Replacing procarbazine with dacarbazine in escalated BEACOPP reduces clinical toxicity with no loss of efficacy yet protects stem cells from excess somatic mutational damage

Internationally it has become increasingly common practice to modify escalated BEACOPP (eBPP) by replacing procarbazine with dacarbazine to reduce haematopoietic stem cell and gonadal toxicity in Hodgkin lymphoma (HL) patients. A similar replacement of procarbazine in COPP (to COPDac) has reduced gonadal toxicity and conferred comparable long-term event-free survival in children (EuroNet-PHL-C1 trial; Mauz-Körholz et al. Lancet Oncol 2021). Using a real-world multi-centre dataset of 25 UK, Ireland and France centres we have 2.5 years median follow-up of 311 high risk advanced stage HL patients treated with first-line escalated BEACOPDac (eBPDac). We have compared toxicity data with 73 UK patients treated with eBPP and outcome data with 2073 patients treated in the German HD18 trial. We show eBPDac patients have a reduced blood transfusion requirement and earlier return of menstrual periods compared with real-world eBPP patients (Figure 1A). We have observed 16 relapses, 3 non-lymphoma deaths and an estimated 3 yr PFS of 92.4% with progression-free survival (PFS) and overall survival (OS) comparable to HD18 (Figure 1B). Through collaboration with the GHSG we are performing a case matched analysis with the HD18 cohort and will present the results at 17-ICML. The differential impact of procarbazine and dacarbazine-containing regimens on stem cell genomic toxicity was investigated by whole genome sequencing (WGS) of haematopoietic stem and progenitor cell (HSPC) colonies from patients treated with eBPP, eBPDac and ABVD. We found that HSPCs from ABVD and eBPDac-treated patients had similar minor excess somatic mutation burdens compared to age-matched normal HSPCs of 183 (CI95% = 110–256) and 291 (CI95% = 242–340) mutations respectively. In contrast, the HSPCs from eBPP-treated patients had a dramatically increased excess mutation burden of 1153 (CI95% = 937–1369). Analysis of the mutational profiles revealed that every patient who received procarbazine had a clear SBS25-like mutational signature, demonstrating that SBS25 is attributable to procarbazine. We have also identified the SBS25 signature in malignant and non-malignant non-haematopoietic tissue in patients previously exposed to procarbazine, suggesting this drug induces the SBS25 signature in multiple somatic tissues. To determine whether procarbazine also induces SBS25 in germ cell DNA we performed duplex sequencing of sperm from an eBPP-treated male, and WGS of buccal DNA from 3 children with pre-conception maternal exposure to eBPP × 6 cycles. Reassuringly, SBS25 was not found in the germline of all 3 children, while the results of the sperm mutation analysis are expected imminently. The research was funded by: Addenbrooke's Charitable Trust Keywords: Chemotherapy, Hodgkin lymphoma, Late Effects in Lymphoma Survivors Conflicts of interests pertinent to the abstract. A. Santarsieri Educational grants: Takeda