Real World Escalated Beacopdac Delivers Similar Outcomes to Escalated Beacopp and Superior Outcomes to Response-Adapted (RATHL) ABVD, While Potentially Reducing Toxicity Compared with Escalated Beacopp
Authors: Santarsieri Anna , Sturgess Katherine , Brice Pauline , Menne Tobias F , Osborne Wendy , Creasey Thomas , Ardeshna Kirit M. , Behan Sarah , Bhuller Kaljit , Booth Stephen , Collins Graham P. , Cwynarski Kate , Davies Andrew , Furtado Michelle , Gallop-Evans Eve , Hodson Andrew , Iyengar Sunil , Jones Stephen G , Linton Kim , Martinez-Calle Nicolas , McKay Pamela , Nagumantry Sateesh K , O'Mahony Deirdre , Phillips Beth , Phillips Neil , Rudge John F , Shah Nimish , Stafford Gwyneth , Sternberg Alex , Trickey Rachel , Uttenthal Benjamin J , Wetherall Nathasha , McMillan Andrew K , Follows George A 
Published: November 2021

Abstract

Background:
In the treatment of advanced Hodgkin lymphoma, it is increasingly common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. However, published data of the "escalated BEACOPDac (eBPDac)" regimen are very limited.
Methods:
This is a retrospective study of 225 patients from 20 centres in the UK, Ireland and France who were treated with eBPDac first line for advanced stage Hodgkin Lymphoma. Toxicity outcomes were compared with 58 matched patients treated with eBPP at 4 UK centres and survival outcomes were compared with 2073 eBPP patients in the HD18 trial 1 and with 1088 patients aged 18-59y in the RATHL trial 2,3. Most eBPDac patients were treated as per HD18 protocol. The 34 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD.
Toxicity outcomes:
Toxicity was compared between eBPDac patients (n=225; median follow-up 22.1 months) and matched real-world UK eBPP patients (n=58; median follow-up 52.7 months) over the first 4 cycles. eBPP and eBPDac patients were well matched with no significant differences in age (median 23 y vs 26 y), sex, stage (stage 3/4 82% vs 83%) and international prognostic score (IPS 3+ 74% vs 65%). 55% of eBPDac patients received only 4 cycles (vs 12% of eBPP patients; p&lt;0.001) reflecting publication of HD18 trial data. Mean day 8 (D8) ALT was similar between the two regimens. Mean D8 neutrophil count tended to be lower in eBPDac than eBPP patients (2.04 vs 2.45; p=0.072; G-CSF given D9), however it increased to 6.48 in eBPDac patients given GCSF from D4. There were fewer non-elective days of inpatient care for eBPDac compared with eBPP (mean 3.35 vs 5.84; p=0.022), and eBPDac patients received fewer red cell transfusions compared with eBPP patients (mean 1.79 units vs 4.16 units; p&lt;0.001). Women aged &lt;35, who completed ≥4 cycles of eBPDac/eBPP had a similar rate of return of menstrual cycles (eBPP 22/25; eBPDac 41/41), although eBPDac patients appeared to restart menstruation earlier post chemotherapy (mean 4.64 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&lt;0.001). The use of Goserelin to suppress ovulation varied between centres.
Disease outcomes:
The eBPDac patients (n=225) were younger than the HD18 patients (median age 26 y vs 35 y, p&lt;0.001) and the RATHL patients (median age 26 y vs 31 y). However, they had higher risk disease than HD18 (IPS 4+ 36% vs 16%, p&lt;0.001) and RATHL patients (IPS 3+ 65% vs 33%, p&lt;0.001) and more stage 4 disease than HD18 (66% vs 36%, p&lt;0.001) and RATHL (66% vs 28%, p&lt;0.001). Of the 225 patients who started eBPDac, 77% achieved iPET2 Deauville score (DS) ≤3, similar to RATHL (DS ≤3: 83.7%) and HD18 (DS ≤3: 76%). Of the eBPDac patients, one patient had primary refractory disease, and ten have relapsed at 6 to 36 months. One 56-year-old eBPDac patient with high IPS died with bowel perforation during cycle 1 and one 34-year-old with alcoholic liver disease died 8 months after treatment while still in remission. There have been no lymphoma-related deaths to date.
Figure 1 shows Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS). The PFS at 22 months (median follow-up) of eBPDac patients was 94.9% (91.7-98.3%) which is similar to HD18 3 year PFS of 92.3% (91.1-93.5%) and appears superior to RATHL 5 year PFS 81.4% (78.9-83.7%). The difference in PFS between eBPDac and RATHL is most marked in IPS3+ patients. The OS rates with all 3 regimens are excellent, with 22 month eBPDac OS estimate of 98.9% (97.4-100%).
Summary/Conclusion:
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 the clear preference of clinicians to offer this regimen to high-risk advanced stage patients, with nearly 2 years median follow-up we have observed similar PFS and OS compared to HD18 but superior survival estimates compared with 18-59y RATHL patients, suggesting that eBPDac is highly efficacious for the treatment of Hodgkin lymphoma.
References:
1Borchmann P et al. Lancet 2017; 390:2790-2802
2Johnson P et al. NEJM. 2016; 374:2419-2429
3Russell J et al. Ann Hematol 2021; 100:1049-1058
Figure 1 Figure 1.

Disclosures
Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Menne: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Astra Zeneca: Research Funding; Jazz: Other: Travel grants; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Bayer: Other: Travel grants; Kyowa Kirin: Other: Travel grants; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Atara: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Honoraria for Lectures; Roche: Other: Honoraria for Lectures. Osborne: Roche: Other; Takeda: Other; Pfizer: Other; Servier: Other; Gilead: Other; Novartis: Other; MSD: Other. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees; Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding. Collins: Pfizer: Honoraria; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Celgene: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Davies: Janssen: Honoraria, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma/AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding. Furtado: Abbvie: Other: Conference support. Gallop-Evans: Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Iyengar: Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: conference support; Janssen: Other: conference support, Speakers Bureau. Linton: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; University of Manchester: Current Employment; Celgene: Research Funding; BeiGene: Research Funding; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Calle: Abbvie: Other. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nagumantry: Takeda, Alexion, Abbvie: Other. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Uttenthal: Jazz: Other; Takeda: Other; Roche: Other. McMillan: Pfizer: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abvie: Membership on an entity's Board of Directors or advisory committees. Follows: Janssen, Abvie, Roche, AZ: Other.