Fertility in patients with advanced-stage classic Hodgkin lymphoma treated with BrECADD versus eBEACOPP: a secondary analysis of the multicentre, randomised, parallel, open-label, phase 3 HD21 trial.

In this secondary analysis of the HD21 trial, we aimed to compare gonadal function recovery and fertility outcomes between these two regimens.

在这项HD21试验的二次分析中，我们的目标是比较这两种方案在睾丸功能恢复和生育结果方面的差异。

Methods

In the multicentre, parallel, open-label, phase 3 HD21 trial, conducted across 233 trial sites in nine countries, patients aged 18-60 years with newly diagnosed, advanced-stage classic Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1) to receive 4-6 cycles of eBEACOPP or BrECADD, guided by interim response.

在一项多中心、平行、开放标签的III期HD21试验中，该试验在九个国家的233个试验点进行，年龄在18-60岁之间、新诊断为晚期经典霍奇金淋巴瘤且东部肿瘤协作组表现状态为0-2的患者被随机分配（1:1）接受4-6个周期的eBEACOPP或BrECADD治疗，治疗方案根据中期反应进行指导。

Patients and investigators were not masked to treatment assignment.

患者和研究人员对治疗分配情况没有遮蔽。

Primary outcomes were progression-free survivaland treatment-related morbidity (reported elsewhere).

主要结果是无进展生存期和治疗相关发病率（已在其他地方报告）。

Here we report an unplanned analysis of fertility outcomes.

这里我们报告了生育结果的非计划分析。

Fertility outcomes included gonadal function recovery (via follicle-stimulating hormone [FSH] concentrations), concentrations of anti-Müllerian hormone (AMH; women only) and inhibin B (men only), frequencies of pregnancies, and incidenceof parenthood.

生育结果包括性腺功能恢复（通过促卵泡生成素[FSH]浓度），抗苗勒管激素（AMH；仅限女性）和抑制素B（仅限男性）的浓度，怀孕频率以及成为父母的发病率。

Gonadal function recovery, AMH, and inhibin B were assessed in the patients of childbearing potential (POCBP) cohort, which included women younger than 40 years and men younger than 50 years without baseline gonadal dysfunction.

在有生育潜力的患者（POCBP）队列中评估了性腺功能恢复、AMH和抑制素B，该队列包括40岁以下的女性和50岁以下的男性，且这些患者在基线时没有性腺功能障碍。

Pregnancy and parenthood analyses also included patients with baseline gonadal dysfunction.

妊娠和为人父母的分析也包括了基线时有性腺功能障碍的患者。

The HD21 trial was registered at ClinicalTrials.gov (NCT02661503) and is ongoing but closed to enrolment.

HD21试验已在ClinicalTrials.gov上注册（NCT02661503），目前正在进行中，但已停止招募新患者。

Results

Between July 22, 2016, and Aug 27, 2020, 1183 POCBP were enrolled (592 in the eBEACOPP group, 591 in the BrECADD group; 692 men, 491 women).

2016年7月22日至2020年8月27日期间，共有1183名POCBP患者被纳入研究（eBEACOPP组592人，BrECADD组591人；男性692人，女性491人）。

FSH measurements were available for 767 patients (420 men and 347 women).

767名患者的FSH测量结果可用（男性420人，女性347人）。

Median follow-up was 49·6 months (IQR 39·7-58·4).

中位随访时间为49.6个月（四分位数间距39.7-58.4个月）。

BrECADD was associated with significantly higher 4-year gonadal function recovery rates compared with eBEACOPP (95·3% [95% CI 92·0-98·8] in the BrECADD group vs 73·3% [66·9-80·4] in the eBEACOPP group, HR 1·69 [95% CI 1·34-2·14] in women; 85·6% [80·8-90·8] vs 39·7% [33·6-46·9], HR 3·28 [2·51-4·30] in men).

与eBEACOPP相比，BrECADD与显著更高的4年性腺功能恢复率相关（BrECADD组为95.3% [95% 置信区间 92.0-98.8]，而eBEACOPP组为73.3% [66.9-80.4]，女性中风险比为1.69 [95% 置信区间 1.34-2.14]；男性中BrECADD组为85.6% [80.8-90.8]，而eBEACOPP组为39.7% [33.6-46.9]，风险比为3.28 [2.51-4.30]）。

AMH and inhibin B concentrations were generally higher in the BrECADD group compared with the eBEACOPP group.

AMH 和 inhibin B 浓度在 BrECADD 组中通常高于 eBEACOPP 组。

A total of 92 pregnancies were reported among female patients, and 36 among partners of male patients.

在女性患者中报告了总共92例怀孕，男性患者的伴侣中报告了36例怀孕。

These led to 108 reported childbirths in 99 patients (59 in the BrECADD group and 40 in the eBEACOPP group).

这导致了99名患者报告了108例分娩（BrECADD组59例，eBEACOPP组40例）。

After therapy, 5-year incidenceof parenthood was significantly higher in men (9·3% [95% CI 6·0-14·5] vs 3·3% [1·7-6·5], p=0·014), but not significantly higher in women (19·3% [13·7-27·3] vs 17·1% [11·9-24·6], p=0·53) with BrECADD versus eBEACOPP.

治疗后，男性5年生育率显著更高（BrECADD组9.3% [95% 置信区间 6.0-14.5]，eBEACOPP组3.3% [1.7-6.5]，p=0.014），而女性在BrECADD组与eBEACOPP组之间没有显著差异（BrECADD组19.3% [13.7-27.3]，eBEACOPP组17.1% [11.9-24.6]，p=0.53）。

interpretation

Compared with eBEACOPP, BrECADD led to significantly better gonadal function recovery, as well as higher parenthood rates (significantly so in men).

与 eBEACOPP 相比，BrECADD 导致了显著更好的性腺功能恢复，以及更高的生育率（在男性中尤其显著）。

These findings support BrECADD as preferred first-line therapy, especially for patients wishing to preserve fertility.

这些发现支持 BrECADD 作为首选的一线治疗方案，特别是对于希望保留生育能力的患者。

funding

Takeda Oncology.

武田肿瘤学。