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
In the treatment of advanced Hodgkin lymphoma, it is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with IV dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. However, published data of the “escalated BEACOPDac (eBPDac)” regimen are limited. From 2009, 205 patients were treated first line with either eBPP (n = 58) at 4 UK centres, or eBPDac (n = 147) at 16 centres in the UK, Ireland and France with median follow up 51.3 months and 22.9 months respectively. Patients were well matched with no significant differences in age (median: 23 y vs 27 y), sex, stage (stage 3/4: 81% vs 83%) and IPS (IPS3+: 74% vs 65%). 51% of eBPDac patients received only 4 cycles (vs 12% eBPP patients; p < 0.001) reflecting publication of HD18 trial data. In total, 74% patients achieved iPET2 Deauville score ≤3 and 90% achieved PET negative remission by end of treatment. 77% of eBPDac patients achieved iPET2 Deauville ≤3 which was statistically similar to the eBPP cohort (67%; p = 0.181) and matched the 76% iPET D2/3 reported in HD18. Of 205 patients, 202 are alive and 197 continue in first remission. Two eBPP patients have relapsed at 13 and 41 months and the latter died of refractory disease. One eBPDac patient had primary refractory disease, and three have relapsed at 2, 7 and 24 months. One 56-year-old eBPDac patient with high IPS died of bowel perforation during cycle 1 and one 34-year-old with alcoholic liver disease died 8 months after treatment while in remission. Toxicity was compared over the first 4 cycles. Mean day 8 (D8) ALT was similar between the two regimens. Mean D8 neutrophil count was lower in eBPDac than eBPP patients (1.81 vs 2.45; p = 0.067; G-CSF given D9), however it increased to 5.61 in eBPDac patients given GCSF from D4. There is a trend toward fewer non-elective days of inpatient care for eBPDac compared with eBPP (mean 3.74 vs 5.83; p = 0.118), and eBPDac patients received fewer red cell transfusions compared with eBPP patients (mean 1.93 units vs 4.16 units; p < 0.001). Women aged <35, who completed ≥4 cycles of eBPDac/eBPP had a similar rate of return of menstrual cycles (eBPP 22/25; eBPDac 29/29), although eBPDac patients appeared to restart menstruation earlier post chemotherapy (mean 4.48 months vs 9.12 months, p = 0.0026). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.60; p < 0.001). The use of Goserelin varied between centres. Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP and may have some toxicity benefits. Despite a predominance of high risk advanced stage patients, with nearly 2 years median follow up we have observed only 2 deaths and 4 progression events from 147 patients treated with eBPDac, suggesting this regimen is highly efficacious in Hodgkin lymphoma. EA – previously submitted to regional or national meetings (up to 1000 attendees) and EHA 2021. Keywords: Hodgkin lymphoma Conflicts of interests pertinent to the abstract A. Santarsieri Honoraria: Janssen P. Brice Other remuneration: Takeda France, Millenium Takeda, BMS T. F. Menne Other remuneration: Kite/Gilead, Amgen, Novartis, Celgene, Daiichi Sankyo, Takeda, Roche, Janssen, Astra Zeneca, Jazz, Pfizer, Bayer, Kyowa Kirin W. Osborne Other remuneration: Roche, Takeda, Pfizer, Servier, Gilead, MSD, Novartis K. M. Ardeshna Other remuneration: Gilead, Celgene G. P. Collins Other remuneration: Gilead K. Cwynarski Other remuneration: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssen M. Furtado Educational grants: Abbvie S. Iyengar Other remuneration: Takeda, Janssen, Gilead, Abbvie, Roche N. Martinez-Calle Other remuneration: Abbvie P. McKay Other remuneration: Epizyme S. K. Nagumantry Other remuneration: Takeda, Alexion, Abbvie N. Shah Other remuneration: Abbvie B. J. Uttenthal Other remuneration: Roche, Takeda, Jazz A. K. McMillan Other remuneration: Pfizer, F Hoffman-La Roche Ltd, BMS, Celgene, Novartis, Gilead, Sandoz, MSD G. A. Follows Other remuneration: Janssen, Abbvie, Roche, Astra Zeneca
Abstract Background Procarbazine-containing chemotherapy regimens associate with cytopenias and infertility, suggesting stem cell toxicity. Procarbazine in eBEACOPP (escalated dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) is increasingly replaced with dacarbazine (eBEACOPDac) to reduce toxicity, although limited genomic and clinical data support this substitution. Methods To assess mutagenic and clinical consequences of dacarbazine-procarbazine substitutions, we compared mutational landscapes in haematopoietic stem and progenitor cells (HSPCs) from patients treated with different Hodgkin regimens and children, sperm and bowel tissue from procarbazine-treated patients. We compared efficacy and toxicity data of a multicentre eBEACOPDac-treated patient cohort, with eBEACOPP clinical trial and real-world datasets. Results eBEACOPP-treated patients exhibit a higher burden of point mutations, small insertions and deletions in HSPCs compared to eBEACOPDac and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)-treated patients. Two novel mutational signatures, SBSA (SBS25-like) and SBSB were identified in HSPCs, neoplastic and normal colon from only procarbazine-treated patients. SBSB was also identified in germline DNA of three children conceived post-eBEACOPP and sperm of an eBEACOPP-treated male. The dacarbazine substitution did not appear to compromise efficacy; 3-year progression-free survival of 312 eBEACOPDac patients (93.3%; CI 95 =90.3-96.4%) mirrored that of 1945 HD18-trial eBEACOPP patients (93.3%; CI 95 =92.1-94.4%). eBEACOPDac-treated patients required fewer blood transfusions, demonstrated higher post-chemotherapy sperm concentrations, and experienced earlier resumption of menstrual periods. Conclusions Procarbazine induces a higher mutational burden and novel mutational signatures in eBEACOPP-treated patients and their germline DNA raising concerns for hereditary consequences. However, replacing procarbazine with dacarbazine appears to mitigate gonadal and stem cell toxicity while maintaining comparable clinical efficacy.
Figure 1: Kaplan-Meier estimates of progression-free survival and overall survival of the eBPDac-treated patients compared with intention-to-treat set in the HD18 trial and 18-59y RATHL patients. Table of patient characteristics and treatment outcomes. When treating advanced stage Hodgkin lymphoma, it is common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3). This is a retrospective study of patients treated with first line escalated BEACOPDac (eBPDac) at 23 centres updated since ASH 2021. With a median follow-up of 28 months, the 24-month progression-free survival (PFS) is 95% (CI 92.2–98.0%). Of 268 eBPDac patients, 226 were treated as per HD18 protocol and 42 as per AHL2011. Survival outcomes were compared with 2073 eBPP patients in the HD18 trial and 1088 patients aged 18-59y in the RATHL trial. The eBPDac patients were younger than the HD18 and RATHL patients but had higher risk and more stage 4 disease. Of the eBPDac patients 76% achieved iPET Deauville score (DS) ≤3, similar to RATHL (DS≤3:83.7%) and HD18 (DS≤3:76%). One patient had primary refractory disease and twelve have relapsed at 6 to 36 months. Three patients have died of non-lymphoma causes. The eBPDac 24-month PFS is similar to HD18 3-year PFS (95% vs 92.3%) and appears superior to RATHL 5-year PFS (81.4%). The difference in PFS between eBPDac and RATHL is most marked in IPS3+ patients. The eBPDac 24-month OS estimate is 99%. Toxicity was compared between eBPDac patients and 68 matched real-world eBPP patients over the first 4 cycles. There were no significant differences in age, sex or stage, but more eBPP patients had high risk disease (IPS3+). Mean day 8 (D8) ALT was similar between the two regimens. Mean D8 neutrophil count was lower in eBPDac patients with D9 GCSF. eBPDac patients received fewer red cell transfusions compared with eBPP patients (mean 1.88 vs 3.83 units, p<0.001) and had fewer non-elective days of inpatient care (mean 3.49 vs 5.66; p=0.021). Of the women aged <35y who completed ≥4 cycles chemotherapy, 52/52 had return of menstrual periods after eBPDac, compared to 25/28 after eBPP. eBPDac patients appeared to restart menstruation earlier post chemotherapy (mean 4.71 vs 8.89 months, p=0.002). However, eBPP patients received more cycles of chemotherapy. To compare haematopoietic stem cell toxicity, peripheral blood mononuclear cells were isolated from 4 eBPDac, 5 eBPP and 3 ABVD patients. Haematopoietic progenitor cells were grown in culture and the colonies harvested have undergone whole genome sequencing. The data is imminent and we will present the mutation burden and mutational signatures associated with these regimens.
Introduction: It is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing with intravenous dacarbazine (250mg/m2 D2-3), hoping to reduce haematopoietic stem cell and gonadal toxicity. However, published data on the so-called ‘escalated BEACOPDac (eBPDac)’ regimen are limited. Methods: We collected retrospective data from 14 UK and Ireland centres that offer this protocol for first line advanced stage Hodgkin Lymphoma, and compared outcomes with matched patients treated with eBPP at 4 UK centres. Results: From 2009, 103 patients were managed first line with either eBPP (n=51) or eBPDac (n=52) with median follow-up 37 months for eBPP and 10.4 months for eBPDac patients. Patients were well matched with no significant differences in age (median: 25), sex, stage (stage 3/4: 82%) and international prognostic score (IPS3+:71%). More patients treated with eBPDac received only 4 cycles of treatment (54% vs 10%; p=0.0007) reflecting recent HD18 trial data (1). In total, 74% patients achieved iPET Deauville score 2 or 3 and 98% patients achieved PET negative remission by end of treatment. Of eBPDac patients, 78% achieved iPET Deauville 2 or 3 which was statistically similar to the eBPP cohort (68%; p=0.344) and matched the 76% iPET D2/3 reported in HD18 (1). Of 103 patients, 102 are alive and 99 continue in first remission. Two eBPP patients have relapsed at 13 and 41 months. One eBPDac patient had primary refractory disease and one eBPDac patient died with bowel perforation. Toxicity was compared over the first 4 cycles. There was no difference in day 8 ALT between the two regimens although the mean day 8 neutrophil count was lower in eBPDac than eBPP patients (1.82 vs 2.35; p=0.056; G-CSF given day 9). There was a trend to fewer non-elective days of in-patient care for eBPDac compared with eBPP (mean: 2.8 vs 6.06; p=0.13), and eBPDac patients received fewer red cell transfusions during cycles 1 to 4 compared with eBPP patients (Mean 2.06 units vs 4.42 units; p=0.0009). Women aged < 35 with > 6 months post chemotherapy follow-up had a similar rate of return of menstrual cycles (eBPP: 20/21; eBPDac: 11/12), although eBPDac patients appeared to restart menstruation earlier post chemotherapy completion (mean: 3.91 months vs 8.65 months, p=0.0002). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.67; p=0.0005). The use of monthly Goserelin to suppress ovulation varied between centres. Conclusions: Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP and may have some toxicity benefits. As it is highly unlikely that this single drug substitution will ever be tested in a prospective trial, publishing real-world data from eBPDac patients is important. References 1. Borchmann P et al. Lancet. 2018;390:2790-2802 Keywords: BEACOPP; dacarbazine; Hodgkin lymphoma (HL). Disclosures: Follows, G: Consultant Advisory Role: BMS, Takeda, Abbvie, Roche, Janssen, Celgene. Osborne, W: Consultant Advisory Role: Roche, Takeda, Servier, Gilead, MSD; Honoraria: Roche, Takeda, Pfizer; Other Remuneration: Novartis. Ardeshna, K: Consultant Advisory Role: Takeda, Roche, Celgene, ADC therapeutics. McKay, P: Consultant Advisory Role: BMS, Takeda, Roche, Janssen, Celgene; Other Remuneration: Lecture fees, support to attend conferences: Takeda, Janssen, Abvie, Gilead. Nagumantry, S: Honoraria: Abbvie, Takeda; Other Remuneration: Lecturing: Alexion, Takeda. Shah, N: Consultant Advisory Role: Abbvie, Janssen. Uttenthal, B: Honoraria: Roche, Takeda, Jazz.
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