STUDY QUESTION What is the influence of age and chemotherapy regimen on the longitudinal blood anti-Müllerian hormone (AMH) variations in a large series of adolescents and young adult (AYA) (15–24 years old) and non-AYA (25–35 years old) lymphoma patients? SUMMARY ANSWER In case of alkylating regimen treatment, there was a deep and sustained follicular depletion in AYA as well as non-AYA patients; however in both groups, the ovarian toxicity was extremely low in cases of non-alkylating treatments. WHAT IS KNOWN ALREADY AMH is now well-recognised to be a real-time indicator of ovarian follicular depletion and recovery in women treated by chemotherapy. Its longitudinal variations may discriminate between highly and minimally toxic protocols regarding ovarian function. It has been shown, in different cancer types, that age, type of chemotherapy regimen and pre-treatment AMH levels are the main predictors of ovarian recovery. Large studies on longitudinal AMH variations under chemotherapy in lymphoma patients are few but can provide the opportunity to assess the degree of follicle loss at a young age. STUDY DESIGN, SIZE, DURATION This prospective cohort study was conducted in the Fertility Observatory of the Lille University Hospital. Data were collected between 2007 and 2016. Non-Hodgkin or Hodgkin lymphoma patients (n = 122) between 15 and 35 years old were prospectively recruited before commencing chemotherapy. Patients were treated either by a non-alkylating protocol (ABVD group; n = 67) or by an alkylating regimen (alkylating group; n = 55). PARTICIPANTS/MATERIALS, SETTING, METHODS Serial AMH measurements were performed at baseline (AMH0), 15 days after the start of chemotherapy (AMH1), 15 days before the last chemotherapy cycle (AMH2), and at time 3, 6, 9, 12, 18 and 24 months from the end of chemotherapy. The whole study population was divided into two groups according to age: AYA (15–24; n = 65) and non-AYA (25–35; n = 57). All patients received a once monthly GnRH agonist injection during the whole treatment period. A linear mixed model was used to account for the repeated measures of single patients. MAIN RESULTS AND THE ROLE OF CHANCE At baseline, non-AYA patients had higher BMI and lower AMH levels than AYA patients. All AYA and non-AYA patients having received ABVD protocols had regular cycles at 12 months of follow-up. In case of alkylating regimens, amenorrhoea was more frequent in non-AYA patients than in AYA patients at 12 months (37% vs 4%, P = 0.011) and at 24 months (24% vs 4%, P = 0.045). We distinguished a similar depletion phase from AMH0 to AMH2 between ABVD and alkylating groups but significantly different recovery phases from AMH2 to AMH + 24 months. AMH recovery was fast and complete in case of ABVD protocols whatever the age: AMH reached pre-treatment values as soon as the 6th month of follow-up in the AYA group (mean (95% CI) in log AMH M0 vs M6: 3.07 (2.86 to 3.27) vs 3.05 (2.78 to 3.31), P = 1.00) and in the non-AYA group (mean (95% CI) in log AMH M0 vs M6: 2.73 (2.40 to 3.05) vs 2.47 (2.21 to 2.74), P = 1.00). In contrast, no patients from the alkylating group returned to pre-treatment AMH values whatever the age of patients (AYA or non-AYA). Moreover, none of the AMH values post-chemotherapy in the non-AYA group were significantly different from AMH2. Conversely in the AYA group, AMH levels from 6 months (mean (95% CI) in log AMH: 1.79 (1.47 to 2.11), P < 0.001) to 24 months (mean (95% CI) in log AMH: 2.16 (1.80 to 2.52), P ≤ 0.001) were significantly higher than AMH2 (mean (95% CI) in log AMH: 1.13 (0.89 to 1.38)). Considering the whole study population (AYA and non-AYA), pre-treatment AMH levels influenced the pattern of the AMH variation both in alkylating and ABVD protocols (interaction P-value = 0.005 and 0.043, respectively). Likewise, age was significantly associated with the pattern of the recovery phase but only in the alkylating group (interaction P-value =0.001). BMI had no influence on the AMH recovery phase whatever the protocol (interaction P-value = 0.98 in alkylating group, 0.72 in ABVD group). LIMITATIONS, REASONS FOR CAUTION There was a large disparity in subtypes of protocols in the alkylating group. The average duration of chemotherapy for patients treated with alkylating protocols was longer than that for patients treated with ABVD. WIDER IMPLICATIONS OF THE FINDINGS These results make it possible to develop strategies for fertility preservation according to age and type of protocol in a large series of young lymphoma patients. In addition, it was confirmed that young age does not protect against ovarian damage caused by alkylating agents. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Agence Régionale de Santé Hauts de France and Agence Onco Hauts-de-France who provided finances for AMH dosages (n° DOS/SDES/AR/FIR/2019/282). There are no competing interests. TRIAL REGISTRATION NUMBER DC-2008-642 and CNIL DEC2015-112.

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对 122 名青少年 (AYA) 和非 AYA 淋巴瘤患者的 AMH 变异进行纵向研究，以评估化疗引起的卵巢毒性，以进一步个性化生育保留咨询

研究问题 年龄和化疗方案对大量青少年和年轻成人 (AYA)（15-24 岁）和非 AYA（25-35 岁）的纵向血液抗苗勒管激素 (AMH) 变化有何影响岁）淋巴瘤患者？总结答案 在烷基化方案治疗的情况下，AYA 和非 AYA 患者的卵泡深度持续减少；然而，在两组中，在非烷基化治疗的情况下，卵巢毒性极低。已知情况 AMH 现在被公认为是接受化疗的女性卵巢卵泡耗竭和恢复的实时指标。其纵向变化可以区分关于卵巢功能的高毒性和低毒性方案。已经表明，在不同的癌症类型中，年龄、化疗方案类型和治疗前AMH水平是卵巢恢复的主要预测因素。关于淋巴瘤患者化疗期间 AMH 纵向变化的大型研究很少，但可以提供评估年轻时卵泡丢失程度的机会。研究设计、规模、持续时间 这项前瞻性队列研究在里尔大学医院的生育观察站进行。数据收集于 2007 年至 2016 年之间。在开始化疗前前瞻性招募了 15 至 35 岁的非霍奇金或霍奇金淋巴瘤患者（n = 122）。患者接受非烷基化方案（ABVD 组；n = 67）或烷基化方案（烷基化组；n = 55）治疗。参与者/材料、设置、方法 在基线 (AMH0) 时进行系列 AMH 测量，化疗开始后 15 天（AMH1），最后一个化疗周期前 15 天（AMH2），化疗结束后 3、6、9、12、18 和 24 个月。整个研究人群根据年龄分为两组：AYA（15-24；n = 65）和非 AYA（25-35；n = 57）。所有患者在整个治疗期间每月接受一次 GnRH 激动剂注射。线性混合模型用于解释单个患者的重复测量。主要结果和机会的作用 在基线时，非 AYA 患者的 BMI 高于 AYA 患者，而 AMH 水平低于 AYA 患者。所有接受 ABVD 方案的 AYA 和非 AYA 患者在 12 个月的随访中都有规律的周期。在烷基化方案的情况下，非 AYA 患者的闭经在 12 个月时比 AYA 患者更频繁（37% vs 4%，P = 0. 011）和 24 个月时（24% 对 4%，P = 0.045）。我们区分了 ABVD 和烷基化基团之间从 AMH0 到 AMH2 的类似消耗阶段，但从 AMH2 到 AMH + 24 个月的恢复阶段显着不同。无论年龄大小，在 ABVD 方案的情况下，AMH 恢复快速且完全：在 AYA 组随访的第 6 个月，AMH 达到治疗前值（平均 (95% CI) log AMH M0 vs M6：3.07 （2.86 至 3.27）vs 3.05（2.78 至 3.31），P = 1.00）和非 AYA 组（平均 (95% CI) log AMH M0 vs M6：2.73（2.40 至 3.05）vs 2.47（2.21 至 2.74） ), P = 1.00)。相反，无论患者年龄如何（AYA 或非 AYA），烷基化组的患者均未恢复到治疗前的 AMH 值。此外，非AYA组化疗后的AMH值均与AMH2无显着差异。相反，在 AYA 组中，AMH 水平从 6 个月（log AMH 中的平均（95% CI）：1.79（1.47 至 2.11），P < 0.001）到 24 个月（log AMH 中的平均（95% CI）：2.16（ 1.80 到 2.52），P ≤ 0.001）显着高于 AMH2（log AMH 中的平均值（95% CI）：1.13（0.89 到 1.38））。考虑到整个研究人群（AYA 和非 AYA），治疗前 AMH 水平影响烷基化和 ABVD 方案中 AMH 变异的模式（交互 P 值分别 = 0.005 和 0.043）。同样，年龄与恢复阶段的模式显着相关，但仅在烷基化组中（相互作用 P 值 = 0.001）。无论采用何种方案，BMI 对 AMH 恢复阶段均无影响（相互作用 P 值 = 烷基化组中的 0.98，ABVD 组中的 0.72）。限制，谨慎的原因 烷基化组中方案的亚型存在很大差异。接受烷基化方案治疗的患者的平均化疗时间长于接受 ABVD 治疗的患者。研究结果的更广泛意义 这些结果使得根据大量年轻淋巴瘤患者的年龄和方案类型制定生育力保存策略成为可能。此外，已证实年轻并不能防止由烷化剂引起的卵巢损伤。研究资金/竞争利益 这项工作得到了 Agence Régionale de Santé Hauts de France 和 Agence Onco Hauts-de-France 的支持，他们为 AMH 剂量提供了资金 (n° DOS/SDES/AR/FIR/2019/282)。没有相互竞争的利益。试用注册号 DC-2008-642 和 CNIL DEC2015-112。