PO.CL06.03 · 临床研究

儿科癌症幸存者中的治疗相关克隆性造血

Therapy-related clonal hematopoiesis in pediatric cancer survivors

编号 7886 展板 17 时间 4/22 09:00–12:00 区域 Section 47 主讲 Michael Kessler, MD

分会场 Targeted Therapies, Predispositions, and Survivorship in Pediatric Cancers

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作者与单位 Authors & Affiliations

Michael R. Kessler¹, Yash Pershad², Robert W. Corty³, Eric T. Shinohara¹, Debra Friedman⁴, Alexander G. Bick², Ben H. Park⁵, Leo Y. Luo¹

¹Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN,²Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN,³Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN,⁴Division of Pediatric Hematology and Oncology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN,⁵Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN

摘要 Abstract

中文摘要

背景：意义未明的克隆性造血（CHIP）是指由体细胞突变导致的造血干细胞克隆性扩增，并与髓系肿瘤及心血管疾病风险升高相关。诸如化疗和放疗等基因毒性治疗被公认为成人癌症人群中CHIP的重要促成因素。然而，儿科人群中CHIP的患病率、突变模式及治疗关联性仍未得到充分表征。方法：我们对被诊断为癌症、在癌症治疗后采集血样的儿科患者（年龄 ≤ 18岁）进行了回顾性分析。CHIP定义为在公认的驱动基因中存在致病性体细胞突变且变异等位基因频率（VAF）≥2%。总体估计CHIP患病率，并按组织学及治疗暴露进行分层。多变量分析采用带Firth校正及暴露调整的logistic回归。将具有已知Li-Fraumeni综合征关联且VAF >40%的TP53变异视为胚系突变，并从分析中排除。结果：在该队列的1,052例患者中，23例（2.2%）被识别出CHIP突变。突变最常发生于TET2（26%）、DNMT3A（22%）及KRAS（13%）基因。接受化疗的患者中CHIP患病率在数值上更高（3.3%对1.4%，p=0.055）。多变量分析显示女性占轻度优势（OR 0.45，p=0.04），且化疗与CHIP风险升高存在趋势（OR 1.9，p=0.16）。在各药物类别中，抗代谢药物治疗显示出最高的CHIP患病率（OR 3.46，p = 0.048），由甲氨蝶呤暴露所驱动（OR 21.5，p = 0.001）。未发现与年龄、组织学或放疗的相关性。结论：我们在儿科癌症患者中发现了较低的CHIP总体患病率，以及与抗代谢药物治疗的关联。需要进一步研究以明确克隆性造血在儿科癌症幸存者中的长期临床意义。按CHIP状态划分的基线特征特征总体（n = 1052）无CHIP突变（n = 1029）有CHIP突变（n = 23） p值年龄（均值 + SD） 11.5 ± 7.4 11.6 ± 7.4 9.3 ± 5.7 0.083 性别 0.091 男 516（49.0%） 509（49.5%） 7（30.4%）女 536（51.0%） 520（50.5%） 16（69.6%）癌症类型 0.5 淋巴系白血病 225（21.4%） 216（21.0%） 9（39.1%）肉瘤 179（17.0%） 177（17.2%） 2（8.7%）胶质瘤 136（12.9%） 135（13.1%） 1（4.3%）神经母细胞瘤 72（6.8%） 71（6.9%） 1（4.3%）肾/肝肿瘤 62（5.9%） 61（5.9%） 1（4.3%）霍奇金淋巴瘤 49（4.7%） 48（4.7%） 1（4.3%）良性肿瘤 46（4.4%） 45（4.4%） 1（4.3%）髓母细胞瘤/胚胎性肿瘤 44（4.2%） 43（4.2%） 1（4.3%）非霍奇金淋巴瘤 43（4.1%） 42（4.1%） 1（4.3%）其他中枢神经系统肿瘤 36（3.4%） 36（3.5%） 0（0.0%）生殖细胞肿瘤 35（3.3%） 33（3.2%） 2（8.7%）非特指癌（Carcinoma NOS） 27（2.6%） 26（2.5%） 1（4.3%）内分泌肿瘤 25（2.4%） 25（2.4%） 0（0.0%）髓系白血病 22（2.1%） 22（2.1%） 0（0.0%）室管膜瘤 20（1.9%） 20（1.9%） 0（0.0%）视网膜母细胞瘤 17（1.6%） 16（1.6%） 1（4.3%）其他肿瘤 14（1.3%） 13（1.3%） 1（4.3%）化疗 0.055 是 430（40.9%） 416（40.4%） 14（60.9%）否 622（59.1%） 613（59.6%） 9（39.1%）化疗类型 0.3 抗有丝分裂药 153（14.5%） 149（14.5%） 4（17.4%）抗代谢药 110（10.5%） 103（10.0%） 7（30.4%）甲氨蝶呤 13（1.2%） 10（1.0%） 3（13.0%）烷化剂 84（8.0%） 81（7.9%） 3（13.0%）抗肿瘤抗生素 55（5.2%） 55（5.3%） 0（0.0%）植物碱 26（2.5%） 26（2.5%） 0（0.0%）杂类药物 1（0.1%） 1（0.1%） 0（0.0%）拓扑异构酶I抑制剂 1（0.1%） 1（0.1%） 0（0.0%）免疫疗法 >0.9 是 6（0.6%） 6（0.6%） 0（0.0%）否 1046（99.4%） 1023（97.2%） 23（100.0%）外照射放疗 >0.9 是 119（11.3%） 117（11.4%） 2（8.7%）否 933（88.7%） 912（88.6%） 21（91.3%）放射性药物 >0.9 是 36（3.4%） 36（3.5%） 0（0.0%）否 1016（96.6%） 993（96.5%） 23（100.0%）

查看英文原文 English abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells due to somatic mutations and is associated with heightened risk of myeloid neoplasms and cardiovascular diseases. Genotoxic therapies such as chemotherapy and radiation therapy are well-recognized contributors to CHIP in adult cancer population. However, CHIP prevalence, mutational patterns, and treatment associations in pediatric populations remain poorly characterized. Methods: We conducted a retrospective analysis of pediatric patients (age ≤ 18) diagnosed with cancer with blood samples collected after cancer therapy. CHIP was defined as the presence of a pathogenic somatic mutation in an accepted driver gene with variant allele frequency (VAF) ≥2%. CHIP prevalence was estimated overall and stratified by histology and therapeutic exposure. Logistic regression with Firth correction and exposure adjustment was used for multivariable analyses. TP53 variants with known Li-Fraumeni syndrome association and VAF >40% were considered germline mutations and excluded from analyses. Results: CHIP mutations were identified in 23 of 1,052 (2.2%) patients in this cohort. Mutations occurred most frequently in the TET2 (26%), DNMT3A (22%), and KRAS (13%) genes. CHIP prevalence was numerically higher among patients who received chemotherapy (3.3% vs. 1.4%, p=0.055). Multivariable analysis showed a modest female predominance (OR 0.45, p=0.04) and a trend toward higher CHIP risk with chemotherapy (OR 1.9, p=0.16). Among drug classes, antimetabolite therapy showed the highest CHIP prevalence (OR 3.46, p = 0.048), driven by methotrexate exposure (OR 21.5, p = 0.001). No correlations were found with age, histology, or radiation. Conclusion: We identified a low overall prevalence of CHIP in pediatric cancer patients and an association with antimetabolite therapy. Further studies are needed to define the long-term clinical implications of clonal hematopoiesis in pediatric cancer survivors. Baseline characteristics by CHIP status Characteristic Overall (n = 1052) No CHIP mutation (n = 1029) CHIP mutation (n = 23) p-value Age (mean + SD) 11.5 ± 7.4 11.6 ± 7.4 9.3 ± 5.7 0.083 Gender 0.091 Male 516 (49.0%) 509 (49.5%) 7 (30.4%) Female 536 (51.0%) 520 (50.5%) 16 (69.6%) Cancer type 0.5 Lymphoid leukemias 225 (21.4%) 216 (21.0%) 9 (39.1%) Sarcoma 179 (17.0%) 177 (17.2%) 2 (8.7%) Glioma 136 (12.9%) 135 (13.1%) 1 (4.3%) Neuroblastoma 72 (6.8%) 71 (6.9%) 1 (4.3%) Renal/Hepatic tumors 62 (5.9%) 61 (5.9%) 1 (4.3%) Hodgkin lymphoma 49 (4.7%) 48 (4.7%) 1 (4.3%) Benign tumor 46 (4.4%) 45 (4.4%) 1 (4.3%) Medulloblastoma / Embryonal tumors 44 (4.2%) 43 (4.2%) 1 (4.3%) Non-Hodgkin lymphoma 43 (4.1%) 42 (4.1%) 1 (4.3%) Other CNS 36 (3.4%) 36 (3.5%) 0 (0.0%) Germ cell tumors 35 (3.3%) 33 (3.2%) 2 (8.7%) Carcinoma NOS 27 (2.6%) 26 (2.5%) 1 (4.3%) Endocrine tumors 25 (2.4%) 25 (2.4%) 0 (0.0%) Myeloid leukemias 22 (2.1%) 22 (2.1%) 0 (0.0%) Ependymoma 20 (1.9%) 20 (1.9%) 0 (0.0%) Retinoblastoma 17 (1.6%) 16 (1.6%) 1 (4.3%) Other tumor 14 (1.3%) 13 (1.3%) 1 (4.3%) Chemotherapy 0.055 Yes 430 (40.9%) 416 (40.4%) 14 (60.9%) No 622 (59.1%) 613 (59.6%) 9 (39.1%) Chemotherapy type 0.3 Antimitotic Agent 153 (14.5%) 149 (14.5%) 4 (17.4%) Antimetabolite 110 (10.5%) 103 (10.0%) 7 (30.4%) Methotrexate 13 (1.2%) 10 (1.0%) 3 (13.0%) Alkylating Agent 84 (8.0%) 81 (7.9%) 3 (13.0%) Antitumor Antibiotic 55 (5.2%) 55 (5.3%) 0 (0.0%) Plant Alkaloid 26 (2.5%) 26 (2.5%) 0 (0.0%) Miscellaneous Agent 1 (0.1%) 1 (0.1%) 0 (0.0%) Topoisomerase I Inhibitor 1 (0.1%) 1 (0.1%) 0 (0.0%) Immunotherapy >0.9 Yes 6 (0.6%) 6 (0.6%) 0 (0.0%) No 1046 (99.4%) 1023 (97.2%) 23 (100.0%) External beam RT >0.9 Yes 119 (11.3%) 117 (11.4%) 2 (8.7%) No 933 (88.7%) 912 (88.6%) 21 (91.3%) Radiopharmaceuticals >0.9 Yes 36 (3.4%) 36 (3.5%) 0 (0.0%) No 1016 (96.6%) 993 (96.5%) 23 (100.0%)

利益披露 Disclosure

M. R. Kessler, None.. Y. Pershad, None.. R. W. Corty, None.. E. T. Shinohara, None.. D. Friedman, None.. A. G. Bick, None.. B. H. Park, None.. L. Y. Luo, None.

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