Procarbazine-Free Escalated Beacopdac in Frontline Therapy of Advanced Hodgkin Lymphoma Reduces Red Cell Transfusion Requirements and May Shorten Time to Menstrual Period Recovery Compared to Escalated Beacopp and Appears to be As Efficacious
Authors: Santarsieri Anna , Sturgess Katherine , Brice Pauline , Menne Tobias F , Osborne Wendy , Creasey Thomas , Ardeshna Kirit M. , Behan Sarah , Booth Stephen , Collins Graham P. , Cwynarski Kate , Iyengar Sunil , Jones Stephen G , O'Mahony Deirdre , Martinez-Calle Nicolas , McKay Pamela , Nagumantry Sateesh K , Rudge John , Shah Nimish , Stafford Gwyneth , Sternberg Alexander , Uttenthal Benjamin J , McMillan Andrew K , Follows George A 
Published: November 2019

Introduction
Since interim results from the EuroNet-PHL-C1 study1were published in 2013 showing that the gonadotoxic drug procarbazine in COPP can be safely replaced with dacarbazine (COPDac) it is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3), hoping to reduce haematopoietic stem cell and gonadal toxicity. However, published data of 'escalated BEACOPDac (eBPDac)' regimen are very limited.
Methods
We collected retrospective data from 15 centres in the UK, Ireland and France, that offer eBPDac therapy for first line advanced stage Hodgkin Lymphoma, and compared outcomes with matched patients treated with eBPP at 4 UK centres. Most patients were treated as per HD15 or HD18 protocol. The 24 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.
Results
From 2009, 141 patients were managed first line with either eBPP (n=52) or eBPDac (n=89) with median follow-up 40 months for eBPP and 12.7 months for eBPDac patients. Patients were well matched with no significant differences in age (median: 28), sex, stage (stage 3/4: 82%) and international prognostic score (IPS3+:65%).
More patients treated with eBPDac received only 4 cycles of treatment (43% vs 12%; p&lt;0.001) reflecting recent publication of HD18 trial data2. In total, 74% patients achieved iPET2 Deauville score 2 or 3 and 96% patients achieved PET negative remission by end of treatment. Of eBPDac patients, 77% achieved iPET Deauville 2 or 3 which was statistically similar to the eBPP cohort (69%; p=0.391) and matched the 76% iPET D2/3 reported in HD181. Of 141 patients, 139 are alive and 136 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, another relapsed seven months after treatment, and one 56-year-old eBPDac patient with high IPS died with bowel perforation during cycle 1.
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 (1.84 vs 2.35; p=0.043; G-CSF given day 9). There was a trend to fewer non-elective days of in-patient care for eBPDac compared with eBPP (mean: 2.78 vs 6.00; p=0.0846), and eBPDac patients received fewer red cell transfusions during cycles 1 to 4 compared with eBPP patients (Mean 1.87 units vs 4.33 units; p&lt;0.001). Women aged &lt; 35, who completed ≥4 cycles of eBPDac/eBPP with &gt; 6 months post chemotherapy follow-up had a similar rate of return of menstrual cycles (eBPP: 20/21; eBPDac: 13/16), although eBPDac patients appeared to restart menstruation earlier post chemotherapy completion (mean: 3.85 months vs 8.65 months, p=0.0018). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.67; p&lt;0.001). 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 in frontline therapy of patients with advanced Hodgkin Lymphoma 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. EuroNet-PHL-C1 study interim report published 14/08/2013 http://www.anzchog.org/docs/public-resources/euronet-recommendation.pdf?sfvrsn=0
2. Borchmann P et al. 2018;390:2790-2802

Disclosures
Brice: BMS: Honoraria; Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding. Menne:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Kyowa Kirin: 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; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Osborne:Novartis: Other: Travel; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy; MSD: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Gilead: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau. Ardeshna:Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Collins:Gilead: Consultancy, Honoraria. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau. Iyengar:Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Roche: Honoraria. Martinez-Calle:ABBVIE: Other: Travel support. McKay:Epizyme: Consultancy, Honoraria. Nagumantry:Takeda: Honoraria, Speakers Bureau; Alexion: Speakers Bureau; Abbvie: Honoraria. Shah:Abbvie: Consultancy. Uttenthal:Roche: Honoraria; Takeda: Honoraria; Jazz: Honoraria. McMillan:BMS: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria; Gilead: Honoraria; MSD: Honoraria; Pfizer: Honoraria, Research Funding. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; AZ: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau.