German Hodgkin Study Group Criteria Research Articles

P069: Characterisation of influencing parameters on oocyte quality preservation in a cohort of Hodgkin lymphoma patients

Background: Hodgkin lymphoma (HL) is the most frequent lymphoma in the young population. The standard of treatment is chemotherapy including alkylating agents known to affect fertility. Fertility preservation is usually proposed before treatment with oocyte cryopreservation as a reference. In different cohorts of healthy women, some factors are well known to have an impact on oocyte quality preservation such as age, anti-Müllerian hormone (AMH), body mass index (BMI). German Hodgkin Study Group (GHSG) distinguishes 3 prognostic groups: early, intermediate, advanced stages (respectively defined GHSG I, II, III in our study). In literature, the parameters influencing fertility preservation outcomes in HL are not clear, namely HL’s stage and inflammation. In this study we evaluated the impact of HL’s stage using GHSG criteria on fertility preservation outcomes. Methods: We performed a retrospective study on 79 women, with newly diagnosed and previously untreated HL who underwent oocyte cryopreservation between 2012 and 2021. The patients were extracted from a cohort of fertility observatory in Lille University Hospital. The primary outcome was the number of metaphase 2 oocyte retrieved (M2). Estradiol level at the ovulation induction and the ratio of M2/follicles >15mm were secondary outcomes. We compared fertility outcomes between two groups: early and intermediate stage (GHSG I+II) and advanced stage (GHSG III). We evaluated in univariate and multivariate analyses the following factors: AMH, BMI, use of hormonal contraception, age and C reactive protein (CRP). Results: The two groups (GHSG I-II and GHSG III) were comparable. In univariate analyses, AMH was the only statistically significant factor regarding the number of M2 (p<0,0001) and Estradiol level (p<0,0001). In multivariate analysis, GHSG score was not statistically significant concerning Estradiol level (p=0,5) contrary to AMH level (p<0,0001). Conclusion: In our study, AMH level is doubtlessly a factor impacting the quality of oocyte preservation. HL’s stage and inflammation do not seem to affect fertility preservation outcomes in the whole cohort. These results, based on the largest cohort of HL patients evaluating HL’s risk groups provide important information about expected cryopreservation outcomes. According to this study, oocyte cryopreservation should be considered even for patients with advanced HL’s stage.

Assessment of Radiation Doses Delivered to Organs at Risk Among Patients With Early-Stage Favorable Hodgkin Lymphoma Treated With Contemporary Radiation Therapy

Response-adapted randomized trials have used positron emission tomography-computed tomography to attempt to identify patients with early-stage favorable Hodgkin lymphoma (ESFHL) who could be treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) without radiation therapy (RT). While maximal efficacy is demonstrated with combined modality therapy, RT is often omitted in fear of late adverse effects; however, the application of modern RT could limit these toxic effects. To determine the radiation doses delivered to organs at risk with modern involved-site RT among patients with ESFHL treated with 20 Gy after 2 cycles of ABVD. This case series included 42 adult patients with ESFHL (according to the German Hodgkin Study Group criteria) who were treated between 2010 and 2019, achieved complete response by positron emission tomography-computed tomography (1-3 on 5-point scale) following 2 cycles of ABVD, and then received consolidative RT. The study was conducted at a single comprehensive cancer center. 2 cycles of chemotherapy followed by 20-Gy involved-site RT. The medical records of patients with ESFHL were examined. Organs at risk were contoured, and doses were calculated. Progression-free survival, defined from date of diagnosis to disease progression, relapse, or death, and overall survival were estimated using the Kaplan-Meier method. The cohort comprised 42 patients with ESFHL (median [range] age at diagnosis, 35 [18-74] years; 18 [43%] women; 24 [57%] with stage II disease). At a median follow-up of 44.6 (95% CI, 27.6-61.6) months, the 3-year progression-free survival and overall survival rates were 91.2% (95% CI, 74.9%-97.1%) and 97.0% (95% CI, 80.4%-99.6%), respectively. The mean heart dose was less than 5 Gy (mean, 0.8 Gy; SD, 1.5 Gy; range, 0-4.8 Gy) in all patients. The mean (SD) breast dose for both breasts was 0.1 (0.2) Gy (left breast range, 0-1.0 Gy; right breast range, 0-0.9 Gy). In this study, combined modality therapy with 2 cycles of ABVD and 20 Gy for ESFHL was highly effective and avoided excess doses to organs at risk, which may limit long-term toxic effects.

Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma

In early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL. To evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL. This was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible. Systemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy. Complete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group. Of 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy. Both strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL. ClinicalTrials.gov Identifier: NCT03004833.

A Pilot Study of Brentuximab Vedotin Combined with AVD Chemotherapy and Radiotherapy in Patients with Newly Diagnosed Early Stage, Unfavorable Risk Hodgkin Lymphoma

A Pilot Study of Brentuximab Vedotin Combined with AVD Chemotherapy and Radiotherapy in Patients with Newly Diagnosed Early Stage, Unfavorable Risk Hodgkin Lymphoma

Low-Dose Consolidation Radiation Therapy for Early Stage Unfavorable Hodgkin Lymphoma

The German Hodgkin Study Group (GHSG) trial HD11 established 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and 30 Gy of radiation therapy (RT) as a standard for early stage (I, II), unfavorable Hodgkin lymphoma (HL). Additional cycles of ABVD may allow for a reduction in RT dose and improved toxicity profile. Patients treated with combined modality therapy at the Duke Cancer Institute for early stage, unfavorable HL by GHSG criteria from 1994 to 2012 were included. Patients who did not undergo post-chemotherapy functional imaging (positron emission tomography or gallium imaging) or who failed to achieve a complete response were excluded. Clinical outcomes were estimated using the Kaplan-Meier method. Late effects were also evaluated. A total of 90 patients met inclusion criteria for analysis. Median follow-up was 5 years. Chemotherapy consisted primarily of ABVD (88%) with a median number of 6 cycles. The median dose of consolidation RT was 23.4 Gy. Four patients had relapses, 2 of which were in-field. Ten-year progression-free survival (PFS) and overall survival (OS) were 93% (95% confidence interval [CI]: 0.82-0.97) and 98% (95% CI: 0.92-0.99), respectively. For the subset of patients (n=46) who received 5 to 6 cycles of chemotherapy and ≤ 24 Gy, the 10-year PFS and OS values were 88% (95% CI: 70%-96%) and 98% (95% CI: 85% - 99%), respectively. The most common late effect was hypothyroidism (20%) with no cardiac complications. Seven secondary malignancies were diagnosed, with only 1 arising within the RT field. Lower doses of RT may be sufficient when combined with more than 4 cycles of ABVD for early stage, unfavorable HL and may result in a more favorable toxicity profile than 4 cycles of ABVD and 30 Gy of RT.

Safety and Early Efficacy in an Ongoing Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 30 Gray Involved-Site Radiotherapy for Newly Diagnosed, Early Stage, Unfavorable Risk Hodgkin Lymphoma

Background: Brentuximab vedotin has not been previously studied in combination with combined modality therapy for the frontline treatment of early stage Hodgkin lymphoma. We designed a pilot study to assess the safety and early efficacy of four cycles of brentuximab vedotin (BV) + AVD chemotherapy followed by 30 Gray involved-site radiotherapy (ISRT) for the treatment for early stage, unfavorable risk HL.Methods: Patients with newly diagnosed, stage I/II, classical HL with unfavorable risk profile (defined by the German Hodgkin Study Group (GHSG) with one of the following criteria: bulky mediastinal mass (≥1/3 maximum transverse thoracic diameter on PA-CXR or ≥10cm by CT imaging in transaxial plane), ESR≥50mm/h or ESR≥30mm/h in patients with “B” symptoms, extranodal involvement, or >2 involved lymph node sites) were eligible. Patients with stage IIB disease with disease bulk or extranodal involvement were included (conventionally classified as advanced stage per GHSG). Patients were treated with four cycles of brentuximab vedotin 1.2 mg/kg with AVD chemotherapy every 2 weeks followed by 30 Gray involved-site radiotherapy. The primary endpoint of the study was to evaluate the safety of this regimen, with particular attention to the development of pulmonary toxicity. A PET/CT was performed after 2 and 4 cycles of therapy. PET scans were interpreted using the Deauville 5-point scale and a negative scan was defined as Deauville 1-3.Results: Interim data for the first 19 of a planned 30 patients enrolled are presented here. Median age was 32 (range, 18-50), 47% female, 100% stage II disease, 53% with disease bulk by GHSG criteria, 53% elevated ESR, 34% B-symptoms, 37% extranodal involvement, 42% >2 involved lymph node sites. All patients with disease bulk had large anterior mediastinal masses measuring >10cm by CT in transverse plane (range, 10-16.9 cm). There were eight patients enrolled who would be considered to have advanced stage disease by the GHSG classification: 3 with IIBX, 3 with IIBE, and 2 with IIBXE disease. To date, 79% (15/19) and 63% (12/19) have completed interim PET-2 and PET-4 imaging studies, respectively. Ninety-three percent of patients (14/15) achieved a negative PET scan after 2 cycles (6, 8, and 1 patients achieved Deauville score of 2, 3, 4, respectively). All patients with disease bulk were PET-2 negative (10/10). Ninety-two percent of patients achieved a negative PET scan after 4 cycles of therapy (1, 8, 2, and 1 patients achieved Deauville score of 1,2,3,4, respectively). The patient with a positive PET-4 scan had a subsequent positive biopsy and will be treated off study for primary refractory HL. The study treatment has been well-tolerated. No pulmonary toxicity has been observed. Serious adverse events have been documented in two patients: febrile neutropenia and grade 3 hypertension. One patient discontinued protocol treatment due to the development of grade 3 peripheral neuropathy after one treatment with BV+AVD. The four patients who have completed combined modality therapy and an end-of-treatment imaging assessment achieved complete responses and no relapses have occurred to date.Conclusion: The combination of BV+AVD chemotherapy followed by ISRT appears well-tolerated with no early signal of increased pulmonary toxicity. In this interim analysis of 19 newly diagnosed patients with early stage, unfavorable risk HL, over ninety percent of the evaluable patients have achieved negative interim PET scans after 2 and 4 cycles of BV + AVD, suggesting this is a highly active treatment program even in patients with substantial disease bulk. Updated safety and response data will be presented at the meeting. DisclosuresHamlin:Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding; Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Amgen: Consultancy; Bristol Myers Squibb,: Consultancy; Jannsen: Consultancy. Matasar:Genentech: Consultancy; Spectrum: Consultancy. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding.

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.

Comparison of dose-dense ABVD and standard ABVD in the treatment of early unfavorable and advanced Hodgkin’s lymphoma: A retrospective analysis

This retrospective analysis compared standard regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with the dose-dense ABVD regimen (ABVD-21) in terms of efficacy and toxicity. Patients who had early-stage unfavorable or advanced Hodgkin's lymphoma (HL) according to German Hodgkin Study Group criteria from March 1999 to February 2011 were analyzed for treatment response, long-term survival and hematological toxicity. There were 85 patients in the ABVD-21 group and 118 patients in the ABVD group respectively. The complete remission rates after completion of treatment were 92.9% and 90.7% for ABVD-21 and ABVD, respectively. During a median follow-up period of 62 months, no significant difference was found in projected 10-year progression-free survival (PFS) and overall survival (OS) rates (84.7% and 94.1% respectively for ABVD-21; 81.4% and 91.5% for ABVD). Subgroup analyses showed that ABVD-21 was significantly better than ABVD for patients with IPS≥3 in terms of PFS and OS rates. Grade 3 to 4 leukopenia (51.8% vs. 28.8%, P=0.001) and neutropenia (57.6% vs. 39.0%, P=0.009) were more common with ABVD-21. We were led to conclude that dose-dense ABVD did not result in better tumor control and overall survival than did ABVD for early-stage unfavorable HL. However, patients at high risk, for example, with IPS≥3, may benefit from dose-dense ABVD.

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

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

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

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

Efficacy of Abbreviated Stanford V Chemotherapy and Involved Field Radiotherapy in Early Stage Hodgkin's Disease: Mature Results of the G4 Trial.

Abstract 1670Poster Board I-696The standard management for early stage Hodgkin's disease (HD) is combined modality therapy. In the G4 protocol, patients (pts) with non-bulky, supra-diaphragmatic stage I-IIA disease received 8 weeks of Stanford V chemotherapy + 30 Gy involved field radiotherapy (IFRT).87 pts were enrolled and treated between 4/1996 and 4/2001. Median age was 30 years (16-59) and stages were IA (n=23), IIA (n=64). Unfavorable risk factors were present in 47 patients (54%) according to German Hodgkin Study Group (GHSG) criteria (> 2 AA sites, ESR > 50 or EN involvement) and 38 (44%) according to EORTC criteria (> 3 AA sites, ESR > 50). Therapy was well tolerated with grade 3-4 non-hematologic toxic events in 7 % of pts. These included constipation (n=3), peripheral neuropathy (n=1), generalized weakness (n=2), chest pain (n=1), mylagias (n=1), abdominal pain (n=1) and an allergic reaction to etoposide (n=1). 42 patients received cytokine support for grade 3-4 neutropenia however only 2 pts developed fever with neutropenia. No cases of clinical bleomycin toxicity or radiation pneumonitis were observed. At a median follow-up of 9 (2-12) years, freedom from progression (FFP) and survival (OS) are 94% and 96% respectively. FFP was 100% for favorable and 89% for unfavorable patients by GHSG criteria (p=0.04) with no differences in OS (96.9% versus 95.7%). All relapses (n=5) occurred in the RT field: limited in 2 patients and combined with distant disease in 3 pts. All relapses were in “unfavorable” risk patients: 5 per GHSG and 4 per EORTC criteria. Secondary therapy included chemotherapy followed by high dose therapy and stem cell support (n=3) and ABVD (n=2). Three pts died, 2 due to disease progression after second-line therapy and one due to metastatic colon cancer. 5 patients developed a second cancer (2 breast, 2 melanomas at unirradiated sites and 1 colon cancer). The cases of breast cancer were considered unrelated to RT as both occurred within 5-years of therapy in women who were > 30 yrs at time of treatment. No secondary AML and no late cardiac or pulmonary toxicities have been observed.In conclusion, for pts with non-bulky stage I/II A HD, abbreviated Stanford V with 8 weeks of chemotherapy and 30 Gy IFRT is a safe and highly effective regimen. It is still too early to assess potential RT-related complications. Our outcomes in “unfavorable” stage I-IIA patients without bulky or symptomatic disease compare favorably with more intensive or prolonged regimens employed by the GHSG and EORTC. DisclosuresNo relevant conflicts of interest to declare.