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Serial circulating tumor DNA sequencing reveals clonal dynamics and can offer treatment guidance in relapsed/refractory diffuse large B-cell lymphoma B Introduction: b Despite recent advances in the treatment of relapsed/refractory (rr)DLBCL, most patients still face progression and death. B Results: b Most patients presented with stage III/IV disease (88.4%), intermediate (58.1%) or high risk (31.4%) international prognostic index (IPI), and received CAR-T cells, high-dose chemotherapy and autologous stem cell transplantation, or other approved treatments. [Extracted from the article]

Purpose: Current clinical challenges in Hodgkin lymphoma (HL) include difficult-to-treat relapsed/refractory disease and considerable long-term toxicities of treatment. Since clinical risk factors lack discriminatory power, intensity of therapy is mainly based on tumor burden. Exploring HL genetics and tumor microenvironment (TME) might provide valuable insights for improved risk stratification., Materials and Methods: In this study, we applied circulating tumor DNA sequencing to 243 patients obtained from pivotal German Hodgkin Study Group trials to identify subtypes of HL. Independent validation of the subtypes was performed in 96 patients treated in the EuroNet-PHL-C2 study. Outcome differences of subtypes were assessed in an event-enriched clinical validation cohort comprising 72 patients from the HD21 trial, using a refined, validated, and clinically feasible assay., Results: We propose a biologic classification of HL consisting of three distinct subtypes: inflammatory immune escape HL is characterized by frequent copy-number variations including immune escape variants such as high-level amplifications of the PD-L1 locus and an inflammatory TME. Virally-driven HL is associated with Epstein-Barr virus and/or human herpesvirus 6 and an inflammatory TME with neutrophils and macrophages, while the tumor mutational burden (TMB) is low. Oncogene-driven HL is defined by a high TMB, recurrent mutations in oncogenic drivers such as TNFAIP3 , ITPKB , and SOCS1 , and a cold TME. A refined and validated assay version aiming at clinically feasible risk stratification showed significant progression-free survival differences between subtypes. In addition, assessment of minimal residual disease (MRD) allowed for the detection of patients at very high risk of relapse within the subtypes., Conclusion: We propose a clinically feasible, noninvasive method for individualized risk stratification and MRD monitoring in patients with HL on the basis of circulating tumor DNA sequencing.

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost- and time-sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof-of-principle for its ability to predict outcomes., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Abstract: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Hodgkin lymphoma is a B-cell lymphoma often affecting young adults. Outcomes following intensive chemo- and radiotherapy are generally favourable but leave patients at high risk for early and late toxicities frequently reducing quality of life. Relapsed/refractory disease is regularly difficult to treat and ultimately results in death in a relevant subset of patients. Current strategies for risk stratification and response evaluation rely on clinical features and imaging only, and lack discriminatory power to detect patients at risk for disease progression. Here, we explore how circulating tumor DNA sequencing might help to overcome these shortcomings. We provide an overview over recent technical and methodological developments and suggest potential use cases for different clinical situations. Circulating tumor DNA sequencing offers the potential to significantly augment current risk stratification strategies with the ultimate goal of further individualizing treatment strategies for patients with HL., Competing Interests: Declaration of Competing Interest JMH is an advisor/consultant for Miltenyi; reports research funding from Incyte and Novartis; and reports travel support from Kite-Gilead and Novartis. Sven Borchmann is a shareholder and has a leadership role in Liqomics and is a consultant for Galapagos. The other authors declare no potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Single-agent immunotherapy has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of antigenic determinants on tumor cells. Creating an antigen-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an antigenic determinant is not known is a major challenge., Methods: We use multiple cell line and poorly immunogenic syngeneic, autochthonous, and autologous mouse models to evaluate the efficacy of a novel combination immunotherapy named tripartite immunotherapy (TRI-IT). To elucidate TRI-ITs mechanism of action we use immune cell depletions and comprehensive tumor and immune infiltrate characterization by flow cytometry, RNA sequencing and diverse functional assays., Results: We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells, cytokine-induced killer cells, Vγ9Vδ2-T-cells (γδ-T-cells) and T-cells enriched for tumor recognition (CTLs) display synergistic antitumor effects, which are further enhanced by cotreatment with anti-PD1 antibodies. Most strikingly, the full TRI-IT protocol, a combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, eradicates and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT coactivates adaptive cellular and humoral, as well as innate antitumor immune responses to mediate its antitumor effect without inducing off-target toxicity., Conclusions: Overall, TRI-IT is a novel, highly effective, antigen-agnostic, non-toxic combination immunotherapy. In this study, comprehensive insights into its preclinical efficacy, even in poorly immunogenic tumors, and mode of action are given, so that translation into clinical trials is the next step., Competing Interests: Competing interests: SB has received travel support from BMS and travel support and consulting fees from Takeda. SB received research funding form Takeda, but this funding did not support the research described in this paper. DK is a cofounder of XRAD Therapeutics, which is developing radiosensitizers. DK is the recipient of a Stand Up To Cancer (SU2C) Merck Catalyst Grant studying pembrolizumab and radiation therapy in sarcoma patients. DK has received research funding from XRAD Therapeutics, Eli Lilly & Co., Bristol Myers Squibb, Varian Medical Systems, and Merck, but this funding did not support the research described in this paper. CR received consulting and lecture fees from Abbvie, Astra-Zeneca, Vertex and Merck. CR received research funding from Gilead Pharmaceuticals. CR is a cofounder of CDL Therapeutics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA., Methods: We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform., Findings: We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction., Conclusions: Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease., Funding: Mildred Scheel School of Oncology Aachen-Bonn-Cologne-Düsseldorf MD Research Stipend, Next Generation Sequencing Competence Network grant 423957469, Deutsche Krebshilfe grant 70112502, Deutsche Forschungsgemeinschaft (DFG) grant EN 179/13-1, the HL MRD consortium, and the Frau-Weiskam und Christel Ruranski-Stiftung., Competing Interests: Declaration of Interests P.J.B. reports research grants from BeiGene, Bristol Myers Squibb, Merck Sharpe & Dohme, and Takeda and personal fees and non-financial support from Bristol-Myers Squibb, Celgene, and Takeda, all outside the submitted work. S.S. received travel grants from GSK. D.M.P. reports being founder and CSO of Exbiome and an occasional advisor for Takeda. B.v.T. reports personal fees and nonfinancial support from Bristol-Myers Squibb; personal fees from Amgen, Pfizer, Gilead Sciences, Pentixapharm, and Roche; grants, personal fees, and nonfinancial support from MSD and Takeda; and grants, personal fees, and nonfinancial support from Novartis. S.B. reports being founder, CEO, and shareholder of Liqomics and personal fees and non-financial support from Bristol-Myers Squibb and Takeda outside the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)