Toxicology-informed sequencing to optimise cancer therapy - Authors' reply.

# Toxicology-informed sequencing to optimise cancer therapy - Authors’ reply *The Lancet 2026* Correspondence that ibrutinib–rituximab can reach Gang Lv, Jing Yuan, Xiangxiang Jiang, inhibitor therapy might be possible chemotherapy-free disease control Jun Wu, *Z Kevin Lu and can be associated with favourable in older patients with mantle-cell lu32@email.sc.edu outcomes, but it is not yet clear lymphoma who were not eligible Department of General Surgery, The First Medical how these results compare with for transplantation. The ENRICH Center of Chinese PLA General Hospital, Beijing, chemotherapy approaches in this China (GL); Institute of Chinese Medical Sciences, trial represents a pivotal advance, group of patients.4 Ongoing studies University of Macau, Macau, China (JY); Department yet its findings invite refinement are assessing the role of MRD- of Clinical Pharmacy and Outcomes Sciences, for broader clinical practice. First, College of Pharmacy, University of South Carolina, directed treatment interruptions the absence of minimal residual Columbia, SC 29208, USA (XJ, ZKL); Department of while receiving first-line BTK inhibitor Sociobehavioral and Administrative Pharmacy, disease (MRD) monitoring reduces treatment for mantle-cell lymphoma.5 Nova Southeastern University, Fort Lauderdale, FL, the opportunity to identify patients USA (JW) We agree that the optimal first-line who could safely discontinue Bruton 1 Lewis DJ, Jerkeman M, Sorrell L, et al. Ibrutinib treatment for patients with mantle-cell tyrosine kinase (BTK) inhibition once and rituximab versus immunochemotherapy lymphoma requires further refinement, in patients with previously untreated mantle deep molecular remission is reached. cell lymphoma (ENRICH): a randomised, open- and that combined chemotherapy plus MRD-guided or circulating tumour label, phase 2/3 superiority trial. Lancet 2025; BTK-inhibitor treatment might benefit 406: 1953–68. DNA (ctDNA)-guided discontinuation patients, particularly those with high risk 2 Zheng J, Qin C, Wang Q, Tian D, Chen Z. could reduce cumulative exposure, Circulating tumour DNA-based molecular features such as high Ki67 and blastoid thereby lessening toxicological residual disease detection in resectable status.2 By contrast, chemotherapy-free cancers: a systematic review and meta- risk, improving adherence, and analysis. EBioMedicine 2024; 103: 105109. combinations of rituximab and anti- optimising health-care resources.2 3 Minotti G. Cardiovascular toxicity of Bruton CD20 antibody appear highly effective tyrosine kinase inhibitors: forget about Second, long-term indefinite in patients with low-risk mantle-cell selectivity but watch the clock. Blood Adv ibrutinib therapy might not align with 2024; 8: 3810–12. lymphoma.5,6 Future studies will refine geriatric oncology principles, where 4 Awan FT, Addison D, Alfraih F, et al. International novel treatment strategies to improve consensus statement on the management of multimorbidity, pharmacodynamic outcomes of patients with high-risk cardiovascular risk of Bruton’s tyrosine kinase variability, and cumulative organ inhibitors in CLL. Blood Adv 2022; 6: 5516–25. mantle-cell lymphoma for whom new stress are central concerns. Time- 5 Wang ML, Jurczak W, Jerkeman M, et al. approaches are required.1 Ibrutinib plus bendamustine and rituximab in restricted, adaptive regimens guided untreated mantle-cell lymphoma. N Engl J Med DJL reports consultancy and honoraria from by MRD or imaging biomarkers could 2022; 386: 2482–94. AstraZeneca, Johnson & Johnson, Beigene, Roche, maintain efficacy while minimising AbbVie, and Lilly. SR is a current employee of AstraZeneca. chronic exposure and drug–drug Authors’ reply interactions.3 Third, the observed We thank Gang Lv and colleagues for *David J Lewis, Simon Rule cardiotoxicity—atrial fibrillation the response to our study.1 We agree david.lewis17@nhs.net and cardiac deaths in approximately that minimal residual disease (MRD) Department of Haematology, University Hospitals 5–7% of participants—highlights monitoring could help to optimise the Plymouth NHS Trust, Plymouth PL6 8DH, UK (DJL); AstraZeneca, Cambridge, UK (SR) the need for toxicology-informed treatment of mantle-cell lymphoma 1 Lewis DJ, Jerkeman M, Sorrell L, et al. Ibrutinib pharmacovigilance, such as baseline with ibrutinib and other Bruton tyrosine and rituximab versus immunochemotherapy cardiac biomarkers, structured rhythm kinase (BTK) inhibitors. However, in patients with previously untreated mantle monitoring, and proactive cardio- no study comparing outcomes of cell lymphoma (ENRICH): a randomised, open- label, phase 2/3 superiority trial. Lancet 2025; oncology collaboration.3,4 Integrating continuous use of BTK inhibitors 406: 1953–68. pharmacologic toxicology with versus an MRD-driven approach has yet 2 Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in molecular response profiling (eg, MRD been reported. Currently, continuous untreated mantle-cell lymphoma. N Engl J Med or ctDNA) could yield an exposure– therapy with BTK inhibitors remains 2022; 386: 2482–94. response–toxicity framework or the standard of care in most first-line 3 Wang M, Salek D, Belada D, et al. Acalabrutinib plus bendamustine-rituximab in untreated a therapeutic monitoring index, mantle-cell lymphoma studies.2,3 mantle cell lymphoma. J Clin Oncol 2025; balancing biological remission with MRD was performed as an 43: 2276–84. systemic tolerance. Lastly, short- experimental endpoint in the ENRICH 4 Giné E, de la Cruz F, Jiménez Ubieto A, et al. Ibrutinib in combination with rituximab for course chemoimmunotherapy trial using a novel flow cytometric panel, indolent clinical forms of mantle cell induction followed by BTK-inhibitor and results will be published in a future lymphoma (Imantle-cell lymphoma-2015): a multicenter, open-label, single-arm, phase II maintenance could offer a pragmatic manuscript, but MRD results were not trial. J Clin Oncol 2022; 40: 1196–205. and globally applicable compromise, used to inform treatment decisions. 5 Jerkeman M, Wader KF, Glimelius I, et al. maintaining remission depth while In low-risk mantle-cell lymphoma, Acalabrutinib and rituximab in elderly patients with newly diagnosed mantle cell lymphoma potentially reducing long-term a single-arm study enrolling selected including a matched population-based external cardiovascular and systemic toxicity.5 patients at low risk has demonstrated comparator—the Nordic lymphoma group NLG-mantle-cell lymphoma8 (ALTAMIRA) that cessation of continuous BTK We declare no competing interests. phase ii trial. Blood 2024; 144 (suppl 1): 747. Correspondence 6 Le Gouill S, Morschhauser F, Chiron D, et al. serious health-related suffering,2 a Melbourne, Melbourne, VIC, Australia (CP, JP); Ibrutinib, obinutuzumab, and venetoclax in figure projected to grow to 48 million by Monash University, Melbourne, VIC, Australia (PK) relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood 2021; 2060; 83% of these deaths will occur 1 Romanello M, Walawender M, Hsu S-C, et al. 137: 877–87. in low-income and middle-income The 2025 report of the Lancet Countdown on health and climate change: climate change countries.4 However, these predictions action offers a lifeline. Lancet 2025; do not take into account the escalating 406: 2804–57. Climate adaptation 2 Knaul FM, Farmer PE, Krakauer EL, et al. impact of climate change and, as such, Alleviating the access abyss in palliative care must address global are probably underestimates. and pain relief—an imperative of universal health coverage: the Lancet Commission Despite presenting a comprehensive inequity of suffering report. Lancet 2018; 391: 1391–454. suite of 57 indicators, the Countdown 3 Tripodoro VA, Fidalgo JFL, Pons JJ, et al. includes no measure of palliative care First-ever global ranking of palliative care: 2025 world map under the new WHO The 2025 Lancet Countdown on health capacity, access, or preparedness. framework. J Pain Symptom Manage 2025; and climate change highlights the Without such metrics, countries have 70: 447–58. accelerating human toll of climate no way to evaluate their capacity to 4 Sleeman KE, de Brito M, Etkind S, et al. The escalating global burden of serious health- inaction and documents record heat- manage or relieve suffering among related suffering: projections to 2060 by world related deaths, widespread food people who are dying, displaced, regions, age groups, and health conditions. Lancet Glob Health 2019; 7: e883–92. insecurity, and intensifying climate- or chronically ill under worsening driven disease risks.1 However, environmental conditions, and no one aspect of the health response that imperative to do so. Adaptation Broadening metrics in is becoming increasingly urgent as the strategies can risk reinforcing global climate emergency intensifies remains inequities by prioritising individuals the Lancet Countdown absent from the report: equitable with curable illness and neglecting on health and climate access to palliative and end-of-life care. those with serious or terminal disease The regions predicted to have the in increasingly harsh, resource-scarce change greatest increases in climate-related environments. mortality (south Asia, sub-Saharan This omission is not only a technical Reading the Lancet Countdown,1 I felt Africa, and small island developing one but also an ethical one. The both concern and unease. The evidence states) are the same regions in which Countdown rightly emphasises of worsening climate-related health the Lancet Commission on palliative equity, gender-responsiveness, and impacts is deeply saddening. But the care and pain relief identified the Indigenous knowledge,1 but not Countdown’s treatment of energy felt world’s most severe burden of the equitable relief of suffering. narrow, presenting renewables as the serious health-related suffering.2 Communities least responsible for only solution while omitting other Many countries in these regions greenhouse gas emissions now face low-carbon options. Having been a have isolated or no palliative care the twin injustice of premature death committed climate activist, I have since services.3 Access to effective pain relief and inadequate care at the end of life. spent several years trying to understand remains profoundly unequal,2 with A just climate response must why energy debates have become 10% of countries accounting for more recognise palliative care as fund- polarised. One recurring concern is than 90% of global medical opioid amental to adaptation and the the narrative that fossil fuels are bad consumption.2 This inequity mirrors resilience of health systems. Climate and renewables are good, although the global distribution of climate change will increasingly bring death, directionally correct, this oversimplifies vulnerability; people in the highest- displacement, and suffering. Ensuring system-level challenges around cost income groups will feel the effects of that these deaths are accompanied by and reliability.2 These concerns should climate change last, whereas people dignity and relief, rather than neglect, be engaged, not waved away. most exposed to the effects of climate is a moral imperative and a test of our Solar and wind play an important change, including people in low- collective humanity. role, but electricity grids must operate income or climate-vulnerable settings, around the clock, including on cold, CP reports a grant from the Australian Government lack the means to relieve health- (Research Training Program PhD Scholarship). All windless winter evenings. A grid related suffering. other authors declare no competing interests. dominated by renewables requires Global mean annual temperatures *Cara Platts, Jennifer Philip, extensive transmission infrastructure, are now more than 1·5°C higher than Paul Komesaroff backup generation, and balancing pre-industrial temperatures, and heat- c.platts@unimelb.edu.au services. Today, that backup is related mortality has increased by 63% overwhelmingly gas, which must Melbourne Medical School, University of since the 1990s.1 Meanwhile, at least Melbourne, Melbourne, VIC 3065, Australia (CP, JP); be maintained even when unused. 25·5 million people die annually from Palliative Care Service, St Vincent’s Hospital As a result, although renewables are 1784 --- [PDF原文](https://sci-net.xyz/storage/7932541/8952117d4f7b16597dcffec0eb16382ce61d5a941b7684b1bee26e8608b832ad/Toxicology-informed-sequencing-to-optimise-cancer-therapy-Authors-reply.pdf) DOI: 10.1016/S0140-6736(26)00791-9