Medicine (RMH) - Research Publications
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ItemEvaluating the cost-effectiveness of [18F]FDG-PET/CT for investigation of persistent or recurrent neutropenic fever in high-risk haematology patients(BMC, 2023-12-15)BACKGROUND: A recent randomised trial demonstrated [18F]fluorodeoxyglucose positron-emission tomography in combination with low-dose CT (FDG-PET/CT), compared to standard of care computed tomography (CT) imaging, positively impacted antimicrobial management and outcomes of acute leukaemia and haematopoietic stem cell transplant recipients with persistent and recurrent neutropenic fever. We conducted an economic evaluation from a healthcare perspective alongside the clinical trial. METHODS: Unit costs in Australian dollars were applied to all resources used (antimicrobials, diagnostic tests, ICU and hospital bed days). Effectiveness was measured as number of patients with antimicrobial rationalisation, 6-month mortality and quality-adjusted life years (QALYs) derived from patient-reported trial-based health-related quality-of-life. Generalised linear models were used to analyse costs and outcomes. Incremental cost-effectiveness ratios (ICERs) for all outcomes and net monetary benefit (NMB) for QALYs were calculated. We performed bootstrapping with 1000 replications using the recycled predictions method. RESULTS: The adjusted healthcare costs were lower for FDG-PET/CT (mean $49,563; 95%CI 36,867, 65,133) compared to CT (mean $57,574; 95% CI 44,837, 73,347). The difference in QALYs between the two groups was small (0.001; 95% CI -0.001, 0.004). When simulated 1000 times, FDG-PET/CT was the dominant strategy as it was cheaper with better outcomes than the standard CT group in 74% of simulations. The estimated NMBs at willingness-to-pay thresholds of $50,000 and $100,000 per QALY were positive, thus FDG-PET/CT remained cost-effective at these thresholds. CONCLUSIONS: FDG-PET/CT is cost effective when compared to CT for investigation of persistent/recurrent neutropenic fever in high-risk patients, providing further support for incorporation of FDG-PET/CT into clinical guidelines and funding. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT03429387.
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ItemEffective CMV prophylaxis with high-dose valaciclovir in allogeneic hematopoietic stem-cell recipients at a high risk of CMV infection(WILEY, 2023-02)BACKGROUND: Cytomegalovirus (CMV) infection increases mortality and morbidity following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Universal antiviral prophylaxis with letermovir is effective but unsubsidized in Australia. Valaciclovir demonstrates anti-CMV activity in high doses, but few current real-world studies explore its use as primary prophylaxis in high-risk patients post-alloHSCT. METHODS: We performed a retrospective analysis of alloHSCT recipients at high risk of clinically significant CMV infection (cs-CMVi), defined as a plasma CMV DNA viral load of >400 IU/ml requiring preemptive therapy, or CMV disease. High-risk recipients were CMV seropositive and underwent T-cell depleted, haploidentical or umbilical cord stem-cell transplants. Consecutive patients transplanted from July 2018 to January 2020, treated with valaciclovir 2 g TDS from day +7 to +100 (HD-VALA), were compared to a historical cohort (July 2017-June 2018) who only received preemptive CMV therapy, and standard valaciclovir (SD-VALA) for varicella/herpes prophylaxis. We compared incidence of and time to cs-CMVi. RESULTS: In the SD-VALA cohort (n = 27, median CMV follow-up duration 259 days), 23/27 (85%) developed cs-CMVi at a median of 39 days. For the HD-VALA cohort (n = 35, median CMV follow-up duration 216 days), 19/35 (54%) developed cs-CMVi, at a median of 68 days. Time to cs-CMVi was significantly longer in HD-VALA cohort (p < .0001). On multivariate analysis, HD VALA reduced the risk of cs-CMVi (HR 0.32, p = .0005). CONCLUSIONS: In alloHSCT recipients at high risk for cs-CMVi, HD-VALA resulted in lower cumulative reactivation, and delayed reactivation, reducing requirement for preemptive CMV therapy in the early post-engraftment period.
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ItemReal-world utility of early measurable residual disease assessments by multi-parametric flow cytometry in adult patients with B-lymphoblastic leukemia receiving Hyper-CVAD induction chemotherapy(WILEY, 2023-02)Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p = .426) or overall survival (OS) (p = .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p = ·005) and OS (p = .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.
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ItemDysregulation of immune cell and cytokine signalling correlates with clinical outcomes in myelodysplastic syndrome (MDS)(WILEY, 2022-04)OBJECTIVES: Myelodysplastic syndromes (MDS) are characterised by ineffective haematopoiesis. Although hypomethylating agents (HMA) have improved survival in higher-risk MDS, most patients eventually succumb to progressive disease. Utilising samples collected prospectively from three MDS clinical trials, we analysed genetic and immunological biomarkers and correlated them with clinical outcomes. METHODS: A hundred and fifty four samples were analysed from 133 de novo MDS patients for T-cell and myeloid cell immunophenotyping and gene expression analysis. Treatments were with HMA or immunomodulatory drug (IMiD) alone or in combination. RESULTS: We observed differences in immune cell subsets between lower- and higher-risk IPSS groups with NKT cells, MDSCs, intermediate-proinflammatory and non-classical monocytes being higher in the latter group, while naïve CD4+ T cells were reduced. Intermediate-proinflammatory monocytes were increased in non-responders and those failing to achieve at least a haematological improvement. Proinflammatory NKT cells were increased at diagnosis for patients failing to derive clinical benefit after 12 months of treatment. Gene expression analysis of paired bone marrow (BM) colony-forming units (CFUs) from diagnosis and 4 cycles post-treatment confirmed that genes involved in cytokine signalling were downregulated in C4 normal colonies. CONCLUSIONS: These findings support the central roles of dysregulation in innate immunity and inflammatory signalling in the pathogenesis of MDS which correlated with clinical outcomes post-treatment.
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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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ItemA phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma(BMC, 2023-01-28)BACKGROUND: N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR-MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity. RESULTS: Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1-20). Grade 3-4 adverse events (AEs) were reported in seven (54%; 95% CI 25-81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0-36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29-539) days and 33 (95% CI 9.7- > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39-91%). PK analysis demonstrated proportional dose-concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months. CONCLUSIONS: NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR-MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.
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ItemPretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome(AMER SOC HEMATOLOGY, 2022-12-01)
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ItemIntratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect(TAYLOR & FRANCIS INC, 2022-12-31)Intratumoural administration of unmethylated cytosine-phosphate-guanine motifs (CpG) to stimulate toll-like receptor (TLR)-9 has been shown to induce tumour regression in preclinical studies and some efficacy in the clinic. Because activated natural killer T (NKT) cells can cooperate with pattern-recognition via TLRs to improve adaptive immune responses, we assessed the impact of combining a repeated dosing regimen of intratumoural CpG with a single intratumoural dose of the NKT cell agonist α-galactosylceramide (α-GalCer). The combination was superior to CpG alone at inducing regression of established tumours in several murine tumour models, primarily mediated by CD8+ T cells. An antitumour effect on distant untreated tumours (abscopal effect) was reliant on sustained activity of NKT cells and was associated with infiltration of KLRG1+ NKT cells in tumours and draining lymph nodes at both injected and untreated distant sites. Cytometric analysis pointed to increased exposure to type I interferon (IFN) affecting many immune cell types in the tumour and lymphoid organs. Accordingly, antitumour activity was lost in animals in which dendritic cells (DCs) were incapable of signaling through the type I IFN receptor. Studies in conditional ablation models showed that conventional type 1 DCs and plasmacytoid DCs were required for the response. In tumour models where the combined treatment was less effective, the addition of tumour-antigen derived peptide, preferably conjugated to α-GalCer, significantly enhanced the antitumour response. The combination of TLR ligation, NKT cell agonism, and peptide delivery could therefore be adapted to induce responses to both known and unknown antigens.
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ItemExercise in allogeneic bone marrow transplantation: a qualitative representation of the patient perspective(SPRINGER, 2022-06)PURPOSE: Exercise is emerging as a vital aspect of care to alleviate the physical and psychosocial symptom burden associated with allogeneic bone marrow transplantation (BMT). Understanding the patient perspective regarding exercise is important to move towards implementation. This study aimed to characterise experiences and views regarding participation in an exercise program in adults receiving treatment for haematological disease with allogeneic BMT. METHODS: Individual semi-structured interviews were conducted with 35 participants from either an early- or late-commencing supervised group-based exercise program. Using an inductive, conventional approach to qualitative content analysis data were independently analysed by two researchers. RESULTS: Six major themes and 33 sub-themes were identified: this encompassed motivation, physical opportunity and capability to exercise; psychosocial effects of group-based exercise; experienced impact of participation in an exercise program; and intervention design considerations. Key barriers to exercise included symptom severity and fluctuating health and distance or difficult access to an exercise facility or equipment, whilst facilitators included encouragement from staff; peer support in the group-based setting; flexibility; education; and ability to measure change. CONCLUSION: This study highlights the importance of a flexible approach to exercise with consideration of individual symptoms and preferences. The perceived psychological impact of exercise should not be underestimated; future exercise programs should be designed in partnership with patients, with consideration of group-based activities to reduce social isolation if this is feasible in the treatment context. Intervention design should also acknowledge the individual's physical and psychological capability, opportunity and automatic and reflective motivation to direct and sustain exercise behaviours following BMT.
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