German Inflammatory Bowel Diseases Study Group

Introduction The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant CD4+ and CD8+ T-cells and only few Hodgkin-Reed-Sternberg cells (HRSC). Despite their low abundance, HRSC comprise the neoplastic cell population that intensively interacts with cells of the TME. Understanding these interactions is crucial to the further development of immune checkpoint blockade (ICB) based treatment options. Clinical trials have shown high efficacy of ICB with anti-PD1 antibodies in relapsed HL and more recently promising results of anti-PD1 antibodies in combination with conventional chemotherapy were reported in the first-line setting. (NIVAHL trial, NCT03004833) In solid cancers, anti-PD1 ICB was shown to revert tumor-induced exhaustion of CD4+ and CD8+ T-cells, thereby enabling T-cell activation and a tumor-directed immune response. Since HL differs in many aspects from non-lymphoid tumors due to e.g. loss of HLA-expression, the exact mechanisms of action of ICB in HL is not fully understood and T-cell expansion after anti-PD1 first-line treatment not yet studied. Methods To characterize T-cell activation at different timepoints and to investigate a possible T-cell mediated immune response in HL, we analyzed T-cell Receptor (TCR) repertoires of the NIVAHL study cohort before (tissue: n=90; blood: n=9) and during anti-PD1 treatment (tissue: n=4; blood: n=9). The final cohort comprised additional TCR repertoires of in-house tissue biopsies of treatment-naïve HL (n=18), relapsed HL after chemotherapy (HL-R; n=18)) and publicly available TCR repertoires of the blood of treatment-naïve HL (n=11), HL-R (n=20) and HL-R patients during anti-PD1 treatment (n=20). (Cader et al. Nat Med. 2020 Sep;26(9):1468-1479) TCR repertoires of in-house reactive lymph nodes (n=8, healthy control) and breast cancer (BC; n=6, positive control) patients served as controls for T-cell activation in the tissue, publicly available TCR repertoires of CMV- (n=22, healthy control) and CMV+ otherwise healthy (n=9, positive control) people as controls in the blood. (De Neuter et al. Genes Immun. 2019 Mar;20(3):255-260) TCR repertoires were sequenced by Adaptive Biotechnologies. For each sample, TCR sequences with the same amino acid sequence were aggregated by the sum of their counts. We computed three measures to describe T-cell expansion: debiased Simpson's Clonality (dSC), Percentage of Singletons (PoS), and clonal expansion. Singletons have recently been defined as TCR sequences detected only once in a given sample. Clonal expansion is computed as the percentage of TCR sequences that increase their frequency in a patient from one timepoint to a following by ≥ 2. Results In tissue biopsies, treatment-naïve HL showed a significantly lower dSC compared to treatment-naïve BC and significantly higher dSC compared to RLN from healthy controls. No significant differences could be observed comparing HL with different treatments (during anti-PD1 vs. after chemotherapy) and treatment-naïve HL vs. HL during anti-PD1 treatment. HL and HL-R biopsies showed a significantly lower clonal expansion of Non-Singletons than BC tumors. In peripheral blood, healthy controls, treatment-naïve HL and HL patients during anti-PD1 treatment showed significantly lower dSC in their CD4+ T-cells compared to CMV+ controls and also compared to HL-R patients. We identified significantly higher dSC in CD8+ T-cells compared to CD4+ T-cells in the blood of HL patients before and during any treatment and in relapsed HL. During anti-PD1 treatment, CD8+ T-cells showed a significantly higher clonal expansion of Non-Singletons than CD4+ T-cells in HL-R and a similar but not significant trend in HL. All observed differences in dSC were significant for the PoS too, but as expected by their respective definitions with an opposing pattern (i.e. dSC high = PoS low). Discussion We did not observe features of intratumoral T-cell expansion in primary HL samples, early during anti-PD1 treatment or at relapse after chemotherapy, suggesting that within the HL tissue, T-cell expansion is hampered. However, patterns of T-cell expansion differed between TME and the peripheral blood, where we observed features of CD8+ T-cell clonal expansion, already prior to any treatment. In summary, our findings suggest a possible anti-tumor immune response of CD8+ T-cells in the peripheral blood of HL patients, that is not found in the TME.

Background: Hodgkin lymphoma (HL) arises from transformed B-cells and is one of the most frequent malignancies in young adults. Current clinical challenges include long-term side effects of front-line therapies and difficult-to-treat relapsed/refractory disease. A deconvolution of different HL subtypes based on genetic and tumor microenvironment (TME) features might be the key for an improved understanding of HL pathogenesis and thus improve therapeutic efforts. Aims: To decipher biologically distinct subtypes of HL noninvasively, thus ultimately enabling further individualization of HL therapies. Methods: We performed circulating tumor (ct)DNA sequencing of n=243 patients with HL from the German Hodgkin Study Group (GHSG) HD21 (NCT02661503) and NIVAHL (NCT03004833) trials. We performed non-negative matrix factorization to detect genetically distinct clusters of HL and gene expression profiling of the tumor tissue to assess potential differences in the TME between these clusters. Results: ctDNA sequencing was successful in the majority of patients and yielded mutational frequencies comparable to previously published cohorts by others and us (Spina et. al., Blood, 2018; Camus et. al., Haematologica, 2020; Sobesky et. al., Med, 2021). Using recurrent mutations and copy number variations (CNV) as features, we were able to detect three genetically distinct clusters of HL by non-negative matrix factorization. Interestingly, these clusters showed significant differences regarding several clinical factors. Cluster 1 was defined by high-level 9p24.1 amplifications (harboring PD-1 and PD-L1), a modest mutational burden, high frequency of B-symptoms as a sign of general inflammation, and impaired early response to therapy. In contrast, Cluster 2 depicted a particularly low mutational burden and frequent evidence of Epstein-Barr-Virus (EBV) infection. Cluster 3 was mainly characterized by a high mutational burden, frequent alteration in genes involved in previously described core HL oncogenic pathways and an absence of B-symptoms. Next, we assessed human leukocyte antigen (HLA) haplotypes. Several haplotypes were protective or predisposing for HL when comparing haplotype frequencies to healthy donors. Using HLA haplotypes to predict neoantigens, we found differences in potential neoantigen frequencies between clusters. Strikingly, when assessing the TME through gene expression profiling of tumor tissue, we were again able to detect three distinct subtypes. These subtypes showed high concordance with the previously defined genetic clusters (Fig 1). While the TME of Cluster 1 and Cluster 2 showed significantly different gene expression profiles, Cluster 3 was characterized by a downregulation of most genes enriched in the other clusters. Cluster 2 was mainly characterized by the presence of cytotoxic CD8 cells, NK-cells, neutrophils, and eosinophils, thus indicating an inflammatory TME driven by myeloid cells as well as an adaptive immune response. In contrast, Cluster 1 showed enriched fractions of B-cells, Tfh-cells and Treg-cells, supporting an evasion of the immune response by the underlying HL. Summarizing their individual features, we named the three detected clusters Inflammatory immune escape HL (Cluster 1), EBV/EBV-like HL (Cluster 2), and Oncogenic driven HL (Cluster 3). Summary/Conclusion: We here present a novel biological classification of HL that consists of three distinct subtypes exhibiting different genetic, clinical and TME features. Consequently, this classification might improve the biological understanding of HL and pave the way towards further individualization of HL therapy.Keywords: Hodgkin’s lymphoma, Genetic, liquid biopsy, ctDNA

Zielsetzung PreCycle (NCT03220178), eine multizentrische Phase IV Studie, evaluiert den Einfluss von ePROs auf die Lebensqualität HR+/HER2-metastasierter Brustkrebspatienten, die mit Palbociclib+Aromatasehemmer oder Palbociclib+Fulvestrant behandelt werden. Teilnahmeberechtigte Patienten, die in CANKADO dokumentieren möchten, werden 2:1 in den aktiven (CANKADO PRO-React) oder inaktiven (CANKADO Inform) Arm randomisiert. Primärer Endpunkt ist die Zeit bis zur Verschlechterung (TTD) der Lebensqualität.

Background:The phase 3 ECHELON‐1 study (NCT01712490) demonstrated that brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (A+AVD) was superior to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), in terms of modified progression‐free survival (PFS) per independent review and per investigator, for the frontline treatment of stage 3/4 classical Hodgkin lymphoma (cHL) (Connors JM, et al. N Engl J Med 2018;378: 331–344). The RATHL, and SWOG S0816 studies utilized positron‐emission tomography (PET) scan‐adapted strategies performed after cycle 2 (PET2), demonstrating short‐ and long‐term toxicities in PET2‐positive (PET2+) patients switched to bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), or escalated BEACOPP, and frequent relapses in PET2‐negative (PET2‐) patients. Long‐term follow‐up of patients with stage 3/4 disease who were aged ≤60 years in the RATHL and SWOG S0816 studies demonstrated 3‐year PFS of 79.8% (PET2‐, 82.1%), and 5‐year PFS of 74% (PET2‐, 76%), respectively.Aims:Here we present a 3‐year update of the ECHELON‐1 study to compare the effects of frontline A+AVD vs ABVD in patients with stage 3/4 cHL, including PFS per investigator and outcomes by PET status for the intention‐to‐treat (ITT) population.Methods:Patients with stage 3/4 cHL were randomized 1:1 to receive up to six cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was conducted, patients with Deauville score of 5 at PET2 were allowed to switch to an alternative therapy. All analyses of PFS are exploratory and per investigator assessment.Results:At a median follow‐up of 37 months, analysis of PFS in the ITT population favored the A+AVD treatment arm (Table), with a 3‐year PFS of 83.1% for A+AVD vs 76.0% for ABVD; the 3‐year PFS values for PET2‐ patients aged <60 years were 87.2% vs 81.0%, respectively. A trend toward benefit for PET2+ patients aged <60 years treated with A+AVD was also observed, with a 3‐year PFS of 69.2% vs 54.7% with ABVD.Data from subgroups, together with safety follow‐up, including for peripheral neuropathy, will be presented.Summary/Conclusion:Follow‐up at 3 years demonstrates that frontline treatment of stage 3/4 cHL with A+AVD provides a durable treatment benefit compared with ABVD that is independent of PET2 status. While direct comparisons cannot be made, efficacy with A+AVD appears favorable in the context of findings with PET‐adapted strategies, without requiring interim PET assessment, escalation of therapy, or bleomycin.image

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

Abstract Background: Elderly breast cancer (BC) patients (pts) have been reported to have worse BC-related outcome than younger pts, even within clinical trials such as TEAM. Shak et al. recently showed in a large SEER data analysis that in the high 21-gene recurrence score (RS) group, older pts (>70y) receive less chemotherapy (CT) and have a worse BC-specific mortality than younger pts. Here, we therefore aimed to see whether there are age-related outcome disparities according to RS groups in pts receiving state-of-the-art CT in the prospective WSG PlanB trial. Material and Methods: PlanB compared 6 cycles of anthracycline-free TC vs. standard anthracycline-taxane based CT (4xECà4xDoc) in patients with high risk pN0 (T2-4, G2-3, <35 years, or high uPA/PAI-1) or pN+ HER2- early BC. 21-gene assay was performed in all HR+ tumors and omission of chemotherapy (CT) recommended in RS≤11 HR+ pN0-1 BC. Final analysis for the CT randomization for RS 12-25 after 60 months median follow-up revealed similar 5-year DFS and OS outcomes for both CT arms (ASCO 2017). Results: In all pts with luminal cancer and RS results (n=2577), there was an age-related significant difference in RS risk group assignment (p<0.0001): in young pts (<40y), 9.1% had RS≤11, 52.7% RS 12-25, and 38.2% RS>25; in pts 40-69 years, 18.3% had RS≤11, 61% RS 12-25, and 20.7%% RS>25; in elderly pts (>70y), 19.5% had RS≤11, 55.3% RS 12-25, and 25.2% RS>25. Among patients receiving chemotherapy, RS>25 vs. RS<25 was associated with significantly poorer DFS separately within the elderly subgroup (HR=3.03, 95%-CI [1.15-7.96]) and in those aged 40-69 years (HR=3.14, 95%-CI [2.18-4.52]); there were only nine events among patients <40y. In particular, among pts receiving CT with RS>25, there were no significant differences in DFS between any two of these three age groups. Conclusion: A substantial percentage of elderly patients (> 70y) presents with high-risk luminal disease; these patients are candidates for CT. In PlanB, about 25% of elderly luminal BC patients had high-risk (RS>25) tumors. Nevertheless, after receiving modern adjuvant CT, their DFS was comparable to that of non-elderly pts with high-risk RS tumors. Consequently, older BC pts with high-risk luminal tumors who are fit enough to receive adjuvant CT should be treated according to guidelines in order to overcome age-dependent survival disparities which have been observed in registries for high-RS tumors. Citation Format: Harbeck N, Gluz O, Wuerstlein R, Clemens M, Malter W, Reimer T, Nuding B, Stefek A, Pollmanns A, Augustin D, Uleer C, Lorenz-Salehi F, Shak S, Chao C, Christgen M, Kates R, Kreipe H, Nitz U. No age-related outcome disparities according to 21-gene recurrence score groups in early breast cancer patients treated by adjuvant chemotherapy in the prospective WSG PlanB trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-06.

BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide.