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

Santarsieri, Anna; Mitchell, Emily; Sturgess, Katherine; Brice, Pauline; Menne, Tobias; Osborne, Wendy; Creasey, Thomas; Ardeshna, Kirit M.; Behan, Sarah; Bhuller, Kaljit; Booth, Stephen; Chavda, Nikesh D.; Collins, Graham P.; Culligan, Dominic; Cwynarski, Kate; Davies, Andrew; Downing, Abigail; Dutton, David; Furtado, Michelle; Gallop‐Evans, Eve; Hodson, Andrew; Hopkins, David R.; Hsu, Hannah; Iyengar, Sunil; Jones, Stephen G.; Linton, Kim; Lomas, Oliver; Martínez‐Calle, Nicolás; Mathur, Abhinav; McKay, Pamela; Nagumantry, Sateesh K.; O’Mahony, Deirdre; Phillips, E.; Phillips, Neil; Rudge, John F.; Shah, Nimish; Stafford, Gwyneth; Sternberg, Alex; Trickey, Rachel; Uttenthal, Ben; Wetherall, Natasha; McMillan, Andrew; Stratton, Michael; Laurenti, Elisa; Campbell, Peter J.; Follows, George

doi:10.1182/blood-2022-166543

Cited by 6 publications

(7 citation statements)

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“…Indeed, N647I (GTT>GAT), the only other STAT3 mutation (besides Y640F) enriched in HL (Supplementary Table S5), also matches the predominant pattern of SBS25. Recently, Santarsieri and colleagues ( 30 ) found that procarbazine, an alkylating drug used in HL treatment, is likely responsible for the SBS25 signature. In our cohort, 192 of 356 HL survivors, including SJHL018702 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The causality of SBS25 to STAT3 Y640F was further supported, with an estimated probably of 0.985 to 1.0, by scWGS data generated from an HL survivor exposed to procarbazine. Recently, Santarsieri and colleagues ( 30 ) found that procarbazine, an alkylating drug used in HL treatment, is likely responsible for SBS25 and recommended that procarbazine be replaced with dacarbazine because dacarbazine is as effective without incurring an excess mutation burden ( 30 ). Our findings from scWGS profiling as well as correlative analysis of procarbazine and CH mutation context in the HL survivors (Supplementary Table S6) provide further support for their recommendation.…”

Section: Discussionmentioning

confidence: 99%

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Dynamics of Age- versus Therapy-Related Clonal Hematopoiesis in Long-term Survivors of Pediatric Cancer

et al. 2023

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We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep-sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH-gene specific to Hodgkin lymphoma survivors, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T-cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial-sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, while therapy-related CH remains stable decades post-treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dynamics of Age- versus Therapy-Related Clonal Hematopoiesis in Long-term Survivors of Pediatric Cancer

et al. 2023

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“…Similarly, SBSB, also with predominant T>A substitutions, is found in all patients exposed to eBEACOPP, but with smaller contributions. These two mutational signatures have been recently ascribed to procarbazine treatment 21,22 . SBSC was detected in patients treated with either ABVD or eBEACOPDac (Figure 1C).…”

Section: Resultsmentioning

confidence: 94%

Procarbazine-induced Genomic Toxicity in Hodgkin Lymphoma Survivors

Santarsieri,

Mitchell,

Pham

et al. 2024

Preprint

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BackgroundProcarbazine-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.MethodsTo 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.ResultseBEACOPP-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%; CI95=90.3-96.4%) mirrored that of 1945 HD18-trial eBEACOPP patients (93.3%; CI95=92.1-94.4%). eBEACOPDac-treated patients required fewer blood transfusions, demonstrated higher post-chemotherapy sperm concentrations, and experienced earlier resumption of menstrual periods.ConclusionsProcarbazine 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.

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“…Many UK centres now use dacarbazine in place of procarbazine (escBEACOPDac) due to evidence of reduction in haematological and gonadal toxicity with the former. 19 A potential reduction in haematological toxicity in older patients may be clinically important, and the intravenous formulation may be attractive by reducing 'tablet burden' in patients who often have polypharmacy. We plan to amend ACOPP in this way in the future ('ACOPDac'), with careful assessment of deliverability and outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Interim assessment after 2 cycles allows timely decision‐making to stop or abbreviate treatment if inadequate response is seen or if there is excessive toxicity. Many UK centres now use dacarbazine in place of procarbazine (escBEACOPDac) due to evidence of reduction in haematological and gonadal toxicity with the former 19 . A potential reduction in haematological toxicity in older patients may be clinically important, and the intravenous formulation may be attractive by reducing ‘tablet burden’ in patients who often have polypharmacy.…”

Section: Discussionmentioning

confidence: 99%

‘ACOPP’ chemotherapy for older and less fit patients with Hodgkin lymphoma—A multicentre, retrospective study

et al. 2023

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SummaryManagement of classical Hodgkin lymphoma in older patients is challenging due to poor tolerance of the chemotherapy regimens used in younger patients. We modified the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), whereby bleomycin and etoposide were removed and cyclophosphamide dose was reduced, for older patients with co‐morbidities. Here we present data from the first 41 patients treated with ‘ACOPP’ across 3 centres, demonstrating that it can be delivered, with a favourable toxicity profile (TRM 2%) and promising efficacy (2‐year PFS and OS, 73% (95% CI: 52–94) and 93% (95% CI: 80–100) respectively).

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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

Cited by 6 publications

References 0 publications

Dynamics of Age- versus Therapy-Related Clonal Hematopoiesis in Long-term Survivors of Pediatric Cancer

Dynamics of Age- versus Therapy-Related Clonal Hematopoiesis in Long-term Survivors of Pediatric Cancer

Procarbazine-induced Genomic Toxicity in Hodgkin Lymphoma Survivors

‘ACOPP’ chemotherapy for older and less fit patients with Hodgkin lymphoma—A multicentre, retrospective study

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