循环肿瘤DNA在经swog s1826治疗的晚期经典霍奇金淋巴瘤患者中的预后价值

IF 3.3 4区医学 Q2 HEMATOLOGY

Hematological Oncology Pub Date : 2025-06-16 DOI:10.1002/hon.70093_21

J. Paczkowska, M. Kaszkowiak, M. LeBlanc, C. Stewart, A. F. Herrera, J. C. Fernando del Castillo, S. M. Castellino, S. C. Rutherford, A. M. Evens, K. Davison, H. Li, D. Neuberg, M. Murakami, J. Makker, B. Kahl, J. P. Leonard, N. L. Bartlett, S. M. Smith, J. Y. Song, K. M. Kelly, G. Getz, J. W. Friedberg, M. A. Shipp

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Serial plasma samples from first 388 pts and paired germline DNAs were evaluated with a targeted sequencing panel that included recurrently mutated genes (single nucleotide variants and indels), somatic copy number alterations, and structural variants in cHL; and probes to detect sites of physiologic and aberrant somatic hypermutation and determine EBV status. Duplex read sequencing was employed to enhance error suppression and recurrent mutations, SCNAs and SVs were detected using computational algorithms optimized for ctDNA analysis. A newly developed computational pipeline, MTB-Tracker, was used to identify clustered SNVs and assess treatment-related changes in molecular tumor burden (MTB), reflected as log-fold changes in haploid genome equivalents per milliliter of plasma (hGE/mL) over time.Results: 375/388 (97%) had detectable clustered SNVs at baseline and were included in the MTB analysis. 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引用次数: 0

摘要

J. Paczkowska， M. Kaszkowiak， M. LeBlanc， C. Stewart， A. F. Herrera， G. Getz， J. W. Friedberg， M. A. Shipp。背景：S1826表明，与Bv-AVD相比，将nivolumab纳入初始化疗（N-AVD）可改善无进展生存期（PFS）。在这项预先计划的分析中，我们使用一种新开发的检测方法评估了S1826中循环肿瘤DNA （ctDNA）检测的预后价值。方法：患者≥12年(y)， 3-4期cHL。前388名患者的连续血浆样本和配对种系dna通过靶向测序面板进行评估，包括反复突变的基因（单核苷酸变异和indel）、体细胞拷贝数改变和cHL的结构变异；以及检测生理和异常体细胞超突变位点和确定EBV状态的探针。采用双读测序来增强错误抑制和反复突变，使用针对ctDNA分析优化的计算算法检测scna和sv。新开发的计算管道MTB- tracker用于识别聚集性snv并评估与治疗相关的分子肿瘤负荷（MTB）变化，反映为每毫升血浆单倍体基因组当量（hGE/mL）随时间的对数倍变化。结果：375/388（97%）在基线时可检测到聚集性snv，并被纳入MTB分析。这些患者的基线临床特征反映了S1826总体人群：中位年龄25岁（范围，12-83岁），28%；18年，10%60岁，37%,IPS 4-7；191例患者接受N-AVD(2年PFS为91%)，184例患者接受BV-AVD（2年PFS为81%）。基线MTB与临床特征相关，包括IPS评分(0-3 vs. 4-7, p <；0.0001)和B型症状(p <；0.0001)。在整个队列中，C3D1时的MTB是预后因素；C3D1检测不到的ctDNA与2年PFS相关，前者为91%，后者为ctDNA+组的64%，p <；0.0001. 在C3D1的每个治疗组中观察到类似的结果(N-AVD: ctDNA−2年PFS 95% vs ctDNA+， 74%；BV-AVD: ctDNA−2年PFS 88% vs ctDNA+ 53%， p和lt；0.0001)。动态评估基线和C3D1之间MTB的变化可以进一步区分低风险组和高风险组（图）。与C3D1未检测到ctDNA的患者相比，>；C3D1时MTB的中位数（3.64）对数倍下降略有不利的结果：总的2年PFS， N-AVD和BV-AVD分别为87%，88%和86%。相反，使用<；C3D1的中位对数倍下降的结果明显较差：2年PFS， N-AVD和BV-AVD分别为41%，59%和25%，均为p <；0.0001. EOT中可检测到的ctDNA的存在与缺失也与PFS （ctDNA -， 2年PFS 92% vs ctDNA+ 42%）、N-AVD （ctDNA -， 2年PFS 93% vs ctDNA+ 47%）和BV-AVD （ctDNA - 2年PFS 91% vs ctDNA+ 39%）显著相关，均p <；0.0001.结论：在C3D1和EOT时，通过ctDNA评估的MTB与整个队列和每个研究组的PFS显著相关。这些发现支持ctDNA在晚期cHL的ctDNA反应适应临床试验中作为一个完整的生物标志物的潜在应用。研究经费声明：由美国国家癌症研究所U10CA180888， U10CA180819, U10CA180821, U10CA180820, U10CA180863, UG1CA189955（所有研究人员），米勒家庭基金（MS）和白血病和淋巴瘤学会奖学金奖（JP）提供资金。百时美施贵宝（Bristol-Myers Squibb）提供资金和药物，SeaGen为在加拿大注册的患者提供药物。关键词：诊断与预后生物标志物；潜在的利益冲突来源：B。KahlHonoraria:百时美施贵宝

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PROGNOSTIC VALUE OF CIRCULATING TUMOR DNA IN PATIENTS WITH ADVANCED STAGE CLASSIC HODGKIN LYMPHOMA TREATED ON SWOG S1826

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PROGNOSTIC VALUE OF CIRCULATING TUMOR DNA IN PATIENTS WITH ADVANCED STAGE CLASSIC HODGKIN LYMPHOMA TREATED ON SWOG S1826

J. Paczkowska, M. Kaszkowiak, M. LeBlanc, C. Stewart, A. F. Herrera, G. Getz, J. W. Friedberg, M. A. Shipp equally contributing author.

Background: S1826 demonstrated that incorporation of nivolumab into initial chemotherapy (N-AVD) improved progression-free survival (PFS) compared with Bv-AVD. In this pre-planned analysis, we assessed the prognostic value of serial circulating tumor DNA (ctDNA) detection in S1826 using a newly developed assay.

Methods: Pts were ≥ 12 years (y) with stage 3–4 cHL. Serial plasma samples from first 388 pts and paired germline DNAs were evaluated with a targeted sequencing panel that included recurrently mutated genes (single nucleotide variants and indels), somatic copy number alterations, and structural variants in cHL; and probes to detect sites of physiologic and aberrant somatic hypermutation and determine EBV status. Duplex read sequencing was employed to enhance error suppression and recurrent mutations, SCNAs and SVs were detected using computational algorithms optimized for ctDNA analysis. A newly developed computational pipeline, MTB-Tracker, was used to identify clustered SNVs and assess treatment-related changes in molecular tumor burden (MTB), reflected as log-fold changes in haploid genome equivalents per milliliter of plasma (hGE/mL) over time.

Results: 375/388 (97%) had detectable clustered SNVs at baseline and were included in the MTB analysis. The baseline clinical characteristics of these pts mirrored the overall S1826 population: median age 25 years (range, 12–83 years), 28% < 18 years, 10% > 60 years, 37% with IPS 4–7; 191 pts received N-AVD (2 years PFS 91%);184 pts received BV-AVD (2 years PFS 81%). Baseline MTB correlated with clinical features including IPS score (0–3 vs. 4–7, p < 0.0001) and B symptoms (p < 0.0001) in all analyzed pts. MTB at C3D1 was prognostic for outcome in the full cohort; undetectable ctDNA at C3D1 was associated with 2 years PFS 91% versus 2 years PFS 64% in the ctDNA⁺ group, p < 0.0001. Similar results were observed within each treatment arm at C3D1 (N-AVD: ctDNA⁻ 2 years PFS 95% versus ctDNA⁺, 74%; BV-AVD: ctDNA⁻ 2 years PFS 88% versus ctDNA⁺ 53%, both p < 0.0001). Dynamic assessment of the changes in MTB between baseline and C3D1 allowed further discrimination of low and higher risk groups (Figure). In comparison to pts with undetectable ctDNA at C3D1, pts with a > median (3.64) log fold drop in MTB at C3D1 had slightly less favorable outcomes: 2 years PFS in all, N-AVD and BV-AVD pts of 87%, 88% and 86%, respectively. In contrast, pts with < median log-fold drop at C3D1 had significantly inferior outcomes: 2 years PFS in all, N-AVD and BV-AVD pts of 41%, 59% and 25%, all p < 0.0001. The presence versus absence of detectable ctDNA at EOT was also significantly associated with PFS (ctDNA⁻, 2 years PFS 92% vs. ctDNA⁺ 42%): N-AVD (ctDNA⁻, 2 years PFS 93% vs. ctDNA⁺ 47%) and BV-AVD (ctDNA⁻ 2 years PFS 91% vs. ctDNA⁺ 39%), all p < 0.0001.

Conclusion: MTB assessed via ctDNA was significantly associated with PFS in the entire cohort and within each study arm at C3D1 and EOT. These findings support the potential use of ctDNA as an integral biomarker in a ctDNA response-adapted clinical trial in advanced stage cHL.

Research funding declaration: Funding provided by the National Cancer Institute U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180863, UG1CA189955 (all investigators), the Miller Family Fund (MS) and a Leukemia and Lymphoma Society Fellowship Award (JP). Funding and drug provided by Bristol-Myers Squibb, drug provided by SeaGen for pts enrolled in Canada.

Keywords: diagnostic and prognostic biomarkers; Hodgkin lymphoma

Potential sources of conflict of interest:

B. Kahl

Honoraria: BMS

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来源期刊

Hematological Oncology 医学-血液学

CiteScore

4.20

自引率

6.10%

发文量

147

审稿时长

>12 weeks

期刊介绍： Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.