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Item[18F]FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial(ELSEVIER SCI LTD, 2022-08)BACKGROUND: Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [18F]flurodeoxyglucose ([18F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [18F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy-referred to here as antimicrobial rationalisation-within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete. FINDINGS: Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [18F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [18F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6-6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [18F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06-5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [18F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11-4·83; p=0·024). INTERPRETATION: [18F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [18F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning. FUNDING: National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study.
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ItemSuccessful identification of predictive profiles for infection utilising systems-level immune analysis: a pilot study in patients with relapsed and refractory multiple myeloma(WILEY, 2021)OBJECTIVES: Patients with multiple myeloma (MM) are at increased risk for infection. Clinical assessment of infection risk is increasingly challenging in the era of immune-based therapy. A pilot systems-level immune analysis study to identify predictive markers for infection was conducted. METHODS: Patients with relapsed and/or refractory MM (RRMM) who participated in a treatment trial of lenalidomide and dexamethasone were evaluated. Data on patient demographics, disease and episodes of infection were extracted from clinical records. Peripheral blood mononuclear cells (PBMCs) collected at defined intervals were analysed, with or without mitogen re-stimulation, using RNA sequencing and mass cytometry (CyTOF). CyTOF-derived cell subsets and RNAseq gene expression profiles were compared between patients that did and did not develop infection to identify immune signatures that predict infection over a 3-month period. RESULTS: Twenty-three patients participated in the original treatment trial, and we were able to access samples from 17 RRMM patients for further evaluation in our study. Nearly half the patients developed an infection (8/17) within 3 months of sample collection. Infections were mostly clinically diagnosed (62.5%), and the majority involved the respiratory tract (87.5%). We did not detect phenotypic or numerical differences in immune cell populations between patients that did and did not develop infections. Transcriptional profiling of stimulated PBMCs revealed distinct Th2 immune pathway signatures in patients that developed infection. CONCLUSION: Immune cell counts were not useful predictors of infection risk. Functional assessment of stimulated PBMCs has identified potential immune profiles that may predict future infection risk in patients with RRMM.