[ 18 F]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.

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 [ ¹⁸ F]flurodeoxyglucose ([ ¹⁸ F]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 [ ¹⁸ F]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 [ ¹⁸ F]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 [ ¹⁸ F]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 [ ¹⁸ F]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 [ ¹⁸ F]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: [ ¹⁸ F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [ ¹⁸ F]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.
Competing Interests: Declaration of interests SH has received a grant from Janssen, and honoraria from Celgene, Janseen, Novartis, and Kite/Gilead. OB has received honoraria from MSD and Abbvie. BT has received grants from Sanofi Pasteur, MSD, and Seqirus; received honoraria from Pfizer, MSD, and Gilead; and is on the data safety monitoring board (DSMB) of a study with CSL-Behring. SC has received educational grants from F2G and MSD Australia. JS has received honoraria from Alexian Australasia, Sobi Pharmaceuticals, Novartis, and Takeda; is on the DSMB and advisory board from Prevail Therapeutics; and has a leadership role in the Australian Bone Marrow Donor Registry. MY has received grants from the National Health and Medical Research Council (NHMRC) of Australia, MSD Australia, and the Medical Research Futures Fund and consulting fees, honoraria, and Advisory Board involvement for MSD Australia. TS has received speaker fees from Novartis and is on scientific committees for Biogen and Hartmann DE. SYT and AD have received a grant from Gilead. RH is the honorary director of Neuroendocrine Cancer Australia and PreMIT Pty and is the founder and equity holder of PreMIT Pty. MS has been awarded two NHMRC grants as well as grants from Gilead, Merck, and F2G and honoraria from Pfizer, Merck, and Gilead and is on the DSMB and advisory board of Pfizer, F2G, and Roche with all payments to an institution. All other authors declare no competing interests.
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