根据血清抗苗勒氏管激素 (AMH) 的评估，EuroNet-PHL-C2 治疗方案对经典霍奇金淋巴瘤 (cHL) 儿童的女孩性腺功能有什么影响？诱导化疗后血清 AMH 水平降低并升高在随后的治疗和 2 年随访期间，晚期 cHL 治疗的患者水平最低。cHL 治疗，特别是烷化剂和盆腔照射，可能具有性腺毒性，导致女性原始卵泡过早减少。目前的 EuroNet-PHL-C2 试验旨在通过强化化疗来减少标准儿童 cHL 治疗中放疗的使用。本研究旨在评估 EuroNet-PHL-C2 方案的性腺毒性作用。这项国际、前瞻性、多中心队列研究嵌入 EuroNet-PHL-C2 试验中，这是一项欧洲 3 期治疗研究，评估标准 cHL 治疗的疗效使用 OEPA-COPDAC-28（OEPA：长春新碱、依托泊苷、泼尼松和多柔比星；COPDAC-28：环磷酰胺、长春新碱、泼尼松和达卡巴嗪）与强化 OEPA-DECOPDAC-21（DECOPDAC-21：COPDAC 加上额外的多柔比星和依托泊苷和在随机设置中增加 25% 的环磷酰胺）。参与者于 2017 年 1 月至 2021 年 9 月期间招募。在荷兰、比利时、德国、奥地利和捷克共和国的 18 个地点招募了年龄≤18 岁、根据 EuroNet-PHL-C2 方案治疗 cHL 的女性患者。所有父母和患者（年龄≥12岁）均提供了书面知情同意书。随着时间的推移（诊断时、治疗期间一到三次以及诊断后 2 至 5 年）评估血清 AMH 水平和月经周期特征，并在治疗水平（TL1、TL2 和 TL3）和治疗组之间进行比较（ OEPA-COPDAC-28 和 OEPA-DECOPDAC-21）。主要分析中排除了接受盆腔放疗后患者获得的血清样本。分析中总共包括 104 名女性，诊断时的中位年龄为 15.6 岁（IQR 13.7；17.0）。九十九人处于青春期（后）期。 18 名女孩被诊断患有早期 cHL (TL1)，86 名女孩被诊断为中期或晚期疾病（50 名 TL2 和 36 名 TL3，66% 接受了 COPDAC-28，34% 接受了 DECOPDAC-21）。五名患者接受了盆腔放射治疗。诊断时 AMH 中位水平为 1.7 µg/l（IQR 0.9；2.7）。经过两个疗程的 OEPA 化疗后，所有患者的 AMH 水平均大幅下降（98% <0.5 µg/l），随后在巩固治疗和随访期间显着上升。 2 年后，68% 的患者达到基线 AMH 值，与基线测量相比，总体中位恢复率为 129%（IQR 75.0；208.9）。 5 名患者 (7%) 的 AMH <0.5 µg/l。在接受晚期疾病治疗的患者中，与早期或中期疾病相比，AMH 水平仍然显着较低，2 年后中位血清 AMH 为 1.3 µg/l（IQR 0.8；2.1）。接受 DECOPDAC-21 巩固治疗的患者在治疗期间的 AMH 水平低于接受 COPDAC-28 治疗的患者，但诊断后 2 年差异不再具有统计学意义。在 35 名未接受激素联合治疗的初潮后女孩中，19 名 (54%) 经历了治疗引起的闭经，两名女孩在 2 年后持续闭经。研究人群包括诊断为 cHL 且通常与青春期过渡同时发生的年轻女孩，在此期间 AMH 水平自然上升。没有对照人群，而 AMH 作为儿童时期生物标志物的解释很复杂。 cHL 疾病的状态可能会影响诊断时的 AMH 水平，与基线 AMH 相比，可能使 AMH 恢复评估变得复杂。当前的分析包括诊断后长达 2-5 年的数据。当前的 PANCARE 指南建议使用环磷酰胺当量剂量评分（CED 评分，作为累积烷化剂暴露的估计），截止值为 6000 mg /m2 来识别年龄<25岁的不孕不育高风险女性。 EuroNet-PHL-C2 协议的所有治疗组均低于此界限，因此根据此指南，接受 cHL 治疗的女孩应被视为不孕风险低。然而，尽管我们观察到化疗后 AMH 有所增加，但值得注意的是，并非所有女孩都恢复到治疗前的 AMH 水平，特别是那些接受 cHL 晚期治疗的女孩。目前尚不清楚我们的测量结果与特定年龄的预期 AMH 水平和模式有何关系。需要额外的（长期）数据来探索根据 EuroNet-PHL-C2 协议治疗的幸存者的临床生殖结果。生育附加研究由荷兰慈善基金会 KiKa（项目 257）资助，该基金会资助所有研究儿童癌症的形式。 C.M-K.、D.K.、W.H.W.、D.H.、M.C.、A.U. 和 A.B.参与了 EuroNet-PHL-C2 方案的开发。其他作者表示不存在潜在的利益冲突。N/A。© 作者 2024。由牛津大学出版社代表欧洲人类生殖和胚胎学学会出版。

What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)?Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL.Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol.This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021.Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses.A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years.The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis.The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol.The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest.N/A.© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.