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732 Replacing Procarbazine with Dacarbazine in Escalated Beacopp Dramatically Reduces the Post Treatment Haematopoietic Stem and Progenitor Cell Mutational Burden in Hodgkin Lymphoma Patients with No Apparent Loss of Clinical Efficacy

Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Hodgkin Lymphomas and T/NK cell Lymphomas: Clinical and Epidemiological: Hodgkin Lymphoma: Retrospective Analyses and Prospective Trials
Hematology Disease Topics & Pathways:
Research, Hodgkin lymphoma, Lymphomas, Clinical Research, Combination therapy, genomics, Diseases, real-world evidence, Therapies, Lymphoid Malignancies, Biological Processes
Monday, December 12, 2022: 11:45 AM

Anna Santarsieri1*, Emily Mitchell2,3*, Katherine Sturgess1*, Pauline Brice4*, Tobias F. Menne, MD PhD5*, Wendy Osborne5*, Thomas Creasey5*, Kirit M. Ardeshna6, Sarah Behan1*, Kaljit Bhuller7*, Stephen Booth8*, Nikesh D. Chavda9*, Graham P. Collins, MBBS, MA, MRCP, FRCPath, DPhil10, Dominic J. Culligan11*, Kate Cwynarski, MD6*, Andrew Davies12*, Abigail Downing13*, David Dutton14*, Michelle Furtado15*, Eve Gallop-Evans13*, Andrew Hodson16*, David Hopkins17*, Hannah Hsu6*, Sunil Iyengar18*, Stephen G. Jones19*, Kim M. Linton20*, Oliver C. Lomas, MD, PhD10, Nicolas Martinez-Calle21*, Abhinav Mathur11*, Pamela McKay, MD17*, Sateesh K. Nagumantry22*, Deirdre O'Mahony23, Elizabeth H. Phillips20*, Neil Phillips24*, John F. Rudge25*, Nimish K. Shah26*, Gwyneth Stafford1*, Alex Sternberg14*, Rachel Trickey13*, Benjamin J. Uttenthal1*, Natasha Wetherall12*, Andrew K. McMillan, MD21, Michael Stratton3*, Elisa Laurenti, PhD2, Peter J. Campbell3* and George A. Follows1*

1Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
2University of Cambridge, Wellcome - Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom
3Wellcome Sanger Institute, Cambridge, United Kingdom
4APHP, Hôpital Saint-Louis, Hemato-Oncologie, Université de Paris, Paris, France
5Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
6University College London Hospitals NHS Foundation Trust, London, United Kingdom
7University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
8Royal Berkshire Hospital, Reading, United Kingdom
9University Hospital Bristol, Bristol, United Kingdom
10Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, ENG, United Kingdom
11Aberdeen Royal Infirmary, Aberdeen, United Kingdom
12University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
13Velindre Cancer Centre, Cardiff, United Kingdom
14Great Western Hospitals NHS Foundation Trust, Swindon, United Kingdom
15Royal Cornwall Hospital, Truro, United Kingdom
16Ipswich Hospital NHS Trust, Ipswich, United Kingdom
17Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
18Royal Marsden Hospital, London, United Kingdom
19Sherwood Forest Hospitals NHS Foundation Trust, Sutton-in-Ashfield, United Kingdom
20Division of Cancer Sciences, University of Manchester and the Christie Hospital, Manchester, United Kingdom
21Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
22Peterborough City Hospital, Peterborough, United Kingdom
23Cork University Hospital, Cork, Cork, IRL
24Royal Stoke University Hospital, Stoke-on-Trent, United Kingdom
25Department of Earth Sciences, Bullard Laboratories, Cambridge, United Kingdom
26Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom

Introduction

When treating Hodgkin lymphoma (HL), it is 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. A similar replacement of procarbazine in COPP (to COPDac) has reduced gonadal toxicity and conferred a comparable long-term event-free survival to children (EuroNet-PHL-C1 trial; Mauz-Körholz et al Lancet Oncol 2021). Our own retrospective study has shown that adults treated with first-line escalated BEACOPDac (eBPDac) have a reduced blood transfusion requirement and earlier return of menstrual periods compared with real-world eBPP patients (pts) with no loss of clinical efficacy compared to HD18 eBPP pts (Santarsieri et al Blood 2021). To better understand the toxicity differences, we performed this study to compare the haematopoietic stem and progenitor cell (HSPC) mutational burden in pts who have received procarbazine and dacarbazine containing regimens. Chemotherapeutic agents are known to damage DNA and this mutational process likely causes many of the long-term chemotherapy toxicities. Little is known about the mutational signatures and mutation burdens caused by HL therapies, although a novel mutational signature (SBS25) has recently been described in two HL cell lines (Petljak et al Cell 2019).

Methods

We whole genome sequenced 6-8 single-cell derived HSPC colonies from each of 12 advanced stage HL pts (n = 91; mean sequencing depth 26X). The pts were all in remission > 6 months and had been previously treated with either eBPDac (6 cycles (n=2); 4 cycles (n=2)), eBPP (6 cycles (n=3); 5 cycles (n=1); 4 cycles (n=1)) or ABVD (n=3; all 6 cycles). Single HSPC somatic mutation burdens and mutation spectra from these chemotherapy exposed individuals were compared to those from our previously published normal cohort (n = 110; mean sequencing depth 24X) (Mitchell et al Nature 2022). In addition we have updated the outcomes of our retrospective multi-centre study of pts treated with eBPDac including additional pts and longer follow-up of the entire cohort.

Mutational analysis

The somatic single nucleotide variant mutation burden in normal adult HSPCs ranges from approximately 400 aged 20yr to 1500 aged 80yr; an average of 18 mutations accumulate with every year (Figure 1A). The HSPCs from ABVD and eBPDac-treated pts had similar minor excess somatic mutation burdens compared to aged-matched normal HSPCs of 183 (CI95% = 110-256) and 291 (CI95% = 242-340) mutations respectively. In contrast, the HSPCs from eBPP-treated pts had a striking and significantly increased excess mutation burden of 1153 (CI95% = 937-1369). Of the eBPP pts, the single patient who received 4 cycles had the lowest number of excess mutations, but noting the inter-patient variation, we cannot yet conclude that eBPP cycle number correlates with the number of mutations. Descriptive analysis of the mutational profiles (Figure 1B) revealed that every patient who received procarbazine had a clear SBS25-like mutational signature, characterised by T>A base substitutions, demonstrating for the first time that this DNA mutational signature is directly attributable to procarbazine.

Clinical data analysis

The clinical data presented last year have been updated with more pts and longer follow-up (n=288; median 2.3 yr). With this high-risk group of advanced stage pts, our data suggest that the eBPDac pts have reduced red cell transfusion requirements, reduced hospitalisation, improved menstrual period recovery and improved sperm count preservation compared with eBPP pts. The eBPDac 24-month PFS is similar to HD18 3-yr PFS (94.9% vs 92.3%) and appears superior to RATHL 5-yr PFS (81.4%). The eBPDac 24-month OS estimate is 99%.

Conclusions

We have shown that dacarbazine-containing regimens (ABVD and eBPDac) confer a lower mutation burden to HSPCs compared with procarbazine-containing eBPP and that procarbazine is the agent responsible for the SBS25 mutational signature. This work provides a model example of how genomic analysis could be used to inform therapeutic decision making in cancer. Our retrospective analysis provides strong supportive evidence that eBPDac is a highly efficacious HL treatment and noting the clear benefits in terms of HSPC genomic health, we would encourage clinicians offering eBPP to HL pts to consider replacing procarbazine with dacarbazine.

Disclosures: Santarsieri: Janssen: Honoraria; Takeda: Other: Conference funding 2021 and 2022. Osborne: MSD: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Roche: Honoraria; Servier: Honoraria; Gilead: Honoraria. Ardeshna: Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria. Collins: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SecuraBio: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants / expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants / expenses, Speakers Bureau. Cwynarski: Roche, Takeda, KITE/Gilead, Incyte: Speakers Bureau; Roche, Takeda, Celgene/BMS, Atara, Gilead/KITE, Janssen, Incyte: Consultancy; Roche, Celgene/BMS, Takeda, KITE: Other: Travel to scientific congress; BeiGene: Research Funding. Davies: Kite, a Gilead company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research support; GSK: Other: Research support; Ascerta Pharma/Astra Zeneca: Honoraria, Other: Research support; Incyte: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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: Research support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research support. Travel to scientific conferences, Research Funding; Celegne (a Bristol Myers Squibb company): 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: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational Support. Iyengar: AbbVie: Other: conference support; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Lilly: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Kite Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau. Linton: BMS/Celgene: Consultancy; Kite/Gilead: Consultancy; Beigene: Consultancy; Roche: Consultancy; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martinez-Calle: AstraZeneca: Honoraria, Other: travel support; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: travel support; Janssen: Honoraria. McKay: Abbvie: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Celgene/BMS: Consultancy; Epizyme: Consultancy; Gilead/Kite: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Recordati Rare Diseases: Consultancy; Roche: Consultancy; Takeda: Consultancy. Nagumantry: Alexion: Honoraria; Janssen: Honoraria. Shah: Abbvie: Consultancy; Janssen: Consultancy. Uttenthal: Takeda: Honoraria; Roche: Honoraria; Jazz: Honoraria. McMillan: Prosethetics: Honoraria; Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria, Other: Travel funding. Laurenti: GlaxoSmithKline: Research Funding. Campbell: FL86 Inc: Consultancy, Other: Founder. Follows: Lilly: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Astra Zeneca: Honoraria.

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