Pre-neutropenic fever (PNF) (fever following chemotherapy but before developing low white cells) and neutropenic fever (NF) (fever in the setting of low white cells) are very common after chemotherapy for acute leukemia, bone marrow transplantation or Chimeric Antigen Receptor T-cell (CAR T) therapy. Often, there is no bacterial cause for fever found, and in the setting of a well patient with resolved fever, some studies have shown it to be safe to cease antibiotic therapy which was commenced at the onset of fever. This reduces the overall exposure to antibiotics, which can be beneficial to the patient (reduced risk of resistant bugs emerging, reduced serious side effects). However, some subgroups of high-risk patients have been underrepresented in these studies (in particular, those who have received a bone marrow transplant from a donor, those with longer duration of low white cells) and none have been performed in Australia, hence applying this data to our setting and patient groups is indirect and further data are needed. This study plans to recruit participants who have received chemotherapy for acute leukemia or a stem cell transplant (either their own cells or a donor's cells) or CAR T-cell therapy and perform a trial to compare early stopping of antibiotics (STOP arm) to the standard of care, which traditionally involves continuing antibiotics until the white cell count reaches above a specific threshold. The primary study outcome is duration of days free of antibiotics within 28 days of study allocation. The investigators will also observe for important clinical outcomes including rates of fever recurrence, bloodstream and other infections, intensive care admission and mortality. Patients will stay in hospital during this period, even in the setting of stopping antibiotics, and these antibiotics can be recommenced urgently according to the sepsis protocol if there is concern for infection.
Conditioning chemotherapy for an autologous or allogeneic haematopoietic cell transplant or CAR T cell therapy, OR
Induction remission chemotherapy for acute leukaemia,
- Prolonged fever prior to defervescence (documented daily temperature ≥38.0°C for ≥ 5 days)
Documented positive blood culture for bacteria since onset of fever episode and prior to randomisation
Documented other infection (clinically or microbiologically defined) requiring antibacterial treatment
Grade 2 or higher mucositis (WHO) or neutropenic enterocolitis
Parallel
Early antibiotic cessation alert
DrugFor all patients, antibiotics will be commenced at onset of fever. For those in the intervention arm an alert will fire in the electronic medical record once a patient is afebrile for 48-96 hours and clinically stable.
Days free of antibiotic therapy in 28 days post randomization (termed empiric antibiotic free days (EAFDs))
The primary study outcome is duration of days free of antibiotics within 28 days of study allocation. Measured as antibiotic free days in last 28 days post fever onset
Days alive and free of antibiotic therapy in 28 days post randomization
Days alive and free of antibiotic therapy in 28 days post randomization
Recurrence of fever (>38deg Celsius) beyond randomization
Recurrence of fever (\>38deg Celsius, confirmed on second reading within 1 hour) post randomization during the same episode of neutropenia, not associated with blood product transfusion * In CAR T treated patients, grade of cytokine release syndrome (CRS), immune-cell associated neurotoxicity (ICANS) at time of fever and any recurrent fever.
Number of occasions antibiotic therapy is recommenced with treatment intent
Number of events antibiotic therapy is recommenced with treatment intent (excluding prophylaxis)
Days of antibiotic therapy during neutropenic period
Days of antibiotic therapy during neutropenic period until ANC\>500 cells/mm3
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Peter MacCallum Cancer Centre, Australia
Lead sponsor
Melbourne Health
Collaborator
