Heger Jan-Michel, Mammadova Laman, Mattlener Julia, Sobesky Sophia, Cirillo Melita, Altmüller Janine, Kirst Elisabeth, Reinke Sarah, Klapper Wolfram, Bröckelmann Paul J, Ferdinandus Justin, Kaul Helen, Schneider Gundolf, Schneider Jessica, Schleifenbaum Julia Katharina, Ullrich Roland T, Freihammer Max, Awerkiew Sabine, Lohmann Mia, Klein Florian, Nürnberg Peter, Hallek Michael, Rossi Davide, Mauz-Körholz Christine, Gattenlöhner Stefan, Bräuninger Andreas, Borchmann Peter, von Tresckow Bastian, Borchmann Sven
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany.
Cancer Center Cologne Essen-Partner Site Cologne, CIO Cologne, University of Cologne, Cologne, Germany.
J Clin Oncol. 2024 Dec 10;42(35):4218-4230. doi: 10.1200/JCO.23.01867. Epub 2024 Sep 30.
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.
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.
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 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 , , and , 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.
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.
霍奇金淋巴瘤（HL）当前的临床挑战包括难以治疗的复发/难治性疾病以及治疗带来的相当大的长期毒性。由于临床风险因素缺乏鉴别力，治疗强度主要基于肿瘤负荷。探索HL遗传学和肿瘤微环境（TME）可能为改善风险分层提供有价值的见解。
在本研究中，我们对从德国霍奇金淋巴瘤研究组关键试验中获得的243例患者应用循环肿瘤DNA测序，以识别HL的亚型。在欧洲网络-PHL-C2研究中治疗的96例患者中对这些亚型进行了独立验证。在一个包含来自HD21试验的72例患者的事件丰富的临床验证队列中，使用一种经过改进、验证且临床可行的检测方法评估亚型的预后差异。
我们提出了一种HL的生物学分类，包括三种不同的亚型：炎症免疫逃逸HL的特征是频繁的拷贝数变异，包括免疫逃逸变异，如 位点的高水平扩增和炎症性TME。病毒驱动的HL与爱泼斯坦-巴尔病毒和/或人类疱疹病毒6以及具有中性粒细胞和巨噬细胞的炎症性TME相关，而肿瘤突变负荷（TMB）较低。致癌基因驱动的HL由高TMB、致癌驱动基因如 、 和 的复发突变以及冷TME定义。一种旨在实现临床可行风险分层的经过改进和验证的检测版本显示各亚型之间无进展生存期存在显著差异。此外，对微小残留病（MRD）的评估能够检测出各亚型中复发风险极高的患者。
我们基于循环肿瘤DNA测序提出了一种临床可行的、非侵入性的方法，用于HL患者的个体化风险分层和MRD监测。
