Early Unfavorable Hodgkin Lymphoma Research Articles

P023: PET2-adapted approach after 2 cycles of ABVD is comparable to 2 cycles of BEACOPP escalated and 2 cycles of ABVD and irradiation in early unfavorable Hodgkin lymphoma

Background: PET2-adapted approach after 2 cycles of ABVD reduced treatment intensity in the majority of patients with early stages of classical Hodgkin lymphoma (cHL) according to EORTC H10 trial. GHSG HD17 enabled omission of radiotherapy in PET4-negative early unfavorable HL treated with 2 cycles of BEACOPP escalated and 2 cycles of ABVD (2 + 2 chemotherapy). We compared PET2-adapted approach with 2 + 2 chemotherapy followed by 30 Gy of involved-node radiotherapy (INRT) regardless of interim PET in patients with early unfavorable cHL assessed according to the GHSG risk factors. Methods: Overall, 224 patients with early unfavorable cHL (aged 18–60 years) prospectively observed in the Czech Hodgkin Lymphoma Study Group Registry between 2003–2021 were analyzed. Patients in clinical stage IIB with massive mediastinal tumor and/or with extranodal disease were excluded. Overall, 194 patients received 2 + 2+INRT chemotherapy and 30 patients were treated with PET2-adapted approach: 29 PET2-negative patients received 4 cycles of ABVD and 30 Gy of INRT and one PET2-positive patient was treated with 2 cycles of ABVD plus 2 cycles of BEACOPP escalated and 30 Gy INRT. Results: Median age at the time of cHL diagnosis was 32 (range 18–59) years. Median follow-up was longer in the 2 + 2+INRT group (98.9, range 6.2–211.7) months compared to the PET2-adapted approach (30.8, range 9.8–90.4) months. The 2-year progression-free survival and 2-year overall survival did not differ between two groups (99.5% [95% CI 98.5%–100%]) and 100% [95% CI 100%–100%]), respectively. The rate of patients with neutropenia grade 3 and anemia grade 3 did not differ significantly between both groups (p=0.09 and p=0.60, respectively). Thrombocytopenia was more frequent in the 2 + 2+INRT group (p0.001). Grade 3 non-hematological toxicity occurred in 3 patients in the 2 + 2+INRT group (2 infections, 1 deep vein thrombosis). Conclusion: This retrospective analysis indicates that there is no superiority in progression-free survival and overall survival when comparing 2 + 2 chemotherapy and INRT to PET2-adapted approach. The toxicity is higher in the 2 + 2+INRT group. This work was supported by the following grants AZV NU22-03–00182 from the Ministry of Health of the Czech Republic and Cooperatio Program awarded by the Charles University in Prague in the Czech Republic.

P016: Reduced steroid exposure is safe and does not reduce disease control among Hodgkin Lymphoma patients treated with escalated BEACOPP (eBEACOPP)

Figure 1: PFS (Kaplan-Meier curves): The outcome of EU and AS patients - 5-y PFS 95% vs. 98%, respectively. Full-length vs. shorter steroid courses - 5 y PFS 98% vs. 95%, respectively. Background: eBEACOPP is the most effective chemotherapy regimen for younger patients with early unfavourable (EU) and advanced stage (AS) Hodgkin lymphoma (HL), but is burdened with early and late toxicities. The original 14 days of steroids contributes to side effects, including severe osteoarticular events, like avascular bone necrosis (AVN). We have been using eBEACOPP since 2009 for AS and since 2014 also for EU patients. We started reducing the length of steroid treatment to 8–10 days in 2016, primarily to reduce the risk of AVN. Methods: We analysed outcomes of our patients, focusing on the comparison of EU and AS patients and those receiving full length and shorter steroid courses. Data was obtained retrospectively, from the hospital database. Results: 162 patients received eBEACOPP as front-line treatment, 130 with AS and 32 with EU HL. Median age was 31 y, range 19–59; 88 (54%) were male. After a median follow-up of 58 mo, 5-y PFS of the whole cohort was 97% and OS 98%. The outcome of EU and AS patients was indistinguishable with a 5-y PFS of 95% vs. 98%, respectively (Fig). Outcome of patients receiving full-length or shorter steroid courses was also indistinguishable, with a 5 y PFS of 98% vs. 95% respectively (Fig). The incidence of AVN was numerically, but statistically insignificantly lower in patients receiving 6 cycles of eBEACOPP with a shorter steroid course (1/42 vs. 4/72, p=0.65). There were no differences in emergency hospital admissions and episodes of febrile neutropenia between the two cohorts. Conclusion: eBEACOPP provides excellent and durable first line disease control. Our data confirms the findings of GHSG of lack of outcome differences between different prognostic groups if eBEACOPP is used as primary treatment. Reducing the duration of steroid treatment to 8 days per cycle is safe, but longer follow-up and more patients are needed to confirm that it reduces serious acute and chronic toxicities.

Radiotherapy update: current role of radiotherapy in the treatment of lymphomas

SummaryRadiotherapy (RT) remains an important modality in the modern treatment of lymphomas. In Hodgkin lymphoma (HL), its role is stage-dependent. In early stage favorable HL, RT is an essential component of combined treatment. In early unfavorable and advanced stage HL, RT can be omitted if patients are positron emission tomography-computed tomography (PET-CT) negative after chemotherapy. In non-Hodgkin lymphomas (NHL), RT can be used as definitive treatment of indolent lymphoma. In aggressive NHL, the role of RT is limited to consolidation therapy of bulky disease, extranodal involvement and in elderly patients. Overall, technology evolved from extended fields to involved-node (INRT) and involved-site radiotherapy (ISRT), with concurrent reduction in doses. This short review summarizes current evidence and provides a future outlook with regard to the role of RT in the treatment of lymphomas.

Is It Better to Start Treatment with ABVD and Continue with PET2-Adapted Approach or Should We Use 2 Cycles of Beacopp Escalated and 2 Cycles of ABVD and Irradiation in Early Unfavorable Hodgkin Lymphoma?

Introduction. EORTC H10 trial confirmed better selection of patients who needed reduced or more intensive treatment using PET response after 2 cycles of ABVD in early stages of classical Hodgkin lymphoma (cHL). GHSG HD17 showed that radiotherapy can be safely omitted in PET4-negative early unfavorable HL treated with 2 cycles of BEACOPP escalated plus 2 cycles of ABVD (2+2 chemotherapy). We compared PET2-adapted approach including 30Gy involved-node radiotherapy (INRT) with 2+2 chemotherapy followed by 30 Gy INRT (or involved-field radiotherapy, IFRT) regardless of interim PET in patients with early unfavorable cHL assessed according to the GHSG risk factors.Methods. Overall 243 patients with early unfavorable cHL (aged 18-60 years) prospectively observed in the Czech Hodgkin lymphoma study group registry between 2003-2020 were analyzed. Patients in clinical stage IIB with massive mediastinal tumor and/or with extranodal disease were not included into this analysis as they were treated with BEACOPP escalated only. Chemotherapy 2+2+30 Gy INRT/IFRT received 213 patients. Overall 30 patients were treated with PET2-adapted approach: 29 PET2-negative patients received 4 cycles of ABVD and 30 Gy INRT and one PET2-positive patient was treated with 2 cycles of ABVD plus 2 cycles of BEACOPP escalated and 30 Gy INRT.Results. Median age at the time of cHL diagnosis was 32 (range 18-59) years. Median follow-up was longer in the 2+2+INRT/IFRT group (91.3, range 6.2-211.2) months when compared to the PET2-adapted approach (19.4, range 6.4-90.4) months. The estimated 2-year progression-free survival (PFS) did not differ in both groups (100% [95% CI 100-100] both), however, the estimated 5-year PFS was significantly better in the 2+2+INRT/IFRT group (99.5% [95% CI 98.5-100]) in comparison to PET2-adapted treatment (75.0% [95% CI 32.5-100]), p<0.001. The estimated 5-year overall survival was comparable in both groups (2+2+INRT/IFRT: 99.5% [95% CI 98.5-100]; PET2-guided treatment: 100% [95% CI 100-100]). Hematological toxicity was reported in most of the patients in both groups. Grade 3 non-hematological toxicity occured in 3 patients in the 2+2+INRT/IFRT approach (2 infections, 1 deep vein thrombosis).Conclusion. This retrospective analysis indicates that 2+2+INRT/IFRT is more effective in the long-term disease control, but there is no difference in overall survival in both groups. The current approach includes 2+2 chemotherapy and INRT is added in PET4-positive patients.This work was supported by the Research project Q 28 Progres awarded by the Third Faculty of Medicine of Charles University in Prague in the Czech Republic. DisclosuresBelada: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding.

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%.

Dose-Intensification in Early Unfavorable Hodgkin Lymphoma: Long-Term Follow up of the German Hodgkin Study Group (GHSG) HD14 Trial

Dose-Intensification in Early Unfavorable Hodgkin Lymphoma: Long-Term Follow up of the German Hodgkin Study Group (GHSG) HD14 Trial

Reclassifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation

The presence of bulky disease in Hodgkin lymphoma (HL), traditionally defined with a 1-dimensional measurement, can change a patient's risk grouping and thus the treatment approach. We hypothesized that 3-dimensional measurements of disease burden obtained from baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), would more accurately risk-stratify patients. To test this hypothesis, we reviewed pretreatment PET-CT scans of patients with stage I-II HL treated at our institution between 2003 and 2013. Disease was delineated on prechemotherapy PET-CT scans by 2 methods: (1) manual contouring and (2) subthresholding of these contours to give the tumor volume with standardized uptake value ≥2.5. MTV and TLG were extracted from the threshold volumes (MTVt, TLGt) and from the manually contoured soft-tissue volumes. At a median follow-up of 4.96 years for the 267 patients evaluated, 27 patients were diagnosed with relapsed or refractory disease and 12 died. Both MTVt and TLGt were highly correlated with freedom from progression and were dichotomized with 80th percentile cutoff values of 268 and 1703, respectively. Consideration of MTV and TLG enabled restratification of early unfavorable HL patients as having low- and high-risk disease. We conclude that MTV and TLG provide a potential measure of tumor burden to aid in risk stratification of early unfavorable HL patients.

Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.

Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.

Prognostic Value of Bone Marrow Tracer Uptake Pattern in Baseline PET Scans in Hodgkin Lymphoma: Results from an International Collaborative Study.

PET/CT-ascertained bone marrow involvement (BMI) constitutes the single most important reason for upstaging by PET/CT in Hodgkin lymphoma (HL). However, BMI assessment in PET/CT can be challenging. This study analyzed the clinicopathologic correlations and prognostic meaning of different patterns of bone marrow (BM) 18F-FDG uptake in HL. Methods: One hundred eighty newly diagnosed early unfavorable and advanced-stage HL patients, all scanned at baseline and after 2 adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) courses with 18F-FDG PET, enrolled in 2 international studies aimed at assessing the role of interim PET scanning in HL, were retrospectively included. Patients were treated with ABVD × 4-6 cycles and involved-field radiation when needed, and no treatment adaptation on interim PET scanning was allowed. Two masked reviewers independently reported the scans. Results: Thirty-eight patients (21.1%) had focal lesions (fPET+), 10 of them with a single (unifocal) and 28 with multiple (multifocal) BM lesions. Fifty-three patients (29.4%) had pure strong (>liver) diffuse uptake (dPET+) and 89 (48.4%) showed no or faint (≤liver) BM uptake (nPET+). BM biopsy was positive in 6 of 38 patients (15.7%) for fPET+, in 1 of 53 (1.9%) for dPET+, and in 5 of 89 (5.6%) for nPET+ dPET+ was correlated with younger age, higher frequency of bulky disease, lower hemoglobin levels, higher leukocyte counts, and similar diffuse uptake in the spleen. Patients with pure dPET+ had a 3-y progression-free survival identical to patients without any 18F-FDG uptake (82.9% and 82.2%, respectively, P = 0.918). However, patients with fPET+ (either unifocal or multifocal) had a 3-y progression-free survival significantly inferior to patients with dPET+ and nPET+ (66.7% and 82.5%, respectively, P = 0.03). The κ values for interobserver agreement were 0.84 for focal uptake and 0.78 for diffuse uptake. Conclusion: We confirmed that 18F-FDG PET scanning is a reliable tool for BMI assessment in HL, and BM biopsy is no longer needed for routine staging. Moreover, the interobserver agreement for BMI in this study proved excellent and only focal 18F-FDG BM uptake should be considered as a harbinger of HL.

Thrombosis in Hodgkin Lymphoma Patients: Incidence, Time Points, Risk Factors and Impact of Stage and Treatment

Thrombotic events are regularly observed in patients receiving treatment for Hodgkin Lymphoma (HL). However, sound data on incidence and risk factors are not known. The aim of the present study was thus to provide a comprehensive analysis of thrombotic events after multimodality treatment for HL.A total of 5,773 patients ≤ 60 years treated within the German Hodgkin Study Group (GHSG) trials HD13-15 between January 2003 and December 2009 were included in this analysis. All reported venous and arterial thrombotic events occurring within 1 year after trial enrollment were evaluated and detailed information on patient characteristics, localizations, time of occurrence and risk factors were collected. We excluded thromboses of superficial veins and thrombophlebitis. Descriptive statistics and logistic regression were used for statistical analysis.A total of 193 thrombotic events occurred for an incidence of 3.3%; there were 11 events in early-favorable, 27 in early-unfavorable and 155 in advanced stage HL, resulting in incidence rates of 0.7%, 1.3% and 7.3%, respectively. The incidence in advanced stage HL was significantly higher than in early stage HL (p<0.001); 175 events were venous and 18 arterial. The most common venous events consisted of arm vein thrombosis in 49.1% (n=86), DVT in 29.1% (n=51), PE in 13.1% (n=23) and sinus vein thrombosis in 1.7% (n=3) of cases. The most common arterial events were MI in 55.6% (n=10), lower extremities arterial thromboembolism in 22.2% (n=4) and CVI in 16.7% (n=3) of cases. 30.6% (n=59) of events were associated with intravenous catheters, 8.8% (n=17) were likely due to tumor compression and 1.0% (n=2) occurred despite prophylactic anticoagulation.We found that 2.6% (n=5), 77.2% (n=149) and 20.2% (n=39) of cases occurred before, during and after chemotherapy respectively. In advanced HL patients treated with 8 x BEACOPPesc, 6 x BEACOPPesc or 8 x BEACOPP-14 , the incidence rates were 6.2% (n=44), 5.5% (n=39) and 10.1% (n=72) respectively. The incidence in patients treated with BEACOPP-14 was significantly higher than in patients treated with the other two regimens (p<0.01). Opposed to rather evenly distributed events during chemotherapy with BEACOPPesc, thromboses during treatment with BEACOPP-14 occurred more frequently at the beginning of chemotherapy.We then analyzed potential risk factors in advanced stage patients using logistic regression analysis, adjusting for treatment in order to identify a high-risk group for developing a thrombotic event. The well-established Khorana score was not associated with a higher risk of thrombosis (odds ratio (OR) per unit [95% confidence interval]: 0.91 [0.76-1.1], p=0.33). Additionally, we screened 21 potential risk factors, including the thrombocyte-to-lymphocyte ratio. Only age (OR per year: 1.02 [1.01-1.03], p=0.01) and smoking (OR: 1.61 [1.07-2.43], p=0.02) emerged as significant risk factors. None of the other following potential risk factors was prognostic: thrombocyte-to-lymphocyte ratio, thrombocytes, leukocytes, lymphocytes, hemoglobin, albumin, WHO activity index, erythropoietin treatment, sex, body mass index, B-symptoms, erythrocyte sedimentation rate, extranodal disease, large mediastinal mass, more than 2 affected areas or Ann Arbor stage (all p≥0.10). Yet, when only including venous events, which are potentially preventable by prophylactic anticoagulation, neither age nor smoking were significant risk factors anymore (p≥0.10).This study is the largest and most comprehensive analysis of thrombotic events in HL patients to date. Compared to both, early-favorable and early-unfavorable HL, advanced stage patients are at higher risk for thrombotic events. The most widely used Khorana score estimating thrombosis risk in cancer outpatients was not prognostic in the HL population investigated here. This is unsurprising considering the young age of the patient population investigated. Other risk factors were also not prognostic. This data does not imply a need for prophylactic anti-coagulation in outpatients treated for early-stage HL. In advanced-stage HL patients, routine prophylactic anticoagulation is not warranted. However, individual patients with additional risk factors that could not be evaluated such as history of thrombosis or reduced mobility might still benefit from prophylactic treatment. DisclosuresEngert:Takeda, BMS: Consultancy, Honoraria, Research Funding.

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

The GHSG trial HD11 established 4 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by involved field radiation therapy (IFRT) as the standard of care for patients with early unfavorable Hodgkin lymphoma (HL). Despite these results, practitioners often still recommend 6 cycles of chemotherapy followed by radiation therapy (RT), especially for patients with high risk features. We compared the outcomes of patients treated with 4 vs. 6 cycles of ABVD followed by RT, including patients with bulky disease. We also examined the relapse rates of patients treated with involved site radiation therapy (ISRT) compared with IFRT. One hundred twenty-eight patients diagnosed with early stage, unfavorable HL by GHSG criteria and treated between 2000 and 2013 were identified. Medical records were reviewed for clinical, pathologic, and treatment information as well as toxicities. Clinical outcomes including overall survival (OS) and freedom from relapse (FFR) were estimated for the entire cohort as well as a subset of bulky patients using the Kaplan-Meier method. One hundred twenty-eight patients were included in the study with a median follow-up of 5.0 years. Seventy patients (55%) received 4 cycles of chemotherapy and 58 patients (45%) received 6 cycles. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4 cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6 cycle group. 68% of all patients received ISRT. Six year OS was 100% and 97% for patients receiving 4 and 6 cycles of chemotherapy, respectively (P = 0.35). Six year FFR was 100% and 98% for patients receiving 4 and 6 cycles of chemotherapy, respectively (P = 0.28). A greater proportion of patients received 6 cycles of chemotherapy if treated before 2010 (year of HD11 report) (P = 0.01) and if bulky disease was present (P < 0.01). A greater proportion of patients developed bleomycin pulmonary toxicity in the group receiving 6 cycles of chemotherapy (20% vs 31%, P = 0.16). Six year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P = 0.58). Patients with bulky disease had a median follow up of 4.7 years. Amongst these patients, there were no significant differences in 4 year FFR between the 4 (100%) and 6 (98%) cycle group (P = 0.48). Four year FFR was 100% and 98% for patients receiving IFRT and ISRT, respectively (P = 0.52). There were no deaths in the patient group with bulky disease. Patients diagnosed with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by radiation therapy. Six cycles of chemotherapy does not appear superior in terms of disease control and may provide little added value in this population, even for patients with high risk features such as bulky disease. Increased relapse rates are not seen with ISRT compared to IFRT after 4 cycles of ABVD.

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

The German Hodgkin Study GroupHD11 trial validated 4 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by involved field radiation therapy (IFRT) for early unfavorable Hodgkin lymphoma (HL) patients. However, practitioners often recommend 6 cycles followed by RT, especially for bulky disease. We compared patient outcomes after treatment with 4 or 6 cycles of ABVD followed by RT (IFRT and involved site RT [ISRT]). We identified 128 patients treated for early unfavorable HL (GHSG criteria) between 2000 and 2013. Clinical outcomes (overall survival [OS] and freedom from relapse [FFR]) were estimated using Kaplan-Meier analysis. Toxicities were evaluated. The median follow-up time was 5.0years. Patients received 4 (70 patients, 55%) or 6 (58 patients, 45%) cycles of chemotherapy. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4-cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6-cycle group. For patients receiving 4 and 6 cycles, the 6-year OS was 100% and 97% (P=.35), respectively, and the 6year FFR was 100% and 98% (P=.28), respectively. More patients received 6 cycles if they were treated before 2010 (HD11 report) (P=.01) and if they had bulky disease (P<.01). Sixty-eight percent of patients received ISRT. The 6-year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P=.58). More patients experienced bleomycin pulmonary toxicity in the 6-cycle group (20% vs 31%, P=.16). For patients with bulky disease, the 4-year FFR was similar with receipt of 4 (100%) or 6 (98%) cycles (P=.48) and IFRT (100%) or ISRT (98%) (P=.52). There were no deaths among patients with bulky disease. Patients with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by ISRT. Six cycles of chemotherapy does not appear superior for disease control, even for bulky disease.

Guidelines for the first line management of classical Hodgkin lymphoma

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

XVII. Radiotherapy in early stage Hodgkin lymphoma

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

Gonadal Function in Survivors After Hodgkin Lymphoma (HL) Treatment within the German Hodgkin Study Group (GHSG) HD13–15 Trials.

AbstractAbstract 2636 Purpose:To improve fertility advice in HL patients before treatment and counseling during survivorship, detailed information on the impact of chemotherapy is needed. Therefore, we analyzed gonadal function in survivors after treatment of early favorable, early unfavorable and advanced stage HL. Methods:Women <40 years and men <50 years at diagnosis in ongoing remission at least one year after treatment within the GHSG HD13–15 trials were included. Hormone parameters, menstrual cycle, symptoms of hypogonadism, measures to preserve fertility, pregnancies, and offspring were evaluated. Results:A total of 1,323 (55%) of 2,412 contacted female and male survivors were evaluable for the current analysis. In women and men, mean age at fertility assessment was 32 and 38 years and mean observation time from the end of treatment was 46 and 48 months, respectively. Comparison of the participating and non-participating patients qualifying for our analysis showed no relevant differences. Hormone levels correlated significantly with therapy intensity (p<.001). After 6–8 cycles BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone), mean Anti-Muellerian hormone (AMH) levels in females were 0μg/l and 88.8% of males had Follicle-stimulating hormone (FSH) and inhibin B levels corresponding to oligospermia. Furthermore, low birth rates were observed in survivors after advanced-stage treatment within the observation time (women: 6.5%, men: 3.3%). Regular menstrual cycle was reported by >90% of early-stage HL female survivors and time to resumption of menstrual activity was mostly reached within one year. After advanced-stage treatment, menstrual activity was strongly related to age. 82% of women younger than 30 years had a regular cycle, compared to only 45% in the older age group (p<.001) and time to recovery was considerably longer than in early-stage patients. 34% of women >30 years suffered severe menopausal symptoms (3–4 fold more frequently than expected). In contrast, male survivors had mean levels of testosterone within the normal range and reported no increased symptoms of hypogonadism. Conclusions:The present analysis in a large group of female and male HL survivors provides well-grounded information on gonadal toxicity of the currently used treatment regimens. Accordingly, the results allow a risk adapted planning of fertility preservation before therapy and a comprehensive support during survivorship. Disclosures:No relevant conflicts of interest to declare.

Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma

To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL). One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible. At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4). Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial

In the HD14 trial, 2×BEACOPPescalated+2×ABVD (2+2) has improved the primary outcome. Compared with 4×ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. Women≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women≥30 years (A: 21%, B: 25%). Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time.

Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial

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

Fertility and Gonadal Function After Treatment of Early Unfavorable Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Study Group (GHSG)

Abstract 432 Purpose:Two cycles of BEACOPPescalated followed by two cycles of ABVD (“2+2”) improves the primary outcome in early unfavorable HL patients as shown in the GHSG HD14 trial. Compared to 4xABVD, this benefit might be compromised by more gonadal toxicity in women and men. We thus analyzed gonadal function and fertility of survivors in the HD14 trial. Methods:Women between 18–40 years and men between 18–50 years at diagnosis in ongoing remission at least one year after therapy, treated with either 4xABVD (arm A) or “2+2” (arm B), were included. In women, different hormone parameters (follicle-stimulating hormone (FSH), Anti-Muellerian-Hormone (AMH)) as well as menopausal symptoms, prophylactic measures to preserve fertility, concurrent hormonal treatment, menstrual cycle, pregnancies, and offspring were evaluated. In men, serum levels of FSH, testosterone, and inhibin B were determined as well as symptoms of hypogonadism (aging males symptom scale, AMS) and children after therapy. Results:From a total of 579 women addressed, 331 participated in the present study (57%) and 263 per-protocol treated patients qualified for the comparison of treatment arms (A: 137, B: 126; mean time from end of therapy 42 and 43 months, respectively). The rates of regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. FSH and AMH, reflecting ovarian reserve, were significantly better in arm A and AMH levels were also low after 4xABVD in women >30 years. In contrast, pregnancies after therapy favored arm B (A: 15%, B: 26%, p=0.043) and motherhood rates were equivalent to the German normal population in both arms. A multivariate analysis revealed prophylactic use of GnRH-analogues as highly relevant and significant prognostic factor for preservation of fertility (OR=12.87, p=0.001). Severe menopausal symptoms were reported frequently in women ≥30 years (A: 21%, B: 25%). From a total of 592 men addressed, 322 participated in the present study (54%) and 235 per-protocol treated patients qualified for the comparison of treatment arms (A: 111, B: 124; mean time from end of therapy 43 and 45 months, respectively). Levels of FSH (A: 4.3 U/l, B: 7.7 U/l, p<0.001) and inhibin B (A: 140.7 ng/l, B: 46.9 ng/l, p<0.001) were significantly better in arm A and children after therapy were also more frequently reported after treatment with 4xABVD (A: 12%, B: 5%, p=0.075). However, levels of testosterone and symptoms of hypogonadism were not different between treatment arms. In addition, symptoms of hypogonadism were equivalent as compared to the reference population. Conclusion:With focus on hormonal markers, results of the present study demonstrate higher gonadal toxicity in women and men after the “2+2” regimen compared to 4xABVD. Accordingly, in men, more children after 4xABVD are reported. In women, fertility is not compromised within the evaluated observation time, especially when GnRH-analogues were used. Disclosures:No relevant conflicts of interest to declare.

Radiotherapy for Early Mediastinal Hodgkin Lymphoma According to the German Hodgkin Study Group (GHSG): The Roles of Intensity-Modulated Radiotherapy and Involved-Node Radiotherapy

Cure rates of early Hodgkin lymphoma (HL) are high, and avoidance of late complications and second malignancies have become increasingly important. This comparative treatment planning study analyzes to what extent target volume reduction to involved-node (IN) and intensity-modulated (IM) radiotherapy (RT), compared with involved-field (IF) and three-dimensional (3D) RT, can reduce doses to organs at risk (OAR). Based on 20 computed tomography (CT) datasets of patients with early unfavorable mediastinal HL, we created treatment plans for 3D-RT and IMRT for both the IF and IN according to the guidelines of the German Hodgkin Study Group (GHSG). As OAR, we defined heart, lung, breasts, and spinal cord. Dose-volume histograms (DVHs) were evaluated for planning target volumes (PTVs) and OAR. Average IF-PTV and IN-PTV were 1705 cm(3) and 1015 cm(3), respectively. Mean doses to the PTVs were almost identical for all plans. For IF-PTV/IN-PTV, conformity was better with IMRT and homogeneity was better with 3D-RT. Mean doses to the heart (17.94/9.19 Gy for 3D-RT and 13.76/7.42 Gy for IMRT) and spinal cord (23.93/13.78 Gy for 3D-RT and 19.16/11.55 Gy for IMRT) were reduced by IMRT, whereas mean doses to lung (10.62/8.57 Gy for 3D-RT and 12.77/9.64 Gy for IMRT) and breasts (left 4.37/3.42 Gy for 3D-RT and 6.04/4.59 Gy for IMRT, and right 2.30/1.63 Gy for 3D-RT and 5.37/3.53 Gy for IMRT) were increased. Volume exposed to high doses was smaller for IMRT, whereas volume exposed to low doses was smaller for 3D-RT. Pronounced benefits of IMRT were observed for patients with lymph nodes anterior to the heart. IN-RT achieved substantially better values than IF-RT for almost all OAR parameters, i.e., dose reduction of 20% to 50%, regardless of radiation technique. Reduction of target volume to IN most effectively improves OAR sparing, but is still considered investigational. For the time being, IMRT should be considered for large PTVs especially when the anterior mediastinum is involved.