Authors' reply to ‘Comments on dose‐dependent impairment of brain functional and microstructural connectivity during leukaemia chemotherapy’

We thank the correspondent for their interest and comments regarding our study. We agree that a lack of a dedicated control cohort is a limitation of our study; however, significant barriers limit this approach. Importantly, the cohorts suggested are not true controls but in fact are receiving alternative interventions based on patient and disease factors. Because intensive cytotoxic induction chemotherapy is standard first-line therapy for acute myeloid leukaemia (AML), patients who instead receive ‘chemotherapy-free’ regimens or supportive care alone are by definition medically unsuitable for chemotherapy, typically due to advanced age and/or comorbidities. These patients may be more likely to have pre-morbid cognitive impairment and to experience different patterns of treatment-related cognitive changes and other complications. Furthermore, even these chemotherapy-free interventions still carry risks of infection, transfusional iron overload and cytokine-mediated neuroinflammation, which are all potential contributors to cognitive impairment. The most appropriate control group would be age-matched healthy volunteers from the community, allowing us to at least confirm that the functional and microstructural changes we observed in our AML cohort over a short (~6 months) timeframe are not replicated in healthy controls. While we acknowledge the potential confounding effects of the active leukaemia state and small cohort group, our finding of a dose-dependent correlation between cumulative cytarabine exposure and reduced functional connectivity is suggestive of a treatment-linked effect rather than disease state alone. We do agree that further work is required to confirm our findings and to understand potential mechanisms for the observed effects. We hope that our study supports patients and clinicians in understanding ‘chemobrain’ symptoms and encourages the scientific community to explore this phenomenon in greater detail. Ashleigh P. Scott: Conceptualization; investigation; funding acquisition; writing – original draft; methodology; validation; visualization; writing – review and editing; formal analysis; project administration; data curation; supervision; resources. Ada Lo: Writing – review and editing. Ying Xia: Writing – review and editing. Kate Thompson: Writing – review and editing. Harriet Bodimeade: Writing – review and editing. Amir Fazlollahi: Writing – review and editing. Nicholas Weber: Resources. Cameron Curley: Resources. Stewart Hunt: Resources. Kirk Morris: Resources. Caroline McNamara: Resources. Nilu Perera: Resources. Elango Subramoniapillai: Resources. Steven W. Lane: Resources. Glen A. Kennedy: Supervision. Olivier Salvado: Supervision. Javier Urriola: Writing – review and editing. Katie L. McMahon: Writing – review and editing; supervision. This study was funded by an RBWH Foundation Grant (18/QRBW/45522). The authors have no conflicts of interest to disclose. This study was approved by the Metro North Human Research Ethics Committee (18/QRBW/45522) and conducted in compliance with applicable laws and regulations, and according to principles of the Declaration of Helsinki 2008. All participants signed individual informed consent prior to any study activities or data collection. The study was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000401156). Individual participant imaging data are not publicly available due to participant privacy requirements, and hence summary data are published in full in the supplementary appendix. Deidentified imaging datasets are available from the corresponding author on reasonable request.