering the number of side-effects that were found in the HD8 trial, we wanted to prove in this analysis, if biophysical parameters for the LQ-model could be determined.

Biophysical analysis of acute toxicity of radiotherapy in Hodgkin’s lymphoma — a comparison between extended field and involved field radiotherapy based on the data of the german hodgkin study group (GHSG)

The correlation between complication probability and dose-volume histograms (DVHs) can be described with the linear-quadratic (LQ) model. The HD8 trial of the German Hodgkin Lymphoma Study Group (GHSG) for early-stage unfavourable Hodgkin’s lymphoma (HL) was designed to test whether radiotherapy (RT) can be reduced without loss of efficacy from extended field (EF) to involved field (IF) after two cycles of COPP alternating with two cycles of ABVD chemotherapy. Considering the number of side-effects that were found in the HD8 trial, we wanted to prove in this analysis, if biophysical parameters for the LQ-model could be determined.

Fertility in male patients with Hodgkin's disease after therapy –results from the German Hodgkin Lymphoma Study Group (GHSG)

6547 Background: Treatment results in Hodgkin Disease (HD) have improved tremendously over the last two decades. Therefore long term sides effects of therapy are of growing importance. Infertility after therapy of HD is considered as a side effect of chemotherapy and radiotherapy. However patients with HD have increased risk for inadequate semen quality even prior to treatment. To investigate the influence of therapy on the fertility status in patients with HD we performed semen analysis before and after treatment. Methods: Semen quality was evaluated in patients with first diagnosis of HD enrolled into trials of the GHSG between 1988 and 2002. Patients had no history of chemotherapy or radiotherapy. All semen analyses were evaluated according to WHO-guidelines. Results: We included 111 male patients with a median age of 26 years (range 16–52 years). At first diagnosis 10 patients were in clinical stage (CS) I, 60 in CS II, 60 in CS III and 8 in CS IV; systemic symptoms were present in 52 patients. In 9 p...

Fertility in male patients with Hodgkin's disease after therapy –results from the German Hodgkin Lymphoma Study Group (GHSG)

6547 Background: Treatment results in Hodgkin Disease (HD) have improved tremendously over the last two decades. Therefore long term sides effects of therapy are of growing importance. Infertility ...