Early Unfavorable Stage Research Articles

ROLE OF CHECKPOINT INHIBITION IN GERMANY

Immune checkpoint inhibition (ICI) has demonstrated an overall excellent benefit-to-risk profile in the treatment of classical Hodgkin lymphoma (cHL); however, cure remains an exception to the rule. The German Hodgkin Study Group (GHSG) has identified several areas of unmet need for ICI development in cHL. First, we aim to better understand the role of immune checkpoints in the interplay between Hodgkin/Reed-Sternberg malignant cells and the abundant microenvironment. Second, we aim to improve efficacy of ICI in multiple relapsed/refractory (r/r) cHL patients, as complete response rates are infrequent and median PFS is still quite limited. Therefore, combination therapies with alternative ICIs targeting TIGIT, LAG3, or TIM3, or combinations with conventional cytotoxic drugs need to be investigated. The GHSG has focused on evaluating the abscopal effects of radiotherapy to improve ICI in multiple r/r cHL. Third, the GHSG strongly believes that ICI should be able to improve first-line therapy of cHL. The GHSG is currently conducting clinical trials to de-escalate the chemotherapy intensity. In early favourable stage cHL patients, we hypothesize that ICI can replace chemotherapy in the combined modality therapy approach. In early unfavourable stage cHL, we use our PET-adapted design to select well-responding patients and remove chemotherapy and/or radiotherapy from the treatment strategy. In advanced stage cHL, we aim to reduce cumulative exposure to conventional chemotherapy. We hypothesize that the combination of anti-PD-1 antibody therapy with our intensive chemotherapy should act synergistically and more patients should achieve an early metabolic complete response. These patients could then be treated with only 4 cycles of combined PD1 chemotherapy. Overall, this new treatment principle should serve to overcome chemotherapy resistance and improve the efficacy of established therapeutic regimens, while reducing the treatment burden for our cHL patients. Keywords: Hodgkin lymphoma, immunotherapy No conflicts of interests pertinent to the abstract.

Prognostic and predictive factors in early stages of classic Hodgkin’s lymphoma

Rationale. In the early stages of classical Hodgkin’s lymphoma (cHL), the cure rate reaches 85–95 %, but the long-term effects of therapy can worsen overall survival. Current trials for early stages of Hodgkin’s lymphoma with favorable prognosis address the task of maintaining cure rates while reducing sequelae. For early unfavorable stages, the challenge is to improve cure rate without increasing toxicity.Purpose. To assess the potential significance of individual risk factors for optimal choice of the first line chemotherapy in early-stage Hodgkin lymphoma.Materials and methods. This single-center retrospective study included 290 patients with early stage cHL who had received ABVD – based (n = 249; 86 %) or BEACOPP‑21 – based (n = 41; 14 %) combined modality therapy from 2000 to 2017. Progression-free survival (PFS) and overall survival (OS) were assessed in Cox regression analysis including 12 clinical parameters.Main results. At a median follow up of 60 months for the entire group, OS was 95 % and PFS was 89 %. In a multivariate analysis PFS, at 5 years, was significantly inferior in patients with mediastinal bulk, baseline lymphocytopenia (≤ 0.6 × 109/L, р = 0.002; < 1.0 × 109/L, р = 0.000) and male gender; OS was inferior only in patients with an absolute lymphocytopenia (AL). In patients with AL, PFS after ABVD-based regimen was, respectively, 12 % in the high-risk group with mediastinal bulk and 56 % without it. PFS of patients without AL when treated with ABVD did not differ compared to BEACOPP‑21 within the same prognostic group: 95.2 % vs. 92.3 % for non-bulky and 86.4 % vs. 84.2 % for bulky disease. In the absence of AL, mediastinal bulk remained the main and only risk factor in multivariate analysis.Conclusions. The ABVD regimen is highly effective in the first line of chemotherapy for cHL, except for cases with baseline lymphocytopenia, in which the early usage of the BEACOPP regimen in the escalated or 14-day variants might be justified. In patients with mediastinal bulk, standard chemotherapy is not effective enough even in the absence of AL; therefore, if an intermediate PET/CT scan is available, it seems more appropriate to use a milder ABVD regimen on the first line and leave intensive therapy for patients with proven refractory disease. Prospects for improving the efficiency are opened with the new N-AVD and A-AVD schemes, the benefits of which should be evaluated, first of all, in patients with AL and mediastinal bulk.

Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Checkpoint inhibitors in Hodgkin lymphoma

Checkpoint blockade contributes to the immunosuppressive microenvironment in classical Hodgkin lymphoma (cHL) and in particular the interaction of Hodgkin cells and macrophages with T‑cells and natural killer cells via programmed cell death1 (PD-1) and programmed cell death1 ligand1 (PD-L1). The aim of this article is the evaluation the role and potential of checkpoint blockade in cHL as compared with the results of standard chemo- and radiotherapy. We analyzed preclinical and clinical data from phaseI and phaseII studies with checkpoint blockade in cHL. In 60-70% of patients with chemotherapy-refractory cHL, PD‑1 blockade results in responses. Overall survival is excellent and asmall number of patients achieve persistent response. Thus, the use of anti-PD‑1 monoclonal antibodies has become an important treatment approach in relapsed cHL in line with the label. The results of first-line therapy are still preliminary; initial phaseII studies using nivolumab in combination with doxorubicin (=adriamycin), vinblastin and dacarbazin (AVD) in early unfavorable or advanced stages showed response rates of up to 90%. Thus, implementing immunomodulatory approaches using PD 1‑blockade have resulted in asignificant reduction of chemotherapy. This might represent aparadigm shift in the therapy of cHL.

Combined modality treatment: Outcome in patients with Hodgkin's lymphoma.

Hodgkin's lymphoma (HL) can be treated with combined modality treatment (CMT) to limit long-term toxicities in the early favorable stage. Early unfavorable and advanced stage HL is mainly treated with chemotherapy followed by radiation to the bulky site. This study examines the impact of CMT in early as well as advanced stage HL. From 2001 to 2011, 125 patients with Stage I to IV HL were analyzed. Median age of the patients was 25 years (range 12-68 years). CMT, chemotherapy, and radiation alone were given to 51, 64, and 10 patients, respectively. Chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was given to 100 patients, 6 patients received ABVD-like regimen, and 9 patients received cyclophosphamide, vincristine, procarbazine, and prednisone regimen. Radiotherapy (RT) was given to 61 (49%) patients, involved field RT to 55 (90%), and extended-field RT to 6 (10%) patients, respectively. Median radiation dose was 30 Gy (18-40 Gy). All 25 patients with early-stage achieved complete response (CR) with CMT. At a median follow-up of 70 months (range 12-230 months), relapse was seen in two patients (1 local and 1 distant). Of 26 patients with advanced stage, 25 achieved a CR and 1 had stable disease with CMT. Relapse occurred in one patient (distant). In patients with early-stage treated with chemotherapy only ( n = 30, 24%), 9 patients had relapse (4 local and 5 distant) while in those with RT only ( n = 10, 8%), 4 developed distant relapse. In patients with advanced stage treated with chemotherapy only ( n = 34, 27%), 8 relapsed (5 local and distant, 3 distant only). Patients with relapse were salvaged with CMT ( n = 6), chemotherapy ( n = 15), or RT ( n = 3). Two patients have died. Five years' disease-free survival (DFS) in patients with early favorable stage, early unfavorable stage, and advanced stage was 91%, 82%, and 73%, respectively ( P = 0.026). DFS was significantly better with CMT than chemotherapy or radiation alone. Five years' overall survival (OS) was 93%, 92%, and 84%, respectively ( P = 0.139). Second malignancy occurred in 3 (2.4%) patients; carcinoma of the tongue, pseudomyxoma peritonei, and non-HL each, respectively. None of these patients had received prior radiation. CMT improved DFS in patients with HL. OS was similar in all patients irrespective of treatment combinations. The incidence of second malignancy was 2.4%.

Hodgkin lymphoma in elderly patients.

We aim to summarize the current knowledge on the treatment of elderly Hodgkin lymphoma patients with a focus on evidence from clinical trials and novel drugs. For elderly Hodgkin lymphoma patients above 60 years without precluding comorbidities a curative treatment approach is warranted. Early favorable stage patients should receive two cycles of multiagent chemotherapy followed by 20 Gy localized radiotherapy. Early unfavorable stage patients should receive four cycles of multiagent chemotherapy followed by 30 Gy localized radiotherapy. For advanced stage patients six cycles of multiagent chemotherapy can be recommended and should be followed by localized radiotherapy on residual disease manifestations. Relapsed or refractory patients should be treated in an individually tailored approach that considers both the patient's objectives and comorbidities. The antibody-drug conjugate brentuximab vedotin is a very effective option for elderly patients with a high response rate albeit limited durability. Anti-programed cell death protein 1 antibodies might also be effective in elderly Hodgkin lymphoma patients with a mechanism of action distinct from chemotherapy. In conclusion, the goal of treatment in newly diagnosed elderly Hodgkin lymphoma patients is curative whenever possible and prospective and retrospective evidence has shown that this is feasible for all disease stages with a variety of multiagent chemotherapy regimen. Relapsed and refractory elderly Hodgkin lymphoma patients can mostly only be treated with the goal of palliation. However, it remains to be seen if novel substances and new combination regimen are able to change that.

Patients with Hodgkin'S Lymphoma Have a Significantly Better Outcome If Treated Within a Clinical Trial

ABSTRACT Aim: Clinical trials have led to a remarkable improvement of treatment outcome for patients with Hodgkin's lymphoma (HL) over the last 3 decades. Prognosis of patients enrolled in clinical trials may even be superior than the one of patients treated in the community. Since the mid 90ies, many patients with HL treated in our Institution have been prospectively included in the German Hodgkin Lymphoma Group (GHSG) trials. However, many other patients with HL have not been included in these trials for various reasons. Methods: We performed a retrospective population-based analysis using the electronic lymphoma database of our Institution and included all patients with HL from January 1996 to December 2012. Primary endpoint was OS which was defined according to the NCI criteria and estimated by the method of Kaplan–Meier. The Cox proportional hazards model was used for the estimation of hazard ratio and its confidence interval in a multivariate analysis. Results: 172 patients were identified. Clinical characteristics at diagnosis were: median age 38 years, 54% male, 13% stage I, 56% stage II, 15% stage III, 16% stage IV, 40% B symptoms, 10% GHSG early stage, 40% GHSG early unfavorable stage and 50% had GHSG advanced stage. With a median follow-up of 5.6 years, the 5-year overall survival of the whole studied population was 79%. The rate of enrollment in the GHSG trials in our Institution was 24%; participation of patients younger than 40 years in randomized trials was significantly higher compared with those older than 40 years. Patients entered in clinical trials had a significantly better outcome irrespectively of age (p = 0.0047). The inclusion in a clinical study maintained its prognostic value at a multivariate analysis in a Cox model controlling for age and for the GHSG risk group. Conclusions: This analysis suggests that patients enrolled in clinical trials may have a better outcome than patients with similar clinical characteristics at diagnosis. We plan to conduct a national survey in collaboration with the Swiss Cancer registries; the proposed research project may allow a better understanding of the different parameters behind this observation and their impact on treatment modalities and prognosis. Disclosure: All authors have declared no conflicts of interest.

Interdisciplinary Evidence-Based Guideline for Diagnosis, Therapy and Follow-up of Adult Hodgkin Lymphoma Patients

Abstract 4230 Background:Hodgkin Lymphoma (HL) is one of the most common malignancies in young adults and has become curable for the majority of patients even in advanced stage. Nowadays, the main challenges are to develop strategies that decrease secondary malignancies and mortality, as well as to retain fertility after treatment. So far, there is no national or international evidence-based guideline giving recommendations for clinical practice in the treatment of HL patients. For this reason, various medical societies, clinical experts from the German Hodgkin Study Group (GHSG) and methodological experts from the Cochrane Haematological Malignancies Group (CHMG) have developed and consented a clinical practice guideline to improve and standardize diagnosis, treatment and follow-up for HL patients. This project was funded by the German Program for Guidelines in Oncology Implementation. Aims:To emphasize the clinically most relevant guideline recommendations related to diagnostics, treatment and follow-up of adult HL patients. Methods:Randomized controlled trials, systeamtic reviews, cohort studies and specific sensitive data included from systematic literature searches in CENTRAL and MEDLINE were appraised for quality and summarized in evidence tables. Based on these tables and trials, guideline authors generated high quality clinical recommendation in an intensive collaboration with the methodological experts clinical experts from different multi-interdisciplinary working-groups. During the final consensus conference, a total of 160 evidence-based recommendations were consented. Results:There is a strong consensus that all patients should be treated within a clinical trial. Chemotherapy is the mainstay of treatment for all stages of HL. The histological diagnosis should be confirmed by a reference pathologist. For early favorable stages, two cycles of ABVD followed by involved-field radiotherapy (IF-RT) at 20 Gy are strongly recommended; early unfavorable stages should be treated with 2 cycles of BEACOPP escalated followed by 2 cycles of ABVD and IF-RT of 30 Gy; for advanced stages six cycles of BEACOPP escalated followed by 30 Gy radiotherapy on PET-positive residual mass ≥ 2cm is strongly recommended. It is also recommended that patients with relapses or refractory disease, and without severe co-morbidities, receive autologous stem cell transplantation, but not myeloablative allogeneic stem cell transplantation. Additionally, treatment options of subgroups, such as nodular lymphocyte predominant HL, elderly patients or those with co-morbidities such as HIV, are specified in this guideline. The additional benefit of PET remains uncertain as of the lack of high-quality evidence, therefore different recommendations have been provided for staging, interim and follow-up evaluations. It is highly important that health care professionals discuss aspects of fertility protection with female and male patients before starting any treatment. Options for preserving fertility in women have to be adopted to treatment intensity. For male patients, it is recommended to cyropreserve sperm cells before starting the therapy, independently of treatment intensity. There is strong consensus that patients have to prevent to conceive a child during treatment. Health-care professionals should encourage patients to exercise and should discuss potential harms of complementary medicine with the patient. Due to their immunomudulating effect, it is not recommended to take mistletoes at any time. It is strongly recommended to motivate patients to give up smoking, due to the strong associated increased risk of secondary tumors, especially bronchial carcinoma. Structured follow-up care should be provided and should in particular detect relapses, long-term organ toxicities and secondary malignancies. Summary/Conclusions:The first evidence-based guideline on the treatment of patients with HL translates scientific evidence and expert knowledge into precise recommendations for these patients into clinical practice. In addition to this clinical value, the guideline will enable healthcare professionals to improve patient information and quality management. Disclosures:Engert:Takeda, Millennium: Honoraria, Research Funding. Borchmann:Millenium The Takeda Oncology Company: Research Funding, Travel Grants Other. von Tresckow:Millenium The Takeda Oncology Company: Honoraria, Travel Grants Other.

Involved-field (IF) Versus Extended-field (EF) Radiation Therapy (RT) for Patients in Early Unfavorable Stages of Hodgkin Lymphoma: 10-year Update of the HD8 Trial of the German Hodgkin Study Group (GHSG)

Combined modality treatment consisting of chemotherapy followed by RT has shown better results in respect to overall survival (OS), progression free survival (PFS) and freedom from treatment failure (FFTF) compared to RT alone for patients in early unfavorable stages of HL. The HD8 trial was designed to test whether IF-RT is as effective as EF-RT. The main aim was to reduce treatment related toxicity. The present analysis shows the 10-year follow-up data.

Large mediastinal tumor mass as a prognostic factor in Hodgkin’s lymphoma

The risk factor "large mediastinal tumor mass" is an internationally accepted unfavorable prognostic factor in the staging of Hodgkin's lymphoma (HL). The definition of this risk factor varies considerably between large cooperative study groups. The purpose of the present analysis was to determine to which degree data obtained from chest radiograph (CRX) give the same results as those from CT scans (CT). A total of 145 de novo HL patients in early unfavorable and advanced stages were included in this study. A total of 94patients had a large mediastinal tumor mass according to the guidelines of the German Hodgkin Study Group (GHSG), while 51had mediastinal lymph node involvement only. The size of mediastinal involvement and the thoracic diameter were measured on CRX and CT. Agreement between CRX and CT was determined by sensitivity and specificity analysis as well as descriptive statistics and correlations. The correlation of the diameters on CRX with those of CT was 0.95 for the tumor size and 0.77 for the thoracic diameter. The diagnostic decision-large mediastinal mass or not-correlated with 0.81 between CRX and CT and was identical in 90.3% of cases. The sensitivity was 0.87 and the specificity 0.96 for CRX, which is considered the current standard. The results show that there is a high agreement between the measurements of CRX and CT. Diagnosis of a large mediastinal mass disagreed in 10% of patients. Since the correct diagnosis of this risk factor is decisive for the adequate multimodal treatment choice, CRX should not be omitted.

Quality control of involved-field radiotherapy for patients with early stage Hodgkin’s lymphoma based on a central prospective review

Based on experience in trials HD10 and HD11 (1998-2003), the radiotherapy reference center of the German Hodgkin Study Group (GHSG) continued their central prospective radiation oncological review in trials HD13 and HD14. The purpose of this analysis was to identify the impact of this procedure on radiotherapeutic management and to compare findings with former trials. Between 2003 and 2009, 1,710 patients were enrolled in the HD13 trial (early favorable stages) and 2,039 patients in the HD14 trial (early unfavorable stages). All patients received a total of 30Gy involved-field (IF) radiotherapy within a combined modality approach. For patients in HD13, there was a correction of disease involvement in 847/1,518 patients (56%), and for patients in HD14 in 1,370/1,905 patients (72%). Most discrepancies were observed in the lower mediastinum (19.2%), infraclavicular (31.7%), upper cervical (12.7%), and supraclavicular (10.8%) lymph nodes. This resulted in a change of disease stage in 241 (7%) patients and a shift into another study protocol in 66 (2%) patients. Due to the incorrect lymph node documentation of the participating study centers, the IF radiotherapy volume had to be enlarged in 1,063/3,423 patients (31%) and reduced in 244/3,423 patients (7.1%). These findings are comparable to the results of the quality control in the trials HD10 and HD11 (2,611 patients reviewed). Central review of the diagnostic imaging and clinical findings of Hodgkin's lymphoma patients shows a considerable number of discrepancies compared with the local evaluation. Thus, meticulous evaluation of all imaging information in close collaboration between the radiation oncologist and diagnostic radiologist is mandatory.

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.

Combined Modality Treatment with Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavourable Hodgkin Lymphoma (HL): Final Analysis of the German Hodgkin Study Group (GHSG) HD11 Trial.

Abstract 717 Purpose:Combined modality treatment consisting of 4 cycles of chemotherapy (CT) followed by involved field radiotherapy (IF-RT) is the standard treatment for early unfavourable HL. In our prior trial for this group of patients (HD8), overall survival (OS) and freedom from treatment failure (FFTF) at 5 years were 91% and 83%, respectively. The HD11 trial thus addressed two major questions: (1) improving outcome by intensifying CT (4xABVD vs. 4xBEACOPPbaseline; Bbas) and (2) defining the best radiation dose (30Gy vs. 20Gy IF-RT). Patients and methods:Between May 1998 and January 2003, 1395 eligible patients aged 16–75 years with untreated early unfavourable stage HL (CS I, IIA with at least one of the risk factors large mediastinal mass (a), extranodal disease (b), elevated ESR (c) or ≥ 3 nodal areas (d); IIB with risk factors c and/or d) were randomized into one of the following 4 treatment arms: 4xABVD + 30Gy (A), 4xABVD + 20Gy (B), 4x Bbas + 30Gy (C) or 4x Bbas + 20Gy (D). Since there are strong indications for an interaction between CT- and RT-doses, a comparison of pooled treatment arms (A+B vs. C+D for comparison of 4×ABVD vs. 4× Bbas and A+C vs. B+D for comparison of 30Gy IF-RT vs. 20Gy IF-RT) would be misleading. Therefore all treatment arms were analysed separately. Results:Patient characteristics were well balanced between the 4 arms (median age 33 years, 49% male, 6% stage I, 29% B-symptoms). CT- and RT-related acute toxicity occurred significantly more often in the arms with the more intensive therapy (CT: 74.1% vs. 51.8%; RT: 12.3% vs. 5.5%). The complete remission rate 3 months after end of therapy was 94.1% for the whole group and did not differ significantly between the 4 arms. The 5-year estimate of FFTF (primary endpoint) is 85.0% (OS 94.5%, PFS 86.0%).Bbas is more effective than ABVD if followed by 20Gy IF-RT (5y-FFTF difference 5.7%, 95%-CI [0.1%; 11.3%]). This effect does not exist in combination with 30Gy IF-RT (5y-FFTF difference 1.6% [-3.6%; 6.9%]). Similar results are observed for the RT-question: After 4 cycles of Bbas, 20Gy is not inferior to 30Gy (5y-FFTF difference -0.1%, 95%-CI [-5.1%; 4.9%]), whereas after 4xABVD, a relevant inferiority of 20Gy cannot be excluded (-4.0% [-9.5%; 1.4%]). Conclusion:A reduction of RT dose from 30Gy to 20Gy IF-RT seems to be justified only in combination with Bbas, but not with a less effective chemotherapy such as 4xABVD. Patients will benefit from an intensified CT such as Bbas only in combination with 20Gy IF-RT but not with 30Gy IF-RT. Disclosures:No relevant conflicts of interest to declare.

Combined Modality Treatment of Hodgkin’s Lymphoma

Substantial clinical progress over the last decades has improved the first-line treatment and prognosis of patients with Hodgkin's lymphoma (HL). This success is mainly based on the introduction of combined modality treatment strategies including chemotherapy in all risk groups and important progress in radiation techniques. The knowledge emerging from numerous clinical trials as well as better staging and imaging techniques helped to develop more effective therapies. According to our current knowledge, a stage and risk factor-based allocation into early favorable, early unfavorable, and advanced stages remains a suitable instrument to tailor risk-adapted therapy. In most of the study groups, patients with early stage HL receive 2 to 4 cycles of chemotherapy followed by radiotherapy to the involved field. The treatment for advanced stages usually consists of 6 to 8 cycles, more intensive regimen, and radiotherapy for residual masses. Here, we review results from current clinical trials and discuss new therapeutic approaches in the combined modality treatment of HL.

Dose-Intensified Combined Modality Treatment with 2 Cycles of BEACOPP Escalated Followed by 2 Cycles of ABVD and Involved Field Radiotherapy (IF-RT) Is Superior to 4 Cycles of ABVD and IFRT in Patients with Early Unfavourable Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Study Group (GHSG) HD14 Trial

Purpose: Combined modality treatment consisting of 4 cycles of chemotherapy and IF-RT is the standard treatment for early unfavourable HL. Overall survival (OS) and freedom from treatment failure (FFTF) in this group of patients was 91% and 83%, respectively, at 5 years 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 January 2007, 1.216 patients aged 16–60 with untreated early unfavourable stage HL (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 and d) were randomized to either 4 cycles of ABVD (arm A) or 2x BEACOPP escalated followed by 2x ABVD (arm B). All patients received 30Gy IF-RT after chemotherapy. Primary objective was the improvement of the FFTF. Here we present the results of the predefined 3rd interim analysis within the prespecified group sequential test design.Results: Of the 1.216 patients included, 1.010 were evaluable for this analysis. Patient characteristics were well balanced between both arms. At 3 years, the FFTF for arm A is 90% (95% CI: 87%–93%), and for arm B 96% (95% CI: 94%–98%). Since the observed inverse normal test statistic exceeds the critical level, the null hypothesis of equal FFTF in each arm can already be rejected. The improved FFTF is mainly due to differences in progression and early relapses (arm A 5.9% versus arm B 1.8%). Protocol adherence for chemotherapy was high and not different in both arms (arm A 98.8%, am B 97.3%). Though the chemotherapy-intensity was higher in the experimental arm, safety was comparable to the standard treatment. Secondary neoplasias occurred in 8 patients in each arm so far.Conclusion: Based on the significantly superior FFTF of the intensified therapy (2x BEACOPP escalated + 2x ABVD + IF-RT) compared to the prior standard (4x ABVD + IF-RT), this more aggressive treatment strategy will become the new standard for early unfavourable HL patients within the GHSG. Whether the improved FFTF translates into an improved overall survival must be awaited. Future strategies should aim at identification of those patient subgroups that profit most from this approach.

Quality Control of Involved Field Radiotherapy in Patients With Early-Favorable (HD10) and Early-Unfavorable (HD11) Hodgkin's Lymphoma: An Analysis of the German Hodgkin Study Group

The German Hodgkin Study Group (GHSG) set up a radiotherapy (RT) reference center within the Department of Radiation Oncology at the University of Cologne to undertake quality assurance of the group's clinical studies. In the HD10 trial (early-favorable stages) and HD11 trial (early-unfavorable stages) all patients received involved field (IF)-RT (30 Gy vs. 20 Gy) within a combined-modality approach. For these patients a central prospective review of all diagnostic imaging was performed by expert radiation oncologists to control disease extension and to define IF treatment volume. On the basis of simulation films, verification films, and radiotherapy case report form (CRF) an expert panel evaluated retrospectively the adequacy of irradiated IF treatment portals according to the RT prescription, applied radiation doses, treatment time, and technical parameters. Between 1999 and 2006 a total of 825 of 1370 randomized patients of the HD10 trial (60%) and 954 of 1422 patients of the HD11 trial (67%) were evaluated by the panel. Radiotherapy was rated as suboptimal in 47% of all reviewed cases. Although the participating RT centers received a precise RT prescription, most difficulties occurred in the adequate coverage of the IF (40%), followed by technical faults (12%). Deviations from the prescribed single daily dose (1.8-2 Gy), weekly dose, and total reference dose were rare (1%). As a consequence of these findings, radiation oncologists were trained on the definition of IF-RT at GHSG meetings and at the annual meetings of the German Society for Therapeutic Radiation Oncology. Possible correlations between RT quality and relapse rate will be investigated.

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

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

Chemotherapy Alone Versus Chemotherapy Plus Radiotherapy for Early Stage Hodgkin Lymphoma.

Both chemotherapy (CT) alone and combined modality therapy (CMT) are effective modalities for the treatment of early stages of Hodgkin lymphoma (HL). However, the optimal choice of treatment is still being discussed. Different research groups reported that ABVD-like CT followed by radiotherapy is highly effective for early favourable and early unfavourable (intermediate) stage HL. A recently conducted randomized trial aimed at determining whether CMT is superior to CT alone in early stages, showed no significant difference in 5 year overall survival (OS) and event-free survival in patients treated with either 4–6 cycles of ABVD alone or 2 cycles of ABVD plus radiotherapy. Thus, this systematic review and meta-analysis was performed for a more comprehensive comparison.Methods: Only randomized controlled trials (RCT) comparing CT alone with CMT in newly diagnosed adults with early stages of HL (CS IA, IB, IIA, IIB) were included. Medline and Cochrane Library were systematically searched for randomized controlled trials from 1975 to 2007. Patients who received CMT were considered as experimental group and patients who received ABVD-like CT alone were considered as control group. Data were collected from full text publications or abstracts and treatment effects for OS were calculated as hazard ratios (HR).Results: A total of 590 references were screened. Four eligible RCTs were identified, including 1207 patients with early-stage HL (early favourable and early unfavourable stages). Between 1983 and 2004, 765 patients where treated with CMT and 442 patients with CT alone. The OS for the CMT group was significantly better than the OS for the CT-alone group (HR: 0.54; 95% CI [0.35 - 0.84]; p = 0.006), but there was evidence for a substantial heterogeneity between the studies (I2 = 69%, p=0.02).Discussion: First results of this systematic review showed improved OS for patients treated with CMT in early-stage HL compared to patients treated with CT alone. The substantial heterogeneity between the trials should be clarified. Further comprehensive analyses are ongoing and will provide more detailed information.

Quality Control of Involved Field Radiotherapy in Patients With Early-Favorable (HD10) and Early-Unfavorable (HD11) Hodgkin's Lymphoma-An Analysis of the German Hodgkin's Study Group (GHSG)

The GHSG set up a radiotherapy (RT) reference center within the Department of Radiation Oncology at the University of Cologne to undertake quality assurance (QA) of the group's clinical studies. The HD4 study (early-favorable stages) had demonstrated the importance of this: major protocol violations (especially the design of the extended field RT fields) were associated with a statistically significant reduction in freedom from treatment failure. In the HD10 (early-favorable stages) and HD11 trial (early-unfavorable stages) all patients received an involved field (IF)-RT (30 Gy vs 20 Gy) within a combined modality approach. For these patients a central prospective review of all diagnostic imaging was performed by expert radiation oncologists to control the disease extension and to define the IF treatment volume. Based on the simulation films, verification films and radiotherapy CRF an expert panel evaluated retrospectively the adequacy of irradiated IF treatment portals according to the RT prescription, applied radiation doses, treatment time and technical parameters. Between 1999 and 2006 a total of 825/1370 randomized patients in HD10 (60%) and 954/1422 patients in HD11 (67%) were evaluated by the panel. RT was rated as suboptimal in 47% of all reviewed cases. Although the RT study centers got a precise RT prescription, most difficulties occurred in the adequate coverage of the IF as defined in the study protocol (40%) followed by technical faults (12%). Deviations from the prescribed single daily dose (1,8–2 Gy), weekly dose as well as total reference dose were rare (1%). As a consequence, radiation oncologists are trained on the definition of IF-RT at GHSG meetings and at the annual meetings of the German Society for Therapeutic Radiation Oncology (DEGRO). Possible correlations between radiotherapy quality and relapse rate will be investigated.

Identification of Prognostic Factors in Early Unfavorable Stage Hodgkin's Lymphoma (HL): An Individual Patient Data Meta-Analysis.

Background: In patients with early unfavorable stage HL, generally defined as stage I and II patients with mediastinal bulk, elevated ESR, 3 3 involved nodal regions, older age or extranodal involvement, progression-free-survival (PFS) is low compared to patients with early favorable or advanced stages disease. This indicates suboptimal treatment strategies and clinical heterogeneity within the group of patients with early unfavorable stage HL. An international collaborative study was initiated to identify factors that may predict for poor prognosis in this patient group.Methods: Medline and Cochrane Library were systematically searched for randomized controlled trials (n>100 patients per study arm) in early stage HL patients with one or more risk factors receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. Individual patient data were collected and risk factors for PFS (including disease progression, relapse or death) identified using multivariate analysis (linear stepwise proportional hazards) stratified by study.Results: Six studies were identified; data from 4,490 adult patients enrolled between 08/1982 and 01/2003 were available for analysis. The median follow up was 64 months; 663 patients experienced an event leading to an overall 5-year PFS rate of 85% (95% CI 83%–88%). Six factors were significantly (P<0.01) associated with poor PFS: male gender (Hazard ratio (HR) 1.69), age (HR per additional life year 1.03), B symptoms (HR 1.25), anemia (HR per 1 g/dL Hb decrease 1.09), WBC (HR per 1000 WBC increase 1.02) and large mediastinal tumor (HR 1.54). Split into quintiles by predicted risk, observed 5-year PFS rates differed significantly (p<0.001): 80% of patients with early unfavorable stage HL achieved 5-year PFS rates ranging from 84% (95% CI 81%–87%) to 92% (95% CI 90%–94%) while 20% of patients had poor 5-year PFS, i.e. 76% (95% CI 73%–79%). Compared to low risk patients, those with high risk were more often male (81% vs 40%), older (median age 50 vs 29 years) and presented more often with B symptoms (62% vs 28%) and large mediastinal tumor (42% vs 27%). These data show that among stage I and II patients with at least one risk factor heterogeneity exists.Conclusion: Using basic characteristics and routine tests, it is possible to identify a subgroup of early unfavorable stage patients with poor PFS while receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. For these patients, treatment optimization is open to discussion in particular when compared to that of patients with advanced stage disease.