Search

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.)

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]

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.)

Diagnosis is the most important step in different diseases, especially in cancers and blood malignancies. There are different methods in order to better diagnose of cancer, but many of them are invasive and also, some of them are not useful for immediate diagnosis. Cell-free DNA (cfDNA) or liquid biopsy easily accessible in peripheral blood is one of the non-invasive prognostic biomarkers in various areas of cancer management. In fact, amounts of cfDNA in serum or plasma can be used for diagnosis. In this review, we have considered some cancers such as hepatocellular carcinoma, lung cancer, breast cancer, and hematologic malignancies to compare the various methods of cfDNA diagnosis. Highlights: The result of early diagnosis along with correct treatment decreases morbidity. Cell-free DNA is a non-invasive way of diagnosing the presence of tumor cells in earlier stages of cancer. DNA released from both solid tumors and hematologic malignancies is usable in this method. Genetic feature of cancer cells at different stages can help in prescribing the amount and type of drugs. [ABSTRACT FROM AUTHOR]

Lymphoma is a highly heterogeneous lymphohematopoietic tumor. As our understanding of the biological and pathological characteristics of lymphoma improves, we are identifying an increasing number of lymphoma subtypes. Genotyping has enhanced our ability to diagnose, treat, and monitor the prognosis of lymphoma. Despite significant improvements in treatment effectiveness, traditional methods for assessing disease response and monitoring prognosis are imperfect, and there is no significant improvement in overall remission rates for lymphoma patients. Minimal Residual Disease (MRD) is often indicative of refractory disease or early relapse. For lymphoma patients, personalized MRD monitoring techniques offer an efficient means to estimate disease remission levels, predict early relapse risk, and assess the effectiveness of new drug regimens. In this review, we delve into the MRD procedures in lymphoma, including sample selection and requirements, detection methods and their limitations and advantages, result interpretation. Besides, we also introduce the clinical applications of MRD detection in lymphoma. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) represents a neoplasm primarily affecting adolescents and young adults, necessitating the development of precise diagnostic and monitoring tools. Specifically, classical Hodgkin lymphoma (cHL), comprising 90% of cases, necessitating tailored treatments to minimize late toxicities. Although positron emission tomography/computed tomography (PET/CT) has enhanced response assessment, its limitations underscore the urgency for more reliable progression predictive tools. Genomic characterisation of rare Hodgkin Reed-Sternberg (HRS) cells is challenging but essential. Recent studies employ single-cell molecular analyses, mass cytometry, and Next-Generation Sequencing (NGS) to unveil mutational landscapes. The integration of liquid biopsies, particularly circulating tumor DNA (ctDNA), extracellular vesicles (EVs), miRNAs and cytokines, emerge as groundbreaking approaches. Recent studies demonstrate ctDNA's potential in assessing therapy responses and predicting relapses in HL. Despite cHL-specific ctDNA applications being relatively unexplored, studies emphasize its value in monitoring treatment outcomes. Overall, this review underscores the imperative role of liquid biopsies in advancing HL diagnosis and monitoring. [ABSTRACT FROM AUTHOR]

Simple Summary: In most cases, it is impossible to differentiate primary central nervous system lymphoma (PCNSL) from other brain tumors or neuroinflammatory diseases without histological confirmation. In most differential diagnoses of PCNSL, preoperative treatment with glucocorticoids is administered. This treatment reduces the symptoms of PCNSL but can also disguise the histological diagnosis, which can lead to an incorrect or delayed diagnosis of PCNSL and postponed therapy. To obtain a broader database for evidence-based decisions in the management of patients with PCNSL, we retrospectively evaluated all patients biopsied and diagnosed with PCNSL at our institution over the last 16 years. Particular focus was placed on the influence of preoperative glucocorticoid therapy and the effect of anticoagulation and dual antiplatelet therapy on the validity of histological diagnosis. In patients with primary central nervous system lymphoma (PCNSL), the choice of surgical strategy for histopathologic assessments is still controversial, particularly in terms of preoperative corticosteroid (CS) therapy. To provide further evidence for clinical decision-making, we retrospectively analyzed data from 148 consecutive patients who underwent surgery at our institution. Although patients treated with corticosteroids preoperatively were significantly more likely to require a second or third biopsy (p = 0.049), it was only necessary in less than 10% of the cases with preoperative (but discontinued) corticosteroid treatment. Surprisingly, diagnostic accuracy was significantly lower when patients were treated with anticoagulation or dual antiplatelet therapy (p = 0.015). Preoperative CSF sampling did not provide additional information but was associated with delayed surgery (p = 0.02). In conclusion, preoperative CS therapy can challenge the histological diagnosis of PCNSL. At the same time, our data suggest that preoperative CS treatment only presents a relative contraindication for early surgical intervention. If a definitive diagnosis cannot be made after the first surgical intervention, the timing of a repeat biopsy after the discontinuation of CS remains a case-by-case decision. The effect of anticoagulation and dual antiplatelet therapy on diagnostic accuracy might have been underestimated and should be examined closely in future investigations. [ABSTRACT FROM AUTHOR]

Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively. 62 of 155 evaluable patients (40%) showed concurrent systemic progression/ relapse. 82% of all CNS events occurred within two years after study inclusion or randomization. 87% of patients showed extranodal involvement outside the CNS. Patients generally had poor outcomes with a median overall survival (OS) of 3.4 months (95% CI 2.9-4.2) and a 2-year OS of 15% (10-22%). Outcomes did not differ depending on the site or time point of CNS events. Patients with isolated CNS events demonstrated significantly better OS (p = 0.023). Twenty-five patients were consolidated with autologous or allogeneic stem cell transplantation and achieved a 3-year OS of 36% (20-66%). This large study including more than 5000 DLBCL patients highlights the unmet medical need to improve the outcome of DLBCL patients suffering from CNS relapse., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Response-adapted treatment using early interim functional imaging with PET after two cycles of chemotherapy (PET-2) for advanced-stage Hodgkin's lymphoma (AS-HL) is the standard of care in several countries. However, the distribution of residual metabolic disease in PET-2 and the prognostic relevance of multiple involved regions have not been reported to date. Methods: We retrospectively analyzed data from all PET-2-positive patients included in HD18. Residual tissue was visually compared with reference regions according to the Deauville score (DS). PET-2 positivity was defined as residual tissue with uptake above the liver (DS4). PFS was defined as the time from staging until progression, relapse, or death from any cause, or to the day when information was last received on the patient's disease status and analyzed using Kaplan-Meier and Cox regressions. Comparisons were made between patients with 1–2 and >2 positive regions in PET-2 as well as patients without PET-2-positive regions randomized into comparator arms of HD18. Results: Between 2008 and 2014, 1964 patients with newly diagnosed AS-HL were recruited in HD18 and randomized following their PET-2 scan. Of these, 480 patients had a positive PET-2 and were eligible for this analysis. Upper and lower mediastinum in almost half of all patients: 230 (47.9%) and 195 (40.6%), respectively. 372 (77.5%) of patients have 1–2 positive regions in PET-2. 5y-PFS for patients with 1–2 regions was 91.7% (CI95: 88.7–94.6) vs. 81.8% (CI95: 74.2–90.1) for those with >2 regions with a corresponding hazard ratio (HR) of 2.2 (CI95: 1.2–4.0). Compared with patients without PET-2-positive disease receiving 6–8 cycles of chemotherapy, patients with 1–2 had a higher risk for a PFS event (HR 1.35; CI95 0.81–2.28), but it was not statistically significant (p=0.25). Patients with >2 PET-2-positive lesions had a significantly higher risk (HR 2.95; CI95: 1.62–5.37; p<0.001). Conclusion: PET-2-positive residuals of AS-HL are mostly located in the mediastinum, and a majority of patients have few affected regions. The risk of progression was twofold higher in patients with more than two positive regions in PET-2. [ABSTRACT FROM AUTHOR]

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Recent genomic studies revealed enhancer of zeste homolog 2 (EZH2) gain‐of‐function mutations, representing novel therapeutic targets in follicular lymphoma (FL) in around one quarter of patients. However, these analyses relied on single‐site tissue biopsies and did not investigate the spatial heterogeneity and temporal dynamics of these alterations. Objectives: We aimed to perform a systematic analysis of EZH2 mutations using paired tissue (tumor biopsies [TB]) and liquid biopsies (LB) collected prior to treatment within the framework of a nationwide multicentric study. Methods: Pretreatment LB and TB samples were collected from 123 patients. Among these, 114 had paired TB and LB, with 39 patients characterized with paired diagnostic and relapse samples available. The EZH2 mutation status and allele burden were assessed using an in‐house‐designed, highly sensitive multiplex droplet digital PCR assay. Results: EZH2 mutation frequency was found to be 41.5% in the entire cohort. In patients with paired TB and LB samples, EZH2 mutations were identified in 37.8% of the patients with mutations exclusively found in 5.3% and 7.9% of TB and LB samples, respectively. EZH2 mutation status switch was documented in 35.9% of the patients with paired diagnostic and relapse samples. We also found that EZH2 wild‐type clones may infiltrate the bone marrow more frequently compared to the EZH2 mutant ones. Conclusion: The in‐depth spatio‐temporal analysis identified EZH2 mutations in a considerably higher proportion of patients than previously reported. This expands the subset of FL patients who most likely would benefit from EZH2 inhibitor therapy. [ABSTRACT FROM AUTHOR]

Surgical biopsy is the gold standard for diagnosing central nervous system (CNS) lymphomas. However, reliable liquid biopsy methods for diagnosing CNS lymphomas have quickly developed and have been implicated in clinical decision-making. In the current report, we introduce two patients for whom liquid biopsy was essential for diagnosing CNS lymphomas and discuss the rapidly growing applications of this technology., (© 2024. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

Animal models are routinely employed to assess the treatments for human cancer. However, due to significant differences in genetic backgrounds, traditional animal models are unable to meet bioresearch needs. To overcome this restriction, researchers have generated and optimized immunodeficient mice, and then engrafted human genes, cells, tissues, or organs in mice so that the responses in the model mice could provide a more reliable reference for treatments. As a bridge connecting clinical application and basic research, humanized mice are increasingly used in the preclinical evaluation of cancer treatments, particularly after gene interleukin 2 receptor gamma mutant mice were generated. Human cancer models established in humanized mice support exploration of the mechanism of cancer occurrence and provide an efficient platform for drug screening. However, it is undeniable that the further application of humanized mice still faces multiple challenges. This review summarizes the construction approaches for humanized mice and their existing limitations. We also report the latest applications of humanized mice in preclinical evaluation for the treatment of cancer and point out directions for future optimization of these models., (© 2023 Wiley Periodicals LLC.)

Simple Summary: The unique tumor composition of classical Hodgkin lymphoma (cHL), with only a small fraction of malignant Hodgkin and Reed–Sternberg cells within the tumor tissue, has created many challenges to characterize the genetic alterations that drive this lymphoid malignancy. Major advances in sequencing technologies and detailed analysis of circulating tumor DNA in blood samples of patients have provided important contributions to enhance our understanding of the pathogenesis of cHL. In this review, we provide an overview of the recent advances in genotyping the clonal and mutational landscape of cHL. In addition, we discuss different next-generation sequencing applications to characterize tumor tissue and cell-free DNA, which are now available to improve the diagnosis of cHL, and to monitor therapeutic response or disease progression during treatment and follow up of cHL patients. Classical Hodgkin lymphoma (cHL) represents a B-cell lymphoproliferative disease characterized by clonal immunoglobulin gene rearrangements and recurrent genomic aberrations in the Hodgkin Reed–Sternberg cells in a reactive inflammatory background. Several methods are available for the molecular analysis of cHL on both tissue and cell-free DNA isolated from blood, which can provide detailed information regarding the clonal composition and genetic alterations that drive lymphoma pathogenesis. Clonality testing involving the detection of immunoglobulin and T cell receptor gene rearrangements, together with mutation analysis, represent valuable tools for cHL diagnostics, especially for patients with an atypical histological or clinical presentation reminiscent of a reactive lesion or another lymphoma subtype. In addition, clonality assessment may establish the clonal relationship of composite or subsequent lymphoma presentations within one patient. During the last few decades, more insight has been obtained on the molecular mechanisms that drive cHL development, including recurrently affected signaling pathways (e.g., NF-κB and JAK/STAT) and immune evasion. We provide an overview of the different approaches to characterize the molecular composition of cHL, and the implementation of these next-generation sequencing-based techniques in research and diagnostic settings. [ABSTRACT FROM AUTHOR]

Multi-agent chemotherapy and RT for decades have remained mainstay of HL therapy and provided cure to the majority of patients. Nearly 80 years after the first reports of curative treatment with radiotherapy (RT) and cytostatic agents, the therapeutic landscape of classical Hodgkin lymphoma (HL) has evolved dramatically. [Extracted from the article]

Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1. Unfolding the potential of anti-programmed cell death protein 1 blockade in Hodgkin lymphoma - combination and personalisation? Classical Hodgkin lymphoma (cHL) is characterised by a complex tumour microenvironment providing a protective niche for the usually programmed death protein ligand 1 (PD-L1) positive malignant Hodgkin- and Reed-Sternberg cells.1 After high objective response rates (ORRs) of ~70% with often durable remission and a favourable safety profile were observed in two pivotal trials, anti-PD1 immune checkpoint inhibition rapidly became a mainstay of treatment for relapsed or refractory (r/r) cHL.2,3 Fuelled by the encouraging efficacy, various trials investigated anti-PD1-based combination treatments or innovative therapeutic approaches with encouraging data: in the first-line setting, outstanding efficacy was reported for anti-PD1 antibodies with either concomitant or sequential doxorubicin, vinblastine and dacarbazine (AVD).4,5 In r/r cHL striking efficacy and good tolerability was recently reported for the combination of pembrolizumab with gemcitabine, vinorelbine and doxorubicin (P-GVD) in a phase II trial conducted by colleagues from the Memorial Sloan Kettering Cancer Center (MSKCC).6 Among 39 transplant-eligible patients with a first episode of r/r cHL, an ORR of 100% and complete response rate (CRR) of 92% by 2014 Lugano criteria was observed already after 2 × P-GVD. [Extracted from the article]

Risk-stratified treatment strategies have the potential to increase survival and lower toxicity in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) patients. This study investigated the prognostic value of serum (s)TARC, vitamin D and lactate dehydrogenase (LDH), TARC immunohistochemistry and quantitative PET parameters in 65 R/R cHL patients who were treated with brentuximab vedotin (BV) and DHAP followed by autologous stem-cell transplantation (ASCT) within the Transplant BRaVE study (NCT02280993). At a median follow-up of 40 months, the 3-year progression free survival (PFS) was 77% (95% CI: 67-88%) and the overall survival was 95% (90-100%). Significant adverse prognostic markers for progression were weak/negative TARC staining of Hodgkin Reed-Sternberg cells in the baseline biopsy, and a high standard uptake value (SUV)mean or SUVpeak on the baseline PET scan. After one cycle of BV-DHAP, sTARC levels were strongly associated with the risk of progression using a cutoff of 500 pg/ml. On the pre-ASCT PET scan, SUVpeak was highly prognostic for progression post-ASCT. Vitamin D, LDH and metabolic tumor volume had low prognostic value. In conclusion, we established the prognostic impact of sTARC, TARC staining, and quantitative PET parameters for R/R cHL, allowing the use of these parameters in prospective risk-stratified clinical trials. Trial registration: NCT02280993., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Sequencing of ctDNA could be utilized in two ways to improve the choice of the right treatment for a given HL patient. The development of contemporary treatment of Hodgkin lymphoma (HL) has been one of the biggest success stories in modern haematology, turning HL into one of the most curable cancers.1 Still, while most HL patients are cured nowadays, a small subgroup of patients will relapse after first-line treatment, and some will ultimately die from HL. 2019; 33 (2): 439 - 46. 5 Borchmann S, Müller H, Hude I, Fuchs M, Borchmann P, Engert A. Thrombosis as a treatment complication in Hodgkin lymphoma patients: a comprehensive analysis of three prospective randomized German Hodgkin Study Group (GHSG) trials. [Extracted from the article]