Background

Procarbazine-containing chemotherapy regimens are associated with cytopenias and infertility, suggesting stem-cell toxicity. When treating Hodgkin lymphoma, procarbazine in escalated-dose bleomycin–etoposide–doxorubicin–cyclophosphamide–vincristine–procarbazine–prednisolone (eBEACOPP) is increasingly replaced with dacarbazine (eBEACOPDac) to reduce toxicity. We aimed to investigate the impact of this drug substitution on the mutation burden in stem cells, patient survival, and toxicity.

Methods

In this two-part retrospective, observational study, we first compared mutational landscapes in haematopoietic stem and progenitor cells (HSPCs) from patients with advanced-stage Hodgkin lymphoma in remission for at least 6 months who had been treated with eBEACOPDac (eBEACOPDac cohort), eBEACOPP (real-world eBEACOPP cohort), or doxorubicin–bleomycin–vinblastine–dacarbazine (ABVD); in buccal DNA from five children of a female patient with classical Hodgkin lymphoma treated with eBEACOPP before conceiving the third child; in sperm DNA from a patient with mild oligospermia treated with eBEACOPP; and in caecal adenocarcinoma and healthy colon tissue from a survivor of Hodgkin lymphoma treated with chlorambucil–vinblastine–procarbazine–prednisolone. For the second part, we analysed efficacy and toxicity data from adult patients (aged >16 years) treated with first-line eBEACOPDac (eBEACOPDac cohort) at 25 centres across UK, Ireland, and France; efficacy was compared with the German HD18 eBEACOPP trial data and toxicity with a UK real-world dataset. Participants in the German HD18 and UK real-world datasets were adults (aged >16 years) with previously untreated Hodgkin lymphoma, treated with first-line eBEACOPP. We had two co-primary objectives: to define the comparative stem-cell mutation burden and mutational signatures after treatment with or without procarbazine-containing chemotherapy (first study part); and to determine progression-free survival of patients with Hodgkin lymphoma treated with eBEACOPP or eBEACOPDac (second study part). Secondary objectives included overall survival and explored differences in specific toxicity outcomes, including transfusion requirements and measures of reproductive health (second study part).

Findings

In the first part of the study (mutational analysis), patients treated with eBEACOPP (n=5) exhibited a higher burden of point mutations in HSPCs compared with those treated with eBEACOPDac (n=4) or ABVD (n=3; excess mutations 1150 [95% CI 934–1366] vs 290 [241–339] vs 186 [116–254]). Two novel mutational signatures, SBSA (SBS25-like) and SBSB, were identified in HSPCs and in a single neoplastic and healthy colon sample from patients who received procarbazine-containing chemotherapy. SBSB was also identified in germline DNA of three children conceived after eBEACOPP and in sperm of a male patient treated with eBEACOPP. SBSC was detected in patients treated with either ABVD or eBEACOPDac. In the second part of the study (efficacy and toxicity analysis), dacarbazine substitution did not appear to compromise efficacy or safety. 312 patients treated with eBEACOPDac (eBEACOPDac cohort; treated 2017–22, 186 [60%] male, median follow-up 36·0 months [IQR 25·2–50·1]) had a 3-year progression-free survival of 93·3% (95% CI 90·3–96·4), which was similar to the 93·3% [95% CI 92·1–94·4]) progression-free survival seen in 1945 patients in the German HD18 eBEACOPP trial (treated 2008–14, 1183 [61%] male, median follow-up 57·0 months [35·4–64·7]). Patients treated with eBEACOPDac required fewer blood transfusions (mean 1·70 units [SD 2·77] vs 3·69 units [3·89]; p<0·0001), demonstrated higher post-chemotherapy sperm concentrations (median 23·4 million per mL [IQR 11·0–632·3] vs 0·0 million per mL [0·0–0·001]; p=0·0040), and had earlier resumption of menstrual periods (mean 5·04 months [SD 3·07] vs 8·77 months [5·57]; p=0·0036) compared with 73 patients treated with eBEACOPP in the UK real-world dataset.

Interpretation

Procarbazine induces a higher mutation burden and novel mutational signatures in patients with Hodgkin lymphoma treated with eBEACOPP and their germline DNA, raising concerns for the genomic health of survivors of Hodgkin lymphoma and hereditary consequences for their offspring. However, replacing procarbazine with dacarbazine appears to mitigate gonadal and stem-cell toxicity while maintaining similar clinical efficacy.

Funding

Addenbrooke's Charitable Trust and Wellcome Trust.

中文翻译：

---

用达卡巴嗪替代丙卡巴肼治疗霍奇金淋巴瘤升级的 BEACOPP 的基因组学和临床后果：一项回顾性观察性研究

 背景

含丙卡巴肼的化疗方案与血细胞减少和不孕有关，提示干细胞毒性。在治疗霍奇金淋巴瘤时，递增剂量博来霉素-依托泊苷-多柔比星-环磷酰胺-长春新碱-丙卡巴肼-泼尼松龙 （eBEACOPP） 中的丙卡巴嗪越来越多地被达卡巴嗪 （eBEACOPDac） 取代以降低毒性。我们旨在研究这种药物替代对干细胞突变负荷、患者生存和毒性的影响。

 方法

在这项由两部分组成的回顾性观察性研究中，我们首先比较了晚期霍奇金淋巴瘤患者造血干细胞和祖细胞 （HSPC） 的突变情况，这些患者已经接受了 eBEACOPDac（eBEACOPDac 队列）、eBEACOPP（真实世界 eBEACOPP 队列）或阿霉素-博来霉素-长春碱-达卡巴嗪 （ABVD） 治疗至少 6 个月;在怀上第三个孩子之前接受 eBEACOPP 治疗的经典霍奇金淋巴瘤女性患者的 5 个孩子的口腔 DNA 中;来自接受 eBEACOPP 治疗的轻度少精症患者的精子 DNA;以及来自霍奇金淋巴瘤幸存者的盲肠腺癌和健康结肠组织，该幸存者接受苯丁酸氮芥-长春碱-丙卡巴肼-泼尼松龙治疗。对于第二部分，我们分析了在英国、爱尔兰和法国的 25 个中心接受一线 eBEACOPDac （eBEACOPDac 队列） 治疗的成年患者 （>16 岁） 的疗效和毒性数据;将疗效与德国 HD18 eBEACOPP 试验数据进行比较，并将毒性与英国真实世界数据集进行比较。德国 HD18 和英国真实世界数据集的参与者是患有既往未经治疗的霍奇金淋巴瘤的成年人 （>16 岁），接受了一线 eBEACOPP 治疗。我们有两个共同的主要目标：确定有或没有含丙卡巴肼化疗后的比较干细胞突变负荷和突变特征（第一研究部分）;并确定接受 eBEACOPP 或 eBEACOPDac 治疗的霍奇金淋巴瘤患者的无进展生存期（第二个研究部分）。次要目标包括总生存期并探索特定毒性结局的差异，包括输血需求和生殖健康指标（第二研究部分）。

 发现

在研究的第一部分（突变分析）中，与接受 eBEACOPDac （n=4） 或 ABVD 治疗的患者 （n=3;超额突变 1150 [95% CI 934-1366] vs 290 [241-339] vs 186 [116-254]）治疗的患者在 HSPC 中表现出更高的点突变负担。在 HSPCs 和接受含卡巴巴肼化疗患者的单个肿瘤和健康结肠样本中鉴定出两种新的突变特征，SBSA （SBS25 样） 和 SBSB。在 eBEACOPP 后受孕的 3 名儿童的种系 DNA 和一名接受 eBEACOPP 治疗的男性患者的精子中也发现了 SBSB。在接受 ABVD 或 eBEACOPDac 治疗的患者中检测到 SBSC。在研究的第二部分 （疗效和毒性分析） 中，达卡巴嗪替代似乎不会影响疗效或安全性。312 名接受 eBEACOPDac 治疗的患者（eBEACOPDac 队列;2017-22 年治疗，186 [60%] 男性，中位随访 36·0 个月 [IQR 25·2–50·1]）的 3 年无进展生存率为 93·3%（95% CI 90·3-96·4），这与德国 HD18 eBEACOPP 试验中 1945 名患者的 93·3% [95% CI 92·1–94·4]）无进展生存率相似（2008-14 年治疗， 1183 [61%] 男性，中位随访 57·0 个月 [35·4–64·7]）。接受 eBEACOPDac 治疗的患者需要较少的输血（平均 1·70 单位 [SD 2·77] vs 3·69 单位 [3·89];p<0·0001），化疗后精子浓度较高（中位数 23·40 万/mL [IQR 11·0–632·3] vs 0·000 万/mL [0·0–0·001];p=0·0040），月经恢复较早（平均 5·04 个月 [SD 3·07] vs 8·77 个月 [5·57];p=0·0036） 与英国真实世界数据集中接受 eBEACOPP 治疗的 73 名患者进行比较。

 解释

丙卡巴嗪在接受 eBEACOPP 治疗的霍奇金淋巴瘤患者及其种系 DNA 中诱导更高的突变负荷和新的突变特征，引起了对霍奇金淋巴瘤幸存者的基因组健康和对其后代的遗传后果的担忧。然而，用达卡巴嗪代替丙卡巴嗪似乎可以减轻性腺和干细胞毒性，同时保持相似的临床疗效。

 资金

Addenbrooke's Charitable Trust 和 Wellcome Trust。