ALBERT

Beschreibung: Key Points Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients. Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD.

Beschreibung: Background: Metabolic tumor volume (MTV) measured by FDG-PET/CT is becoming established as an independent risk factor for treatment failure in Hodgkin lymphoma (HL). Moreover, response to treatment with novel agents including checkpoint inhibitors may be better reflected by a decrease in MTV than by currently used response criteria. Our aim was to evaluate the early response to first-line HL treatment with the PD-1 inhibitor nivolumab using MTV. Methods: The analysis set included 59 patients with newly diagnosed, early-stage unfavorable HL treated within the prospective, multicenter, open label, randomized, phase II NIVAHL trial of the German Hodgkin Study Group (GHSG). Patients in NIVAHL were randomized to receive either four double cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine (4x Nivo-AVD, group A, n=31) or a sequential therapy starting with 4x nivolumab monotherapy followed by 2xNivo-AVD and 2x AVD (group B, n=28). Early response to treatment was assessed at a 1st interim restaging after either 2x Nivo-AVD or 4x nivolumab. All NIVAHL patients who underwent PET at both initial staging and early response assessment, with images available to the central review panel for quantitative analysis before April 30th 2019, were included. MTV was calculated using a fixed SUV threshold of 4 for both staging and restaging. Results: Patient characteristics of the MTV analysis subset presented here did not differ in any relevant way from the overall NIVAHL trial population. Median age of the 59 patients was 27 years (range 18-57) with a female predominance (61%). All patients presented with stage II disease (IIB 27%) and ≥3 involved areas was the most common risk factor (75%) followed by elevated erythrocyte sedimentation rate (51%), extranodal disease (17%) and large mediastinal mass (14%). Mean MTV at initial staging was 124 ml (range 4 - 578 ml) and 177 ml (11 - 581 ml) in groups A and B, respectively. In both groups a marked decrease in MTV was observed at the 1st interim restaging (Figure 1): After 2x Nivo-AVD all patients in group A showed a reduction of MTV 〉80% (mean percentage change in MTV -99.8%). In group B a reduction of MTV 〉80% was observed in 26/28 patients (93%), while in 2/28 patients an increase

Beschreibung: Background The anti-PD1 antibody nivolumab is approved for relapsed or refractory classical Hodgkin lymphoma (cHL) showing high overall response rates (ORR) and a favorable safety profile. However, complete response (CR) is rare in this setting, and most patients develop progressive disease. To evaluate the efficacy of combined nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) as 1st-line treatment for early-stage unfavorable cHL, we conducted the GHSG NIVAHL trial. Methods NIVAHL is a prospective, randomized, investigator-sponsored single-stage phase II trial that enrolled treatment-naïve early-stage unfavorable cHL patients between 18 and 60 years at 35 German centers (NCT03004833). In arm A, patients received 240mg nivolumab and AVD at standard doses on day 1 and 15 of each 28-day cycle for a total of four cycles (4xNivoAVD). In arm B, the same treatment was administered sequentially, starting with 4x nivolumab in 2-weekly intervals, followed by 2xNivoAVD and 2xAVD. Both groups received 30Gy involved-site radiotherapy (IS-RT). Primary endpoint is the centrally reviewed PET/CT-based CR rate after completion of protocol therapy including IS-RT. 55 patients per group were enrolled in order to exclude a CR rate ≤80% with a power of 90% on a one-sided alpha level of 2.5% each. Secondary endpoints will be analyzed descriptively and include treatment-related morbidity (TRMorbidity), progression-free (PFS), overall survival (OS), response at interim and final restaging as well as patient-reported outcomes. Sequential biopsies, blood and microbiome samples were collected for correlative studies. Results Between 04/2017 and 10/2018, a total of 110 patients were enrolled with one patient disqualified due to alteration of HL diagnosis by central pathology review (N=109, group A n=55, group B n=54). The median age of the predominantly female patients (60%) was 27 years. Stage II was present in 95% of cases with ≥3 involved areas as most common risk factor (69%), followed by elevated ESR (48%), large mediastinal mass (20%) and extranodal disease (13%). Mean duration of chemoimmunotherapy was 15 (standard deviation (SD) 3) weeks and 22 (SD 6) weeks with a mean relative dose intensity of 87.4 (SD 15.9)% and 85.8 (SD 24.2)% in groups A and B, respectively. Severe protocol deviations occurred in 4 patients in group A and 5 in group B. Reasons were toxicity (n=5), patient's wish (n=2), incorrect allocation to early-stage unfavorable risk group (n=1) and progressive disease (n=1). Another 2 patients refused to receive IS-RT. Any adverse events (AEs) were reported for 98% of patients. AEs ≥°3 were observed in 73% and 78%, respectively, and serious AEs occurred in 38% and 28% of patients in groups A and B, respectively. TRMorbidity defined as organ toxicity ≥°3 or anemia, thrombocytopenia or infection °4 was documented in 16% and 22% of patients; all of these were organ toxicities predominantly of liver and gastrointestinal tract, with 19/21 events occurring during the first 2 treatment cycles. Data on ongoing or late toxicities is limited by short follow-up. Until 07/2019, 4 cases of persistent hypothyroidism have been reported. At the 1st interim restaging after 2xNivoAVD and 4x nivolumab, the ORR was 100% (54/54) and 96% (49/51), with a CR rate of 85% and 53% in groups A and B, respectively. Interim remission status was not assessed in 1 and 3 patients, respectively, due to treatment discontinuation after incorrect allocation to early-stage unfavorable risk group (n=1) or toxicity (n=3). After completion of systemic therapy, ORR was 100% (54/54) and 98% (50/51) with a CR rate of 81% and 86%, respectively. One patient in group B developed histologically proven primary progressive HL during nivolumab monotherapy while no other case of progressive or relapsed disease or death has been documented so far. The centrally reviewed CR rate at the end of treatment will be reported at the meeting. Additionally, initial data from currently ongoing histopathologic and immunologic studies will also be presented. Conclusion Concomitant and sequential therapy with nivolumab and AVD is feasible with acceptable toxicity. In early-stage unfavorable cHL, concomitant Nivo-AVD induces a high early CR rate. The interim CR rate observed with 4x nivolumab monotherapy is higher than previously reported in relapsed or advanced-stage disease. The primary endpoint and initial PFS data will be reported at the meeting. Disclosures Bröckelmann: Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding. Kerkhoff:EUSA: Honoraria; Hexal: Honoraria; Celgene: Honoraria, Other: Travel Support; Roche: Honoraria; Novartis: Honoraria. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses. von Tresckow:MSD Sharpe & Dohme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria; Amgen: Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. OffLabel Disclosure: Nivolumab 240mg i.v. 2-weekly for 1st-line treatment of classical Hodgkin lymphoma.

Beschreibung: Background: Detailed knowledge on prognostic factors in patients with rrHL treated with ASCT is essential to determine which patients could benefit from innovative treatment approaches with novel drugs to either improve prognosis or decrease toxicity. In this study we therefore aimed at developing a comprehensive prognostic score for progression free survival (PFS) after ASCT in a large international cohort. Methods: A comprehensive set of risk factors was evaluated in patients of the German Hodgkin Study Group (GHSG) and the French H96 trial in phase I of the study. Potential risk factors at relapse including clinical stage, B-symptoms, extranodal disease, time to relapse (TTR), performance status (ECOG), mediastinal or lung involvement, bulky disease, anemia, lymphopenia, leukocytosis, albumin, LDH, ESR, chemosensitivity and number of salvage regimens were analyzed with multivariable Cox proportional hazards regression analyses. Sensitivity analyses accounted for missing values with covariance based estimation techniques in the full data set. Validation in phase II was performed in patients treated at the Memorial Sloan Kettering Cancer Center and in Danish hospitals. Results: In phase I we identified 656 patients treated with single ASCT after salvage and high-dose chemotherapy (HDCT) from 1993 to 2012.The median age was 35 years and the median follow-up after ASCT was 60 months. All above listed risk factors with exception of LDH, albumin, leuko- and lymphocytes and mediastinal involvement had significant impact on PFS with hazard ratios (HR) from 1.39 to 2.22. The multivariate analysis identified stage IV disease, TTR ²3 months, ECOG ³1, bulk ³5 cm and inadequate response to salvage chemotherapy (= 5 cm RF- 347 76.4% 66.9% 76.0% -- -- RF+ 174 61.5% 50.2% 64.2% 1.73 (1.30,2.31) 1.60 (1.11,2.30) 0.0114 Non-response to salvage (

Beschreibung: Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to anti-programmed-death-receptor-1 (PD1) treatment and characterized by scarce Hodgkin and Reed-Sternberg cells (HRSC) perpetuating a unique tumor microenvironment (TME). Whilst in solid tumors anti-PD1 effects appear largely mediated by cytotoxic CD8+ T-cells, HRSC frequently lack major histocompatibility complex expression and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical response and high interim complete response rate to anti-PD1 based 1st-line treatment was recently reported for patients with early-stage unfavorable cHL treated in the GHSG phase II NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained in NIVAHL patients before and during the first days of nivolumab 1st-line cHL therapy. Mirroring the rapid clinical response, HRSC had disappeared from the tissue within days after the first nivolumab application. The TME shows a reduction of Tr1 T-cells and PD-L1+ tumor associated macrophages (TAM) already at this early timepoint of treatment. Interestingly, neither a cytotoxic immune-response nor a clonal T-cell expansion was observed in the tumors or peripheral blood. These early changes of the TMA were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL suggestive for withdrawal of pro-survival factors rather than induction of an adaptive anti-tumor immune response as main mechanism of action.

Beschreibung: Background The anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (r/r cHL) due to high overall response rates (ORR) with a favorable safety profile. However, complete responses (CR) are rare, and patients eventually develop progressive disease. Treatment options in this situation are very limited and usually regarded palliative. Innovative therapies for patients with progressive r/r cHL or insufficient response to anti-PD1 antibodies are hence an unmet clinical need. Radiotherapy (RT) is highly effective and potentially curative in cHL. Local RT results in immunogeneic cell-death at times leading to immune-mediated systemic effects termed abscopal response (AR). Case reports in different cancers including cHL highlight this effect of local therapies potentially enhanced by systemic immunotherapies. Combining the approved systemic anti-PD1 treatment with local RT to a single cHL lesion might hence work synergistically and result in improved tumor control with limited additional toxicity. It thereby would constitute a viable therapeutic option for patients with r/r cHL and could in the future also be incorporated in earlier lines of therapy. However, prospective data regarding this treatment strategy is lacking and will be generated with the recently activated herein presented GHSG AERN trial. Study Design & Methods AERN is an investigator-sponsored, prospective, international, multicenter, single-arm, two-stage phase II trial (NCT03480334) conducted at 10 European trial sites in Austria, Germany, United Kingdom, Netherlands and Norway. Patients with r/r cHL on active anti-PD1 therapy 〉18 years of age without serious concomitant diseases or organ dysfunction are eligible for enrollment. Patients either have to present with progressive disease (PD) or stable disease (SD) 〉6 months as best response to the ongoing anti-PD1 antibody. After registration for the screening phase, eligibility will be verified by a centralized GHSG review facility who will also define a single target lesion for RT to ensure at least one cHL lesion outside the 10% RT isodose for evaluation of the primary endpoint (abscopal response rate after 6x nivolumab, ARR-6). All patients will receive 240mg nivolumab at 2-weekly intervals and 20 Gy RT to the target lesion at 2 Gy fractions on ten consecutive working days starting day 6 of nivolumab treatment. Nivolumab will be discontinued in case of inacceptable toxicity or further disease progression and continued for a maximum of 18 months within the AERN trial. During the first stage of the trial, 9 qualified patients will be treated and their response to treatment will be centrally evaluated after the first 6 nivolumab doses. If no AR is observed in stage I, the trial will be terminated for futility. Otherwise 20 additional patients will be enrolled into the second stage for a total trial population of 29 r/r cHL patients. The null hypothesis H0: ARR-6 〈 5% will be tested against a one-sided alternative at a confidence level of α = 5%, and at least 4 AR need to be observed for the rejection of H0. Secondary endpoints include e.g. ORR, overall ARR, CR rate, PFS and OS but also feasibility aspects, (S)AEs and quality of life (QoL) measures. To understand the underlying mechanisms of efficacy but also resistance or toxicity a comprehensive set of correlative studies will be conducted. Baseline and sequential blood samples as well as tumor biopsies and rectal swabs for microbiome analyses will be taken during AERN in patients with separate informed consent. This allows detailed evaluation of serological, cellular, functional, histological and genetic parameters to elucidate synergies between anti-PD1 and RT. Ultimately the correlative studies should help to further refine anti-PD1 based combination therapies, ideally beyond the setting of r/r cHL. In summary AERN, to our knowledge, is the first prospective trial formally evaluating the postulated abscopal effect in r/r cHL. The trial addresses an unmet clinical need in r/r cHL patients with insufficient or lost response to anti-PD1 antibodies. AERN additionally will provide proof-of-concept for a synergy of local RT with checkpoint inhibition substantiated by comprehensive correlative studies in blood, tumor tissue and microbiome. Recruitment has started but preliminary data regarding safety or efficacy are not yet available. Figure Disclosures Bröckelmann: MSD Sharpe & Dohme: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding. Greil:Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Sanofi Aventis: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sandoz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. Zijlstra:Janssen: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Illidge:Div of Cancer Sciences, Faculty of Biology, Medicine and Health, Univ of Manchester, National Institutes of Health and Research Biomedical Research Center, Manchester Academic Health Sciences, Christie Hospital National Health Service Foundation Trust: Employment; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses.

Beschreibung: Introduction In comparison to aggressive NHL, CNS involvement is exceedingly rare in patients (pts) with Hodgkin lymphoma (HL). Thus, the clinical features and outcomes are not well described. Patients and Methods For this international retrospective analysis, institutional (n =4), national (n =2) and cooperative group (n =1) databases were reviewed for pts with classical HL who developed histologically proven CNS involvement at any stage during their disease course. We included pts diagnosed with CNS involvement after January 1, 1995 and collected clinicopathological characteristics (at both initial diagnosis and at time of CNS involvement), treatment details and outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method from date of CNS involvement to date of disease progression or death from any cause and death from any cause, respectively. Results We screened 32,047 patients with classical HL in our combined databases and identified 18 pts with histologically confirmed CNS lymphoma, with an estimated crude incidence of 0.05%. These pts had a median age of 40 (range 20 - 84) years at the time of diagnosis of CNS involvement. The characteristics at the time of initial diagnosis of HL are summarized in table 1. CNS involvement was present at the time of initial diagnosis in 10 pts (56%) of whom 3 had isolated CNS involvement and 5 had concurrent systemic involvement (details were unavailable in 2 pts). CNS HL was a feature of relapsed/refractory disease in 8 (44%), 7 of whom had concurrent systemic involvement. The most common presenting symptoms were pyramidal weakness (n=7, 39%), headache (n=5, 28%), sensory change (n=4, 22%) and confusion (n=3, 17%). Lesions were parenchymal (n=10, 62%), leptomeningeal (n=2, 12%) or both (n=4, 25%). The median number of discrete CNS lesions detected by imaging was 1 (range 0 - 〉10), which affected cortical (n=9, 50%) or subcortical structures (n=6, 33%) and the spinal cord (n=2, 11%). The disease appeared to arise from the dura in 9 cases (50%), and the median size of the largest lesion was 2.5 cm (range 1 - 6). Cerebrospinal fluid (CSF) analysis was performed in 10 (56%) pts; of these, cytology was positive in 4 cases with a median CSF white cell count of 10/uL (range 0 - 136). CSF protein was elevated in 7 cases. Immunohistochemistry for Epstein-Barr virus RNA was done on 6 CNS biopsies, of which 3 were positive. Information regarding therapy was available in 15 pts; 9 received radiotherapy (alone (n=4), with steroids (n=1), with systemic (n=2) or intrathecal chemotherapy (n=2)). A further 3 pts were treated with systemic therapy (alternating cycles of R-IVAC/MTX (n=1), brentuximab vedotin (n=1), MTX, cytarabine and thiotepa (n=1), 2 with steroids alone and 1 with surgical resection alone. Of 13 pts formally evaluated for response, 7 (54%) achieved complete and 1 (8%) partial response, for an overall response rate of 62%. 1 patient underwent consolidative autologous stem cell transplantation. After a median follow up of 3.6 (range 0.8 - 13.2) years from diagnosis of CNS involvement, 9 pts experienced disease progression: 1 in the CNS alone, 3 at systemic sites alone, and 5 with both systemic and CNS sites with a median PFS of 9.5 months (Fig 1A). At last follow up, 11 pts have died (6 of progressive disease, 3 from sepsis and 2 from unknown causes) with a median OS of 37 months (Fig 1B). CNS involvement at initial diagnosis vs at relapse (Fig 1C,D) was associated with favorable PFS and OS, whilst isolated CNS involvement was associated with superior PFS but not OS (Fig 1E,F). Conclusion CNS involvement in HL is exceedingly rare and has a distinct clinical presentation with predilection for parenchymal lesions with dural extension (as opposed to true hematogenous spread), providing an important differential diagnosis for meningioma in this setting. CNS HL presenting as an initial manifestation of disease appears to be associated with favorable outcomes. Table 1. Characteristics of patients at initial diagnosis of HL Characteristics at initial diagnosis of HL data avail. n (%) Male 18 11 (61) Histologic subtype 17 Nodular-sclerosing 13 (77) Lymphocyte-rich 3 (18) Lymphocyte-depleted 1 (6) Stage 18 1 2 (11) 2 5 (28) 3 3 (17) 4 8 (44) B sx 18 10 (56) Pruritus 15 3 (20) Nodal size 〉10 cm 14 3 (21) Hb 15 x 109/L 13 2 (15) lymphocytes

Beschreibung: With defined chemotherapy and radiotherapy (RT) and risk-adapted treatment, early-stage classical Hodgkin lymphoma (HL) has become curable in a majority of patients. Hence, a major current goal is to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease (ie, limited stage without risk factors [RFs]) are frequently treated with 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (2×ABVD) followed by 20-Gy involved-field or involved-site RT (IF/ISRT). In patients with early-stage unfavorable disease (ie, limited stage with RFs), 4 cycles of chemotherapy are usually consolidated with 30-Gy IF/ISRT. Compared with 4×ABVD, 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (2×BEACOPPescalated) followed by 2×ABVD improved 5-year progression-free survival (PFS), with similar 5-year overall survival. Recently, treatment strategies based on [18F]fluorodeoxyglucose positron emission tomography (PET) response were evaluated. In early-stage unfavorable HL, a majority of patients achieved a negative interim PET after 2×ABVD and an excellent outcome after 4×ABVD, whereas in those with a positive interim PET, 2×BEACOPPescalated improved 5-year PFS. Furthermore, a PET-guided RT approach was evaluated to decrease long-term toxicity. Although both the RAPID and H10 trials reported poorer disease control without RT, PET-guided omission of RT can constitute a valid therapeutic option in patients with an increased risk of RT-associated toxicity (eg, because of sex, age, or disease localization). Implementation of drugs such as the anti-CD30 antibody-drug conjugate brentuximab vedotin or the anti–programmed death 1 antibodies nivolumab or pembrolizumab might allow further reduction of overall mortality and improve quality of life in affected patients.

Beschreibung: The DNA double-strand break (DSB) is the most cytotoxic lesion and compromises genome stability. In an attempt to efficiently repair DSBs, cells activate ATM kinase, which orchestrates the DNA damage response (DDR) by activating cell cycle checkpoints and initiating DSB repair pathways. In physiological B cell development, however, programmed DSBs are generated as intermediates for effective immune responses and the maintenance of genomic integrity. Disturbances of these pathways are at the heart of B cell lymphomagenesis. Here, we review the role of DNA repair and cell cycle control on B cell development and lymphomagenesis. In addition, we highlight the intricate relationship between the DDR and the tumor microenvironment (TME). Lastly, we provide a clinical perspective by highlighting treatment possibilities of defective DDR signaling and the TME in mantle cell lymphoma, which serves as a blueprint for B cell lymphomas.

Beschreibung: Background The primary analysis of the investigator-sponsored randomized multicenter phase II GHSG NIVAHL trial showed feasibility and excellent short-term efficacy of anti-PD1 based 1st-line treatment of early-stage unfavorable classical Hodgkin lymphoma (cHL). Achieving long-term disease control without excessive treatment-related morbidity is of utmost importance when developing innovative 1st-line cHL therapies. Duration of response and development of persisting immune-related toxicities are of concern in the setting of 1st-line anti-PD1 treatment. Methods NIVAHL enrolled treatment naïve early-stage unfavorable cHL patients at 28 German centers and individuals were randomized to either receive fully concomitant 4x Nivo-AVD (group A) or sequential 4xnivolumab, followed by 2x Nivo-AVD and 2x AVD (group B). Both groups received consolidative 30Gy IS-RT and the primary endpoint was complete response (CR) rate at end of study treatment. Detailed methods, patient characteristics and the primary endpoint analysis of NIVAHL have been recently published (Bröckelmann PJ et al. JAMA Oncol 2020). Herein we present extended follow-up of the NIVAHL trial to assess efficacy in terms of 2-year progression-free (PFS) and overall survival (OS) as well as safety with regards to long-term toxicities or organ impairment documented during the first year of follow-up after treatment. Results A total of 109 patients with cHL confirmed by central pathology review were enrolled between 04/2017 - 10/2018 and followed for a median of 20 and 21 months in groups A (n=55) and B (n=54), respectively, for the present analysis. All of the 7 patients deemed in partial remission (PR) at end of study treatment (EOT) converted into an ongoing CR after end of study without additional treatment during follow-up. With no relapse and no death observed since the primary analysis, the 2-year PFS estimates are 100% and 98% (95%CI 88-100%) in groups A and B, respectively, and the 2-year OS is 100% in both groups. With a median observation time for late-toxicities of 14 months after EOT (range 6-26 months) among 103 patients, any potentially treatment-related AE during follow-up was reported in 65% of patients (A: 74%, B: 56%). The highest documented CTCAE grade of late AEs was °I in 33%, °II in 25% and °III in 7% of patients with no °IV-V AEs observed. A total of 54% had at least one late event related to AVD, 47% to nivolumab and 32% to RT, with multiple relations attributable per event. Mean FEV1 and DLCOc did not decrease from baseline (91.1% -〉 96.4% and 86.2% -〉 83.3%, respectively). Decreased LVEF after EOT was reported in 2/56 patients with available data (4%). After EOT, 18% of patients required medication for adverse events. Corticosteroid ≥ and 〈 10mg prednisolone equivalent was required in 3% and 2% of patients, respectively, for a toxicity at any time during follow-up. No patient required corticosteroid treatment at last available follow-up. Most frequent toxicities reported after EOT included fatigue (21%), hypothyroidism (17%), respiratory tract disorders (16%), leukopenia (14%) and nervous system disorders (14%). Hypothyroidism was the event most frequently solely attributed to nivolumab during follow-up. The median time to onset after EOT was 5 months and affected patients nearly exclusively female (15/16 [94%]). After median follow-up of 10 months (range 0-21), hypothyroidism remained unchanged in 10 of 16 affected patients and resolved in 3 patients. Conclusion The excellent disease control of concomitant and sequential nivolumab and AVD in early-stage unfavorable cHL is confirmed with the currently available follow-up. Treatment-related toxicities ongoing or emerging during follow-up are predominantly associated with chemo- and/or RT. The most frequent nivolumab-associated late toxicity is hypothyroidism. No patient currently requires chronic corticosteroid treatment. Disclosures Bröckelmann: Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD Sharp & Dohme: Research Funding. Keller:Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau. Meissner:Celgene: Other: Travel support; Bristol Myers Squibb: Other: Travel support; Takeda: Other: Travel support; Merck Sharp & Dohme: Other: Travel support; Hexal: Other: Travel support. Trautmann:Bristol Myers Squibb: Honoraria. Kerkhoff:BMS: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Lead Discovery Center GmbH: Consultancy; Seattle Genetics: Research Funding; Gilead: Honoraria; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zimmermann:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb: Other: Travel Expenses; MSD: Other: Travel Expenses; Novartis: Other: Travel Expenses. Fuchs:Bristol Myers Squibb: Honoraria, Research Funding; Affimed: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria. von Tresckow:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD Sharp & Dohme: Honoraria, Research Funding; Roche: Honoraria; Kite/Gilead: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Borchmann:Takeda: Research Funding; Bristol Myers Squibb: Research Funding. Engert:Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Takeda: Honoraria, Research Funding; MSD Sharp & Dohme: Honoraria; AstraZeneca: Honoraria; Sandoz: Honoraria. OffLabel Disclosure: Nivolumab 240mg Q2W alone or in combination with AVD for 1st-line treatment of classical Hodgkin lymphoma.