CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study.

ABSTRACT: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

Enablers and barriers to referral and delivery of multidisciplinary prehabilitation in the autologous stem cell transplant population: a theory-based interview study.

PURPOSE: Health care professionals (HCP) play a vital role in effectiveness of prehabilitation programs, but information is limited about what assists HCP deliver an effective service. This study evaluated HCP perceptions of enablers and barriers to two behaviours: referral for, and delivery of, multidisciplinary prehabilitation prior to autologous stem cell transplant. METHODS: Based on the Theoretical Domains Framework (TDF) of behaviour change, we conducted semi-structured interviews, purposively sampling 14 participants (from various healthcare disciplines) at a tertiary cancer centre. Discipline-specific topic guides were created based on the TDF and the behaviours appropriate to each discipline. Interviews were audio-recorded, transcribed verbatim, anonymised, content analysed (grouping, then labelling, thematically similar responses), and classified into theoretical domains. Structured decision rules were used to classify themes as high, medium, or low priority. RESULTS: Fifty enablers and 31 barriers were identified; of these 26 enablers and 16 barriers classified as high priority. Four domains had the most frequent high-priority enablers: Social professional role and identity (e.g. multidisciplinary teamwork); Beliefs about consequences (e.g. patient benefit); Memory, attention, and decision processes (e.g. refer as early as possible); and Environmental context and resources (e.g. electronic medical records are beneficial). High-priority barriers were most frequent in four domains: Memory, attention, and decision processes (e.g. conflicting views about who should be referred); Environmental context and resources (e.g. lack of time); Social influences (e.g. families); and Emotions (e.g. patient distress). CONCLUSION: Participants reported more enablers than barriers. Findings can support delivery of prehabilitation programs in hospital settings where uptake remains low.

Impact of an allied health prehabilitation service for haematologic patients receiving high-dose chemotherapy in a large cancer centre.

PURPOSE: Evaluate the impact of a new multidisciplinary allied health prehabilitation service in haematologic cancer patients receiving high-dose chemotherapy with autologous stem cell transplant (AuSCT). METHODS: In a tertiary cancer centre, 12 months of prospectively collected data was retrospectively analysed. Patients were referred to an allied health service for individualised exercise prescription, nutrition intervention and, if indicated through screening, psychological intervention. Impact and operational success were investigated using the RE-AIM framework: patient uptake of the service and sample representativeness (reach); effectiveness in terms of changes in outcomes from initial to pre-transplant assessment; adoption of the service by key stakeholders; fidelity of the prescribed exercise program (implementation); and the extent to which the new service had become routine practice (maintenance). RESULTS: One hundred and eighty-three patients were referred to the AuSCT service over 12 months, of whom 133 (73%) were referred into the prehabilitation service, 128 (96%) were eligible and 116 (91%) participated. Patients were representative of Australian AuSCT patients. Eighty-nine patients reached pre-transplant assessment by data censoring; 6-min walk distance (n = 45/89, 51%) improved a mean (95% CI) of 39.9 m (18.8 to 61.0, p = < 0.005) from baseline. Fidelity of exercise prescription was moderate with 72% of eligible patients receiving the intended exercise interventions. The referral trend over time (maintenance) was high after the initiation period. CONCLUSION: The prehabilitation service was well adopted by clinicians. Clinically relevant improvements in outcomes were demonstrated. Recommendations, including development of well-integrated discipline-specific assessment intervention and measurement protocols, are highlighted for service improvement. Prehabilitation should be routinely considered to support patients undergoing AuSCT.

Cytomegalovirus DNAemia and disease: current-era epidemiology, clinical characteristics and outcomes in cancer patients other than allogeneic haemopoietic transplantation.

BACKGROUND: High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. METHODS: A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. RESULTS: Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. CONCLUSION: Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.

The role of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG PET/CT) in assessment of complex invasive fungal disease and opportunistic co-infections in patients with acute leukemia prior to allogeneic hematopoietic cell transplant.

INTRODUCTION: Individuals diagnosed with acute lymphoid and myeloid malignancies are at significant risk of invasive fungal and bacterial infections secondary to their marked immunocompromised states with a significant high risk of mortality. The role of metabolic imaging with 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) has been increasingly recognized in optimizing the diagnosis of invasive infection, monitoring the response to therapy and guiding the duration of antimicrobial therapy or need to escalate to surgical intervention. METHODS: Two distinct cases of pulmonary co-infection of rare fungal and bacterial pathogens are explored in severely immunocompromised individuals where FDG PET/CT aided both patients to make a full recovery and transition to HCT. The first case explores mixed Scedosporium apiospermum and Rhizomucor pulmonary infection on a background of T cell/myeloid mixed phenotype acute leukemia ultimately warranting long-term antifungal therapy and lobectomy prior to HCT. The second case explores Fusarium and Nocardia pulmonary infection on a background of relapsed AML also warranting surgical resection with lobectomy and long-term antimicrobials prior to transition to HCT. DISCUSSION: The cases highlight the utility of FDG PET/CT to support the diagnosis of infections, including the presence or absence of disseminated infection, and to provide highly sensitive monitoring of the infection over time. FDG PET/CT played a key role in directing therapy duration decisions and prompted the necessity for surgical intervention. Ultimately, the use of FDG PET/CT allowed for a successful transition to HCT highlighting its value in this clinical setting. CONCLUSION: FDG PET/CT has an emerging role in the diagnostic and monitoring pathway for complex infections in high-risk immunocompromised patients.

Mycosis fungoides and Sézary syndrome: Australian clinical practice statement.

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial.

BACKGROUND: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. METHODS: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. FINDINGS: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. INTERPRETATION: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. FUNDING: Kyowa Kirin.

A phase 1 clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results.

Marizomib (MRZ) is an irreversible, pan-subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low-dose dexamethasone (Lo-DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3-0·5 mg/m2 ) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo-DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities (DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients.

Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy.

Numerous systemic treatment options exist for patients with mycosis fungoides (MF) and Sézary syndrome (SS), but no large comparative studies are published. To study the efficacy of treatments, a retrospective analysis of our cutaneous lymphoma database was undertaken, with 198 MF/SS patients undergoing systemic therapies. The primary end point was time to next treatment (TTNT). Patients with advanced-stage disease made up 53%. The median follow-up time from diagnosis for all alive patients was 4.9 years (range 0.3-39.6), with a median survival of 11.4 years. Patients received a median of 3 lines of therapy (range 1-13), resulting in 709 treatment episodes. Twenty-eight treatment modalities were analyzed. The median TTNT for single- or multiagent chemotherapy was only 3.9 months (95% confidence interval [CI] 3.2-5.1), with few durable remissions. α-interferon gave a median TTNT of 8.7 months (95% CI 6.0-18.0), and histone deacetylase inhibitors (HDACi) gave a median TTNT of 4.5 months (95% CI 4.0-6.1). When compared directly with chemotherapy, interferon and HDACi both had greater TTNT (P < .00001 and P = .01, respectively). This study confirms that all chemotherapy regimens assessed have very modest efficacy; we recommend their use be restricted until other options are exhausted.

Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia.

In a phase I study of autologous chimeric antigen receptor (CAR) anti-LeY T-cell therapy of acute myeloid leukemia (AML), we examined the safety and postinfusion persistence of adoptively transferred T cells. Following fludarabine-containing preconditioning, four patients received up to 1.3 × 109 total T cells, of which 14-38% expressed the CAR. Grade 3 or 4 toxicity was not observed. One patient achieved a cytogenetic remission whereas another with active leukemia had a reduction in peripheral blood (PB) blasts and a third showed a protracted remission. Using an aliquot of In111-labeled CAR T cells, we demonstrated trafficking to the bone marrow (BM) in those patients with the greatest clinical benefit. Furthermore, in a patient with leukemia cutis, CAR T cells infiltrated proven sites of disease. Serial PCR of PB and BM for the LeY transgene demonstrated that infused CAR T cells persisted for up to 10 months. Our study supports the feasibility and safety of CAR-T-cell therapy in high-risk AML, and demonstrates durable in vivo persistence.

Targeting the ribosome to treat multiple myeloma.

The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models in vitro and in vivo. In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell-cycle arrest and apoptotic cell death. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 in vivo. In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk∗MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.

Alemtuzumab therapy in T-cell prolymphocytic leukemia: comparing efficacy in a series treated intravenously and a study piloting the subcutaneous route.

Intravenous alemtuzumab is an effective and well-tolerated treatment for T-cell prolymphocytic leukemia (T-PLL). Alemtuzumab given intravenously as first-line treatment in 32 patients resulted in an overall response rate of 91% with 81% complete responses. Studies in B-cell chronic lymphocytic leukemia have shown subcutaneous alemtuzumab to be equally as effective as intravenous alemtuzumab. The UKCLL05 pilot study examined the efficacy and toxicity of this more convenient method of administration in 9 previously untreated patients with T-PLL. Only 3 of 9 patients (33%) responded to treatment. Furthermore, 2 of 9 patients (22%) died while on treatment. Recruitment was terminated because of these poor results. After rescue therapy with intravenous alemtuzumab and/or pentostatin, median progression-free survival and overall survival were similar to the intravenous group. Alemtuzumab delivered intravenously, but not subcutaneously, remains the treatment of choice for previously untreated T-PLL.

Romidepsin for cutaneous T-cell lymphoma.

Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.

Allogeneic stem cell transplantation achieves long-term remissions in mantle cell lymphoma, including in TP53-mutated disease.

Cytarabine-containing chemoimmunotherapy followed by autologous transplantation and rituximab maintenance achieves durable remissions for most patients with mantle cell lymphoma (MCL). However, patients with TP53-mutated disease have poor outcomes with standard approaches. We previously reported that allogeneic stem cell transplantation (alloSCT) achieved durable remissions in MCL, however follow-up among patients with TP53-mutated disease was limited. Here we report extended follow-up of the overall cohort (n = 36) and TP53-mutated subset (n = 13) (median follow-up 10.8 and 4.2 years, respectively). Estimated overall survival was 56% at 10 years for the overall cohort and 59% at 4 years for the TP53-mutated subset. Among patients with TP53-mutated disease, no relapses occurred beyond 6 months post-transplant. Survival after post-alloSCT disease relapse was poor (median 2.1 years). These data confirm that alloSCT can be curative in MCL, including patients with TP53-mutated disease, and should be considered for earlier utilization in this subgroup for whom conventional chemoimmunotherapy is ineffective.

Treatment approaches for patients with TP53-mutated mantle cell lymphoma.

Mantle cell lymphoma is an uncommon subtype of lymphoma characterised by clinical and biological heterogeneity. Although most patients with mantle cell lymphoma have durable responses after chemoimmunotherapy, there is a need to prospectively identify high-risk subsets of patients for whom disease control with standard chemotherapy will be short lived. Among the available prognostic factors, TP53 mutations are uniquely informative owing to their strong association with early disease progression and death among patients receiving conventional chemoimmunotherapy, with the highest negative prognostic value compared with other established risk indicators, including the mantle cell lymphoma international prognostic index, histological features, elevated Ki-67, and other genetic lesions. The poor outcomes for patients with TP53-mutated mantle cell lymphoma receiving chemoimmunotherapy and second-line Bruton tyrosine kinase inhibitors represent an urgent need for alternative approaches. In this Review, we synthesise the available data to inform the management of this high-risk subset of patients and present a treatment strategy prioritising clinical trials and early use of cellular therapies.

High Rates of Seroprotection and Seroconversion to Vaccine-Preventable Infections in the Early Post-Autologous Stem Cell Transplant Period.

In patients early post-autologous stem cell transplant, seroprotection rates were high for Hemophilus influenzae type B and tetanus toxoid (70%-90%) but lower for Streptococcus pneumoniae (30%-50%) including after revaccination. There were high rates of seropositivity (67%-86%) to measles, mumps, and rubella and varicella zoster virus. Durability of protection requires assessment.

Acute kidney injury requiring dialysis following carmustine and etoposide during autologous stem cell transplantation.

BACKGROUND: The Stanford BCNU protocol (carmustine, etoposide and cyclophosphamide) is a high-dose conditioning regimen widely used prior to autologous stem cell transplantation. While acute renal failure requiring renal replacement therapy is a known but rare complication of autologous stem cell transplantation, acute nephrotoxicity following carmustine and etoposide has not yet been reported. CASE: We present the first case of carmustine-induced acute kidney injury in the setting of autologous stem cell transplantation and perform a review of the literature. Renal failure was associated with a sharp rise in serum creatinine, oliguria and trace proteinuria. Urgent haemodialysis was required; however, renal failure resolved after 7 days. CONCLUSION: Although a rare complication, its severity mandates close monitoring of renal function as early recognition and treatment may limit long-term sequelae.

[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.

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.