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