Santarsieri Anna, Mitchell Emily, Pham My H, Sanghvi Rashesh, Jablonski Janina, Lee-Six Henry, Sturgess Katherine, Brice Pauline, Menne Tobias F, Osborne Wendy, Creasey Thomas, Ardeshna Kirit M, Baxter Joanna, Behan Sarah, Bhuller Kaljit, Booth Stephen, Chavda Nikesh D, Collins Graham P, Culligan Dominic J, Cwynarski Kate, Davies Andrew, Downing Abigail, Dutton David, Furtado Michelle, Gallop-Evans Eve, Hodson Andrew, Hopkins David, Hsu Hannah, Iyengar Sunil, Jones Stephen G, Karanth Mamatha, Linton Kim M, Lomas Oliver C, Martinez-Calle Nicolas, Mathur Abhinav, McKay Pamela, Nagumantry Sateesh K, Phillips Elizabeth H, Phillips Neil, Rudge John F, Shah Nimish K, Stafford Gwyneth, Sternberg Alex, Trickey Rachel, Uttenthal Benjamin J, Wetherall Natasha, Zhang Xiao-Yin, McMillan Andrew K, Coleman Nicholas, Stratton Michael R, Laurenti Elisa, Borchmann Peter, Borchmann Sven, Campbell Peter J, Rahbari Raheleh, Follows George A
Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; University of Cambridge, Wellcome-Medical Research Council Stem Cell Institute, Cambridge, UK; Faculty of Health, Medicine, and Social Care, Anglia Ruskin University, Cambridge, UK.
Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; University of Cambridge, Wellcome-Medical Research Council Stem Cell Institute, Cambridge, UK.
Lancet Oncol. 2025 Jan;26(1):98-109. doi: 10.1016/S1470-2045(24)00598-9. Epub 2024 Dec 12.
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.
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).
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.
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.
Addenbrooke's Charitable Trust and Wellcome Trust.
含丙卡巴肼的化疗方案与血细胞减少和不育有关，提示存在干细胞毒性。在治疗霍奇金淋巴瘤时，递增剂量的博来霉素-依托泊苷-阿霉素-环磷酰胺-长春新碱-丙卡巴肼-泼尼松（eBEACOPP）方案中的丙卡巴肼越来越多地被达卡巴嗪替代（eBEACOPDac）以降低毒性。我们旨在研究这种药物替代对干细胞突变负担、患者生存率和毒性的影响。
在这项两部分的回顾性观察研究中，我们首先比较了晚期霍奇金淋巴瘤缓解至少6个月的患者的造血干细胞和祖细胞（HSPCs）中的突变图谱，这些患者接受了eBEACOPDac（eBEACOPDac队列）、eBEACOPP（真实世界eBEACOPP队列）或阿霉素-博来霉素-长春花碱-达卡巴嗪（ABVD）治疗；一名女性经典霍奇金淋巴瘤患者在怀上第三个孩子之前接受eBEACOPP治疗，其五个孩子的口腔DNA；一名轻度少精子症患者接受eBEACOPP治疗后的精子DNA；以及一名接受苯丁酸氮芥-长春花碱-丙卡巴肼-泼尼松治疗的霍奇金淋巴瘤幸存者的盲肠腺癌和健康结肠组织。在第二部分中，我们分析了英国、爱尔兰和法国25个中心接受一线eBEACOPDac（eBEACOPDac队列）治疗的成年患者（年龄>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，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中的参与者为先前未治疗的霍奇金淋巴瘤成年患者（年龄>16岁），接受一线eBEACOPP治疗。我们有两个共同主要目标：确定含或不含丙卡巴肼化疗治疗后的比较性干细胞突变负担和突变特征（第一研究部分）；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（第二研究部分）。次要目标包括总生存期，并探索特定毒性结果的差异，包括输血需求和生殖健康指标（第二研究部分）。
在研究的第一部分（突变分析）中，与接受eBEACOPDac（n = 4）或ABVD（n = 3；额外突变1150 [95% CI 934 - 1366] vs 290 [241 - 339] vs 186 [116 - 254]）治疗的患者相比，接受eBEACOPP（n = 5）治疗的患者HSPCs中的点突变负担更高。在接受含丙卡巴肼化疗的患者的HSPCs以及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。SBSB也在接受eBEACOPP后受孕的三个孩子的生殖系DNA以及一名接受eBEACOPP治疗的男性患者的精子中被鉴定出来。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，达卡巴嗪替代似乎并未损害疗效或安全性。312例接受eBEACOPDac治疗的患者（eBEACOPDac队列；2017 - 2022年治疗，18� [60%]为男性，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例患者（2008 - 2014年治疗，1183 [61%]为男性，中位随访57.0个月[35.4 - 64.7]）的93.3% [95% CI 92.1 - 94.4]）无进展生存率相似。与英国真实世界数据集中73例接受eBEACOPP治疗的患者相比，接受eBEACOPDac治疗的患者需要的输血次数更少（平均1.70单位[SD 2.77] vs 3.69单位[3.89]；p<0.0001），化疗后精子浓度更高（中位2340万/mL [IQR 11.0 - 632.3] vs 0.0万/mL [0.0 - 0.001]；p = 0.0040），月经恢复更早（平均5.04个月[SD 3.07] vs 8.77个月[5.57]；p = 0.0036）。
丙卡巴肼在接受eBEACOPP治疗的霍奇金淋巴瘤患者及其生殖系DNA中诱导更高的突变负担和新的突变特征，这引发了对霍奇金淋巴瘤幸存者基因组健康及其后代遗传后果的担忧。然而，用达卡巴嗪替代丙卡巴肼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。
阿登布鲁克慈善信托基金和惠康信托基金。
