Incidence of Febrile Neutropenia in Newly Diagnosed Acute Myeloid Leukaemia Patients during Intensive Induction Chemotherapy: A Systematic Review and Meta-Analysis

Incidence of Febrile Neutropenia in Newly Diagnosed Acute Myeloid Leukaemia Patients during Intensive Induction Chemotherapy: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Incidence of Febrile Neutropenia in Newly Diagnosed Acute Myeloid Leukaemia Patients during Intensive Induction Chemotherapy: A Systematic Review and Meta-Analysis U.M Wariyapperuma, P.M Nanayakkara, I Wettasinghe, P.P.R Siriwardena, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8456536/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Febrile neutropenia (FN) is a life-threatening complication of intensive induction chemotherapy for acute myeloid leukaemia (AML) [ 1 ]. It is the leading cause of treatment-related mortality and adversely affects remission as well as overall survival. The reported incidence of febrile neutropenia is high and heterogeneous. This systematic review and meta-analysis aim to estimate the pooled incidence of FN during AML induction and to characterize associated infections to enhance optimal management of these high-risk patients. Methods The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024628474) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies included adults (≥ 18 years) with newly diagnosed AML patients undergoing intensive induction (7 + 3-like anthracycline–cytarabine regimens). We searched PubMed, Embase, Scopus, and Web of Science for the last 10 years from 1st of December 2024. Febrile neutropenia incidence proportions were pooled using a Der Simonian–Laird random-effects model after logit transformation. Heterogeneity was assessed with the I² (I-squared) statistic, and leave-one-out sensitivity analyses were conducted to evaluate result robustness. An artificial intelligence language model (ChatGPT, OpenAI) was used solely to assist with language editing and clarification. Results Three studies were included in the final analysis, all conducted in Asian countries classified as high- or upper-middle-income settings. The pooled incidence of febrile neutropenia during induction chemotherapy was 88% (95% CI, 76%–95%). Considerable heterogeneity was observed (I² = 85%), due to differences in definitions of febrile neutropenia, chemotherapy protocols, and supportive care practices. One study with a narrow febrile neutropenia definition was included only in sensitivity analyses to maintain methodological consistency. However, the pooled estimates remained stable (ranging from 85% to 93%) upon sequential exclusion of individual studies. Gram-positive cocci were the predominant pathogens, and Aspergillus species accounted for the majority of fungal infections. All included studies had moderate to high risk of bias, mainly due to inconsistent febrile neutropenia definitions and limited microbiological documentation. Conclusions Febrile neutropenia occurs at a very high frequency during AML induction, highlighting the importance of vigilant infection prophylaxis and prompt empirical therapy. Adoption of the standard febrile neutropenia definition and supportive care planning is recommended to improve treatment outcomes in AML induction. Acute Myeloid Leukaemia Febrile Neutropenia Induction Chemotherapy Neutropenia Infection Systematic Review Meta-Analysis Immunocompromised Host Bacterial Infections Fungal Infections Figures Figure 1 Figure 2 Figure 3 Introduction Acute myeloid leukaemia (AML) is an aggressive form of hematologic malignancy with a rising global incidence, particularly among older adults. The incidence of AML has significantly increased over the past decades, with the median age at diagnosis around 68 years, and incidence increasing sharply with age [ 2 , 3 ]. Intensive induction chemotherapy combining cytarabine with anthracycline is the cornerstone of the management of newly diagnosed AML. This regimen aims to achieve complete remission and restore normal hematopoiesis by eliminating leukemic blasts from the bone marrow, thereby facilitating subsequent consolidation therapy or allogeneic hematopoietic stem cell transplantation [ 1 , 4 ]. However, this causes profound bone marrow suppression, leading to severe neutropenia, which makes the patient susceptible to potentially severe bacterial and fungal infections [ 5 ]. Newly diagnosed AML patients represent a distinct group, in whom the incidence and characteristics of febrile neutropenia can be explored more reliably before exposure to prior chemotherapy or immunosuppression [ 1 ]. Evaluating this subset is of utmost importance, as febrile neutropenia during initial induction remains a major determinant of subsequent morbidity, mortality, and treatment decisions, and has a direct impact on remission outcomes and overall survival [ 4 , 6 , 7 ]. Febrile neutropenia is defined as “a single oral temperature ≥ 38.3°C or ≥ 38.0°C sustained for ≥ 1 hour in a patient with an absolute neutrophil count < 0.5 × 10⁹/L or expected to fall below that threshold” [ 8 , 9 ]. A single episode of fever during neutropenia is an oncologic emergency, as it may be the only sign of sepsis in these immunocompromised patients. The reported incidence of febrile neutropenia during AML induction is strikingly high, and infections remain the main cause of treatment-related mortality [ 6 , 10 ]. Among the documented infective organisms, bacterial infections predominate, while prolonged and profound neutropenia predisposes to invasive fungal infections [ 5 , 11 ]. The reported incidence is heterogeneous, and there is no estimated pooled febrile neutropenia incidence. Understanding the real-world prevalence and microbiological patterns is crucial for optimizing empiric therapy, refining prophylactic strategies, and improving survival outcomes in AML. This systematic review and meta-analysis aim to (1) estimate the pooled incidence of febrile neutropenia during AML induction; (2) describe the timing of febrile neutropenia onset, and (3) characterize the spectrum of bacterial and fungal pathogens involved to enhance evidence-based practice and guide future research in this high-risk patient population. Methodology Protocol and Registration This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines and registered prospectively in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42024628474. Eligibility Criteria Peer-reviewed original research studies, including randomized controlled trials, clinical controlled trials, cohort, and observational studies, were eligible if they investigated the incidence or prevalence of febrile neutropenia during first-cycle, intensive anthracycline–cytarabine induction chemotherapy in adults (≥ 18 years) with newly diagnosed acute myeloid leukaemia. Exclusion criteria comprised case reports, editorials, expert opinions, review articles, conference abstracts without full text, animal or paediatric studies, and reports not published in English. Information Sources A comprehensive literature search was performed across PubMed, Embase, Scopus, and Web of Science for the last 10 years from 1st December 2024. Reference lists of all included studies and relevant reviews were manually screened to identify additional records. Search Strategy The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to acute leukaemia , chemotherapy , and febrile neutropenia , for example: (“epidemiology*” OR “prevalence*” OR “frequency*” OR “incidence*” OR “Epidemiology*”[MeSH Terms] OR “Prevalence*”[MeSH Terms] OR “Incidence*”[MeSH Terms]) AND (“leukaemias*” OR “leukaemia*” OR “leukemia*” OR “acute myeloid leukaemia” OR “AML”) AND (“chemotherapy*” OR “induction chemotherapy*” OR “drug therapy*”) AND (“neutropenic sepsis*” OR “febrile neutropenia*” OR “neutropenia*” OR “infection*” OR “sepsis*” OR “bacteremia*”[MeSH Terms]). Search strategies were adapted for each database. No date or geographic restrictions were applied. Selection Process All search results were imported into Rayyan for screening and deduplication. Two reviewers (UMW and PMN) independently screened titles and abstracts against predefined eligibility criteria, followed by full-text assessment of potentially eligible studies. Disagreements were resolved through discussion, with review by a third reviewer (PPRS) when required Data Collection Process Data were extracted independently by two reviewers (UMW, PMN) using a custom-made standardized form, and cross-verified by a third investigator (PPRS). Disagreements were resolved by consensus. No study authors were contacted for additional data. Data Items The primary outcome assessed was the incidence of febrile neutropenia. For each included study, we extracted the total sample size and the number of patients who developed FN. Effect estimates were reported in the format proportion with 95% confidence interval (95% CI) In addition to the primary outcome, several other variables were extracted to support contextual interpretation. These included Study identifiers: first author, publication year, study country, study design, and sample size. Patient characteristics: mean or median age and sex distribution. Intervention-related variables: chemotherapy regimen, anthracycline dosing schedule, and supportive-care practices. FN-related variables: definition of FN used, median day of onset, median fever duration, and median duration of neutropenia. Drug-related variables: antimicrobial prophylaxis, empirical antimicrobial therapy, use of G-CSF, and type and duration of antibiotic treatment. Microbiological profile: bacterial isolates, fungal pathogens, presence of a documented microbial source, and clinical sites of infection. Making assumptions for missing, ambiguous, or inconsistently presented information was done through consensus discussions among the investigators (UMM, PMN, IW, PPRS, and SS), guided by their clinical, methodological, and haemato-oncological expertise. Study Risk-of-Bias Assessment Methodological quality was independently assessed by two reviewers (PMN and SS) using design-specific tools: RoB 2 for the RCT and ROBINS-I for the observational studies. Each domain was rated as low , some concerns , or high risk . No automation tools were used. Reporting bias assessment The meta-analysis included three studies. Therefore, formal statistical assessments of reporting bias, such as funnel plot asymmetry, Egger’s regression test, or small-study effects, were not conducted, as these methods require a minimum of 10 studies to yield reliable results. Instead, the potential risk of bias due to missing results was evaluated qualitatively by reviewing study protocols, published methods, and reported outcomes to ensure that FN incidence was consistently and completely reported. Certainty assessment The certainty of the evidence for the primary outcome was assessed qualitatively, as the limited number of included studies (n = 3) restricted the application of a full Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Because the evidence base comprised a mix of study designs, a randomized controlled trial, one retrospective cohort study, and one national multicenter registry study, certainty was judged using domain-level considerations rather than numerical scoring. Key factors evaluated included risk of bias inherent to each design, consistency of outcome definitions, indirectness related to clinical and methodological variability, imprecision due to sample size differences, and potential unmeasured confounding. No upgrading criteria, such as a clear dose–response relationship or residual confounding likely to increase effect size, were applicable. As a result, certainty of evidence was appraised through structured qualitative judgment rather than formal GRADE rating. Meta-analysis A meta-analysis was undertaken to estimate the pooled incidence of febrile neutropenia during remission-induction chemotherapy for acute myeloid leukaemia. Three eligible studies reporting febrile neutropenia incidence were included [ 12 – 14 ]. Study-level proportions were transformed using the logit function and combined with a DerSimonian–Laird random-effects model to account for between-study variability. A continuity correction of 0.5 was applied to studies with proportions of 0 or 1. Heterogeneity was quantified using the I² statistic, and sensitivity analyses were performed by sequentially excluding each study. Use of artificial intelligence tools An artificial intelligence language model (ChatGPT, OpenAI, San Francisco, CA, USA) was used solely to assist with language editing and clarification. The tool was not used for study design, data extraction, data analysis, interpretation of results, or generation of scientific content. All methodological decisions, analyses, interpretations, and conclusions are the sole responsibility of the authors. The detailed search strategies for all databases are provided in Additional file 1. The extracted dataset used for the meta-analysis is available in Additional file 3. Results Study Selection The PRISMA flow process yielded 3 eligible studies from 4489 records identified across databases [ 12 , 13 , 14 ]. After removing duplicates (1,590 unique records), 737 titles/abstracts were screened, 75 full-text articles were reviewed, and 3 studies met all criteria (Fig. 1). Figure 1 – PRISMA Flow Diagram for study selection Risk of bias assessment While all studies contributed relevant incidence data, the overall risk-of-bias assessment revealed methodological limitations across all three studies (Fig. 2). Vaezi et al was rated as having some concerns, primarily due to insufficient detail on randomization and lack of blinding, although outcome measurement was considered low risk. Penthinapong et al were judged to be at high risk of bias due to confounding inherent in its retrospective design and limited adjustment for prognostic variables, despite low risk in outcome measurement. Kato et al were rated as having some concerns overall, with particular issues related to incomplete data capture, potential confounding, and reporting bias in its registry-based cohort. Figure 2. Risk of bias assessment of included studies Study characteristics Vaezi et al and Penthinapong et al defined febrile neutropenia using standard National Comprehensive Cancer Network (NCCN)/ Infectious Diseases Society of America (IDSA) criteria [ 8 , 9 ], whereas Kato et al applied a narrower definition restricted to fever of unknown origin (FUO) without documented infection [ 15 ]. Penthinapong et al. conducted a retrospective single-center cohort study of 141 patients treated with idarubicin/cytarabine. FN was reported as a primary endpoint with detailed microbiological data and timing. Vaezi et al conducted a prospective randomized trial of 114 patients comparing daunorubicin 60 mg/m² vs 80 mg/m², and FN incidence and infectious complications were prospectively followed up. Kato et al was a multicenter surveillance study across a national protocol enrolling 980 patients and reported microbiologically documented infections separately. This study was included only in the sensitivity analysis due to a narrow FN definition. Table 1 summarises study characteristics. Table 1 Characteristics of the included studies Study Country Design Sample size (N) Patient demographics (Age, Sex %) Study period Induction chemotherapy regimen FN definition used Kato et al., 2018 Japan Retrospective analysis of national multicenter trial cohort (JALSG AML201) 980 Median age 47 years; 60% male 2001–2005 JALSG AML201 protocol: standard anthracycline + cytarabine induction (equivalent to 3 + 7 based on Japanese leukemia trial standards) fever of unknown origin (FUO) without documented infection Penthinapong et al., 2023 Thailand Retrospective cohort 141 Mean age 40.7 ± 13.4; 58.2% female 2008–2021 Idarubicin + cytarabine, either 3 + 7 (82.3%) or 2 + 5 (17.7%) NCCN + IDSA definitions: Temp ≥ 38.3°C once OR ≥ 38°C > 1 h and ANC < 500/mm³ or expected to fall < 500/mm³ in 24–48 h Vaezi et al., 2017 Iran Prospective randomized controlled trial 114 Mean age 42 years; 62% male 2011–2014 Cytarabine 100 mg/m² × 7 days + daunorubicin 60 mg/m² ×3 days (Arm 1) or 80 mg/m² ×3 days (Arm 2) NCCN + IDSA definitions: Temp ≥ 38.3°C once OR ≥ 38°C > 1 h and ANC < 500/mm³ or expected to fall < 500/mm³ in 24–48 h Table 1 : Study Characteristics of included studies Incidence and Timing of Febrile Neutropenia All studies confirmed FN as an almost universal complication of induction chemotherapy. Penthinapong et al documented FN in 125/141 (88.7%) patients, with a median onset on day six (IQR, 7) from the initiation of chemotherapy. The median duration of fever was 14 days, while neutropenia persisted for a median of 21 days, and antibiotic therapy was administered for a median of 27 days. Vaezi et al reported that 100% (114/114) of patients developed febrile neutropenia irrespective of daunorubicin dose. The median duration of antibiotic use was 20 days in both arms, and neutrophil recovery was observed on day 20 (60 mg/m²) compared to day 22 (80 mg/m²) (p = 0.469). Kato etal, with its narrow definition, reported FN in 786/980 (80.2%) of patients during induction. The overall FN incidence in studies using standard-definition was very high, with febrile episodes characteristically occurring between day five and seven, coinciding with the expected neutrophil nadir. Microbiological Profile In the selected cohorts, the microbial pathogens of febrile neutropenia during induction chemotherapy were characterized by a predominance of gram-positive organisms and a significant incidence of invasive fungal infections. Penthinapong et al confirmed a microbiological source in 43.2% of febrile neutropenia episodes, with gram-positive bacteria accounting for 60.5% of isolates. Enterococcus faecium was the most frequently identified pathogen, and pneumonia represented the predominant clinical focus (28.0% of cases). Fungal infections were also documented, and Aspergillus spp. accounted for the majority of fungal infections. Vaezi et al reported invasive fungal infections in 32.7% of patients treated with daunorubicin 60 mg/m² and 49.1% of those receiving 80 mg/m². However, this difference did not show statistical significance. The bacterial aetiology was not documented for this study. In kato etal pulmonary infections occurred in 10.3% of patients, and Blood culture positivity for bacteria or fungi was reported in 8.3%. Invasive pulmonary aspergillosis was reported as a major complication. This study also did not provide a detailed microbiological profile. Table 2 – summarises the microbiological profile. Table 2 summarises the microbiological profiles Table 2 Summary of microbiological profiles of included studies Study Microbiological Source Identified Bacterial Profile Fungal Profile Most Common Infection Site Penthinapong et al., 2023 43.2% of FN episodes Gram-positive 60.5%; most common: Enterococcus faecium Aspergillus spp. identified in invasive fungal infections Pneumonia (28.0%) Vaezi et al., 2017 Not reported Not detailed Invasive fungal infections in 32.7% (60 mg/m²) and 49.1% (80 mg/m²) Not reported Kato et al., 2018 Bacteremia/fungemia in 8.3% of patients Gram-positive 65.1%; most common: Staphylococcus epidermidis Invasive pulmonary aspergillosis reported Pulmonary infections (10.3%) Use of Antimicrobial Prophylaxis, empirical therapy, and Granulocyte colony-stimulating factor (G-CSF) The use of antimicrobial prophylaxis, empirical treatment, and granulocyte colony-stimulating factor (G-CSF) during induction chemotherapy was reported variably. Penthinapong et al primarily focused on the incidence and outcomes of febrile neutropenia, but did not provide details regarding prophylactic or empirical antimicrobial regimens or G-CSF use. Similarly. Vaezi et al did not disclose any details on the above. In contrast, Kato et al documented data from a multicentre registry and reported institutional practices. For antibacterial prophylaxis, 52% of hospitals used fluoroquinolones and 30% used trimethoprim–sulfamethoxazole. Oral fluconazole was noted as the antifungal prophylaxis commonly used. Reported empiric choices for FN included anti-pseudomonal cephalosporin monotherapy (29%) or carbapenem monotherapy (21%), as well as combination regimens with an aminoglycoside. In later surveys, more institutions had moved to monotherapy regimens, with either antipseudomonal cephalosporins or carbapenems. Meta-Analysis of Febrile Neutropenia Incidence Across the three included studies, the incidence of FN during remission induction ranged from 80% to 100%. The pooled febrile neutropenia incidence was 0.88 (95% CI 0.76–0.95) under a random-effects model, indicating that nearly nine in ten patients experienced FN during induction therapy. Substantial heterogeneity was observed (I² = 85%), primarily reflecting differences in chemotherapy regimens and supportive-care practices. Leave-one-out sensitivity analysis produced pooled estimates between 0.85 and 0.93, confirming the robustness of the overall result. Figure 3. Forest plot of the pooled incidence of febrile neutropenia with the random effect model assumption Reporting biases Across the included studies, febrile neutropenia incidence was reported in a manner consistent with the described methods, and no obvious evidence of selective non-reporting of the primary outcome was identified. Nevertheless, given the small evidence base, the possibility of unpublished or unreported results cannot be excluded. Certainty of evidence Based on the qualitative certainty assessment, the overall certainty of evidence for the primary outcome (incidence of febrile neutropenia) was considered limited. Although all included studies reported the primary outcome using comparable definitions, certainty was reduced by methodological heterogeneity and differences in study design. The randomized controlled trial contributed higher internal validity, whereas the retrospective cohort and national registry studies were subject to potential residual confounding. Variability in sample size and event rates across studies also contributed to imprecision. Taken together, these factors resulted in a cautious interpretation of the pooled estimate, with findings considered informative but subject to uncertainty. Discussion This review confirms febrile neutropenia as an inevitable outcome of intensive induction chemotherapy for acute myeloid leukaemia. The reviewed cohorts, spanning geographical regions across both high-income and low- to middle-income countries, consistently reported a high incidence of febrile neutropenia. This is a consequence of profound iatrogenic neutropenia, induced by the intensity of the induction chemotherapy regimens used, to eradicate leukemic blasts [ 16 ]. The timing of febrile neutropenia in the cohorts coincides with the neutrophil nadir, and the prolonged duration of the neutropenia observed during AML induction justifies the extended duration of antibiotic therapy reported across the studies, in keeping with current Infectious Diseases Society of America (IDSA) and European Society for Medical Oncology (ESMO) guidelines that recommend continuation of empiric antibiotics until neutrophil recovery [ 6 , 7 ] The microbiological findings in these studies highlight the epidemiological shift of microbial agents in neutropenic AML patients. The observed predominance of gram-positive bacterial infections is in keeping with the epidemiological trend from past decades [ 5 ]. Historically, Gram-negative bacilli dominated, attributed to chemotherapy-induced mucosal damage with subsequent gut translocation of enteric flora. It is postulated that the widespread use of fluoroquinolone prophylaxis and the frequent use of central venous catheters have led to a rise in Gram-positive infections [ 5 , 9 ]. While Gram-positive organisms emerge in numbers, the most severe infections leading to neutropenic sepsis and mortality are still accounted for by Gram-negative infections [ 7 , 16 ]. This reinforces the fact that, irrespective of the aetiology, FN in AML patients should be treated as a high-risk clinical entity. We also noted a significant burden of invasive fungal infections across the studies, particularly pulmonary infections with Aspergillus species. These findings align with both current evidence and recommendations for mold-specific antifungal prophylaxis during AML induction [ 10 ]. This study also highlights the impact of the definitional variations on the incidence of FN. The narrow febrile neutropenia definition substantially lowered the reported incidence (80% vs 95%). Therefore, it is imperative to implement a standard FN definition both in research and clinical settings to ensure uniformity of clinical decision-making and data interpretation. While adhering to standard FN definition criteria, the selective reporting of clinically or microbiologically documented infections separately will allow for more scientific comparison between studies in the future. We noted several limitations among the included studies that may affect the strength and generalizability of the pooled estimates. One of the important limitations was geographical and resource-level limitations. There were only three studies, and all three studies were from the Asian continent (Japan, Iran, Thailand), belonging to high and upper-middle income levels, which may affect the generalizability of the findings. The limited eligible study number reflects the limited literature specifically reporting febrile neutropenia incidence during the induction cycle for newly diagnosed AML. While the absence of Western and low-income categories may reflect stricter eligibility criteria, inconsistent outcome reporting, or publication bias, during the literature review and article screening stages of this review, the authors noticed that, over the last decade, western countries have focused more on alternating induction regimes, including low-intensity and immune-targeted therapies [ 17 , 18 , 19 ]. This may also have led to the absence of data from the western part of the world. In contrast, limited access to diagnostics, research funding, and underreporting are likely to have caused the underrepresentation of data from resource-limited settings [ 20 ]. Another important limitation was the heterogeneous definitions of febrile neutropenia. While Penthinapong et al and Vaezi et al used standard definitions, Kato et al applied a narrower definition. This heterogeneity hindered direct comparability, which necessitated sensitivity analyses to overcome the definitional variations. Further, two of the studies (Penthinapong et al., Kato et al.) were observational, and the other (Penthinapong et al) was single-center and retrospective, which may lead to potential selection and information bias. Only Vaezi et al. was a randomized controlled trial, though even this had methodological concerns, such as a lack of blinding and incomplete reporting of allocation procedures. Standardized protocols for febrile neutropenia diagnosis and supportive care were not utilized by any of the studies. In addition, key factors and important outcomes related to febrile neutropenia, such as infection-related mortality, microbiological profiles, prophylactic and supportive care practices, and intensive care admissions, were either partially documented or entirely omitted. For example, although Vaezi et al reported overall 30-day mortality failed to specify infection-related deaths or intensive care admissions. Similarly, empirical antibiotic regimens were not detailed in Penthinapong or Vaezi et al. Only Kato et al systematically documented institutional antimicrobial and supportive care practices. This limited the assessment of adherence to guideline-based practices. Although this review was designed and conducted according to PRISMA 2020 guidelines, several limitations in the review process need to be acknowledged. The review included only English-language publications indexed in major databases. While this ensured methodological rigor and easy accessibility, it may have excluded relevant non-English literature or regional repositories, introduced language and indexed bias. Further, we have excluded literature such as conference abstracts, case reports, or clinical trial registries. As a consequence, evolving data from ongoing trials or institution-level reports may have been missed, leading to potential publication bias and limiting insight into real-world febrile neutropenia management practices. Although we employed a broader search strategy, it may have been insufficient to capture febrile neutropenia data within larger AML treatment studies. Some prospective multicentre trials or national registries may collect febrile neutropenia outcomes but do not report them as standalone endpoints, and therefore may have been overlooked. This review unravels a new research dimension in AML treatment. Instead of focusing on febrile neutropenia and associated risk factors, future research should move forward to identifying and risk-stratifying patients who develop febrile neutropenia before they go on to severe neutropenic sepsis, including the development and validation of risk-stratification tools. Researchers should also focus on the identification of changing microbial profiles and monitoring antibiotic resistance patterns to improve evidence-based care. In conclusion, this systematic review and meta-analysis highlight febrile neutropenia as an inevitable complication of intensive induction chemotherapy in AML patients. While Gram-positive organisms have overtaken Gram-negative infections, invasive fungal infections pose a substantial risk, reinforcing the need to treat these patients under a high-risk category with broad-spectrum antibiotics and Mold-active prophylaxis. The universal occurrence of febrile neutropenia with the absence of reliable predictors of its occurrence brings out the unmet need in research and clinical practice to focus on improving outcomes after the onset of febrile neutropenia. Therefore, by shifting focus to early recognition and prevention of consequences of febrile neutropenia, like severe sepsis, multiorgan failure, and death, we can hope to ensure more patients will survive intensive induction therapy to achieve complete remission. Abbreviations AML Acute myeloid leukaemia ANC Absolute neutrophil count CI Confidence interval ESMO European Society for Medical Oncology FN Febrile neutropenia FUO Fever of unknown origin G CSF–Granulocyte colony–stimulating factor GRADE Grading of Recommendations Assessment, Development and Evaluation ICU Intensive care unit IDSA Infectious Diseases Society of America IQR Interquartile range I² I–squared statistic (measure of heterogeneity) MeSH Medical Subject Headings NCCN National Comprehensive Cancer Network PRISMA Preferred Reporting Items for Systematic Reviews and Meta–Analyses PROSPERO International Prospective Register of Systematic Reviews RCT Randomized controlled trial RoB 2 Risk of Bias 2 tool ROBINS I–Risk of Bias in Non–randomized Studies of Interventions Declarations Ethics approval and consent to participate Not applicable. This study is a systematic review and meta-analysis based entirely on previously published studies. It did not involve the collection or analysis of individual-level human data, human tissue, or animal subjects, and therefore did not require ethical approval or informed consent. Consent for publication Not applicable. This manuscript does not contain any person’s data, images, videos, or identifiable information. Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary information files. Extracted datasets are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding No specific funding was received for this study. Authors' contributions UMW conceptualized the study, developed the protocol, registered the study in PROSPERO, conducted the literature search, performed data extraction and statistical analysis, interpreted the results, and drafted the manuscript. PMN and IW independently screened studies for eligibility, contributed to data extraction, and assessed risk of bias. PPRS served as the content expert, resolved conflicts during study selection and data extraction, and contributed to methodological oversight, interpretation of findings, and critical revision of the manuscript for important intellectual content. SS contributed to methodological design, data interpretation, contextualization of findings within the current literature, and critical review of the manuscript. All authors read and approved the final manuscript. Acknowledgements Not Applicable References Hansen BA, Wendelbo Ø, Bruserud Ø, Haukås E, Reikvam H. Febrile neutropenia in acute leukemia: epidemiology, etiology, pathophysiology, and treatment. Mediterr J Hematol Infect Dis. 2020;12(1):e2020009. Zhou Y, Huang G, Cai X, Liu Y, Qian B, Li D, et al. Global burden of acute myeloid leukemia, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. 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Clinical profile, treatment, and outcomes of febrile neutropenia in hematologic disorders: a look at 30-day mortality predictors. Sci Rep. 2025;15(1):23905. 10.1038/s41598-025-06787-z . Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, et al. CPX-351 versus 7 + 3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukemia: 5-year results of a randomized phase 3 trial. Lancet Haematol. 2021;8(7):e481–91. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519–31. Ronnacker J, Muller PJ, Mikesch JH, Zukunft S, Weinbergerová B, Šrámek J, et al. Gemtuzumab ozogamicin in first-line treatment of core-binding factor acute myeloid leukemia: insights from a retrospective multicenter analysis. Leukemia. 2025;39(9):2174–80. Khoja A, Kazim F, Ali NA. Barriers to conducting clinical trials in developing countries. Ochsner J. 2019;19(4):294–5. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1SearchStrategies.pdf Additionalfile3PRISMA2020ChecklistwithLineNumbers.docx Additionalfile3Dataextractionsheet.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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2","display":"","copyAsset":false,"role":"figure","size":720519,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRisk of bias assessment of included studies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8456536/v1/f88d900683815973ab535571.jpg"},{"id":99668100,"identity":"a589f0e9-e93b-471b-b61d-56af9cb69ba2","added_by":"auto","created_at":"2026-01-07 06:16:20","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":443305,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of the pooled incidence of febrile neutropenia with the random effect model assumption\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8456536/v1/71552a56c387564a0162412f.jpg"},{"id":103487328,"identity":"7df6dbfe-903a-4d7a-974a-e9121479b2f2","added_by":"auto","created_at":"2026-02-26 09:13:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2604546,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8456536/v1/85563ea9-fef4-4cf4-a93f-a98bc1186b96.pdf"},{"id":99668095,"identity":"f4013d2f-719f-4348-bdaa-e0af3c2fc831","added_by":"auto","created_at":"2026-01-07 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The incidence of AML has significantly increased over the past decades, with the median age at diagnosis around 68 years, and incidence increasing sharply with age [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Intensive induction chemotherapy combining cytarabine with anthracycline is the cornerstone of the management of newly diagnosed AML. This regimen aims to achieve complete remission and restore normal hematopoiesis by eliminating leukemic blasts from the bone marrow, thereby facilitating subsequent consolidation therapy or allogeneic hematopoietic stem cell transplantation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, this causes profound bone marrow suppression, leading to severe neutropenia, which makes the patient susceptible to potentially severe bacterial and fungal infections [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNewly diagnosed AML patients represent a distinct group, in whom the incidence and characteristics of febrile neutropenia can be explored more reliably before exposure to prior chemotherapy or immunosuppression [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Evaluating this subset is of utmost importance, as febrile neutropenia during initial induction remains a major determinant of subsequent morbidity, mortality, and treatment decisions, and has a direct impact on remission outcomes and overall survival [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFebrile neutropenia is defined as \u0026ldquo;a single oral temperature\u0026thinsp;\u0026ge;\u0026thinsp;38.3\u0026deg;C or \u0026ge;\u0026thinsp;38.0\u0026deg;C sustained for \u0026ge;\u0026thinsp;1 hour in a patient with an absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;0.5 \u0026times; 10⁹/L or expected to fall below that threshold\u0026rdquo; [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A single episode of fever during neutropenia is an oncologic emergency, as it may be the only sign of sepsis in these immunocompromised patients. The reported incidence of febrile neutropenia during AML induction is strikingly high, and infections remain the main cause of treatment-related mortality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Among the documented infective organisms, bacterial infections predominate, while prolonged and profound neutropenia predisposes to invasive fungal infections [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe reported incidence is heterogeneous, and there is no estimated pooled febrile neutropenia incidence. Understanding the real-world prevalence and microbiological patterns is crucial for optimizing empiric therapy, refining prophylactic strategies, and improving survival outcomes in AML. This systematic review and meta-analysis aim to (1) estimate the pooled incidence of febrile neutropenia during AML induction; (2) describe the timing of febrile neutropenia onset, and (3) characterize the spectrum of bacterial and fungal pathogens involved to enhance evidence-based practice and guide future research in this high-risk patient population.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eProtocol and Registration\u003c/p\u003e \u003cp\u003eThis systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines and registered prospectively in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42024628474.\u003c/p\u003e \u003cp\u003eEligibility Criteria\u003c/p\u003e \u003cp\u003ePeer-reviewed original research studies, including randomized controlled trials, clinical controlled trials, cohort, and observational studies, were eligible if they investigated the incidence or prevalence of febrile neutropenia during first-cycle, intensive anthracycline\u0026ndash;cytarabine induction chemotherapy in adults (\u0026ge;\u0026thinsp;18 years) with newly diagnosed acute myeloid leukaemia. Exclusion criteria comprised case reports, editorials, expert opinions, review articles, conference abstracts without full text, animal or paediatric studies, and reports not published in English.\u003c/p\u003e \u003cp\u003eInformation Sources\u003c/p\u003e \u003cp\u003eA comprehensive literature search was performed across PubMed, Embase, Scopus, and Web of Science for the last 10 years from 1st December 2024. Reference lists of all included studies and relevant reviews were manually screened to identify additional records.\u003c/p\u003e \u003cp\u003eSearch Strategy\u003c/p\u003e \u003cp\u003eThe search strategy combined Medical Subject Headings (MeSH) and free-text terms related to \u003cem\u003eacute leukaemia\u003c/em\u003e, \u003cem\u003echemotherapy\u003c/em\u003e, and \u003cem\u003efebrile neutropenia\u003c/em\u003e, for example:\u003c/p\u003e \u003cp\u003e(\u0026ldquo;epidemiology*\u0026rdquo; OR \u0026ldquo;prevalence*\u0026rdquo; OR \u0026ldquo;frequency*\u0026rdquo; OR \u0026ldquo;incidence*\u0026rdquo; OR \u0026ldquo;Epidemiology*\u0026rdquo;[MeSH Terms] OR \u0026ldquo;Prevalence*\u0026rdquo;[MeSH Terms] OR \u0026ldquo;Incidence*\u0026rdquo;[MeSH Terms]) AND (\u0026ldquo;leukaemias*\u0026rdquo; OR \u0026ldquo;leukaemia*\u0026rdquo; OR \u0026ldquo;leukemia*\u0026rdquo; OR \u0026ldquo;acute myeloid leukaemia\u0026rdquo; OR \u0026ldquo;AML\u0026rdquo;) AND (\u0026ldquo;chemotherapy*\u0026rdquo; OR \u0026ldquo;induction chemotherapy*\u0026rdquo; OR \u0026ldquo;drug therapy*\u0026rdquo;) AND (\u0026ldquo;neutropenic sepsis*\u0026rdquo; OR \u0026ldquo;febrile neutropenia*\u0026rdquo; OR \u0026ldquo;neutropenia*\u0026rdquo; OR \u0026ldquo;infection*\u0026rdquo; OR \u0026ldquo;sepsis*\u0026rdquo; OR \u0026ldquo;bacteremia*\u0026rdquo;[MeSH Terms]).\u003c/p\u003e \u003cp\u003eSearch strategies were adapted for each database. No date or geographic restrictions were applied.\u003c/p\u003e \u003cp\u003eSelection Process\u003c/p\u003e \u003cp\u003eAll search results were imported into Rayyan for screening and deduplication. Two reviewers (UMW and PMN) independently screened titles and abstracts against predefined eligibility criteria, followed by full-text assessment of potentially eligible studies. Disagreements were resolved through discussion, with review by a third reviewer (PPRS) when required\u003c/p\u003e \u003cp\u003eData Collection Process\u003c/p\u003e \u003cp\u003eData were extracted independently by two reviewers (UMW, PMN) using a custom-made standardized form, and cross-verified by a third investigator (PPRS). Disagreements were resolved by consensus. No study authors were contacted for additional data.\u003c/p\u003e \u003cp\u003eData Items\u003c/p\u003e \u003cp\u003eThe primary outcome assessed was the incidence of febrile neutropenia. For each included study, we extracted the total sample size and the number of patients who developed FN. Effect estimates were reported in the format \u003cem\u003eproportion with 95% confidence interval (95% CI)\u003c/em\u003e\u003c/p\u003e \u003cp\u003eIn addition to the primary outcome, several other variables were extracted to support contextual interpretation. These included\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eStudy identifiers: first author, publication year, study country, study design, and sample size.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatient characteristics: mean or median age and sex distribution.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIntervention-related variables: chemotherapy regimen, anthracycline dosing schedule, and supportive-care practices.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFN-related variables: definition of FN used, median day of onset, median fever duration, and median duration of neutropenia.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDrug-related variables: antimicrobial prophylaxis, empirical antimicrobial therapy, use of G-CSF, and type and duration of antibiotic treatment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMicrobiological profile: bacterial isolates, fungal pathogens, presence of a documented microbial source, and clinical sites of infection.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eMaking assumptions for missing, ambiguous, or inconsistently presented information was done through consensus discussions among the investigators (UMM, PMN, IW, PPRS, and SS), guided by their clinical, methodological, and haemato-oncological expertise.\u003c/p\u003e \u003cp\u003eStudy Risk-of-Bias Assessment\u003c/p\u003e \u003cp\u003eMethodological quality was independently assessed by two reviewers (PMN and SS) using design-specific tools: RoB 2 for the RCT and ROBINS-I for the observational studies. Each domain was rated as \u003cem\u003elow\u003c/em\u003e, \u003cem\u003esome concerns\u003c/em\u003e, or \u003cem\u003ehigh risk\u003c/em\u003e. No automation tools were used.\u003c/p\u003e \u003cp\u003eReporting bias assessment\u003c/p\u003e \u003cp\u003eThe meta-analysis included three studies. Therefore, formal statistical assessments of reporting bias, such as funnel plot asymmetry, Egger\u0026rsquo;s regression test, or small-study effects, were not conducted, as these methods require a minimum of 10 studies to yield reliable results. Instead, the potential risk of bias due to missing results was evaluated qualitatively by reviewing study protocols, published methods, and reported outcomes to ensure that FN incidence was consistently and completely reported.\u003c/p\u003e \u003cp\u003eCertainty assessment\u003c/p\u003e \u003cp\u003eThe certainty of the evidence for the primary outcome was assessed qualitatively, as the limited number of included studies (n\u0026thinsp;=\u0026thinsp;3) restricted the application of a full Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Because the evidence base comprised a mix of study designs, a randomized controlled trial, one retrospective cohort study, and one national multicenter registry study, certainty was judged using domain-level considerations rather than numerical scoring. Key factors evaluated included risk of bias inherent to each design, consistency of outcome definitions, indirectness related to clinical and methodological variability, imprecision due to sample size differences, and potential unmeasured confounding. No upgrading criteria, such as a clear dose\u0026ndash;response relationship or residual confounding likely to increase effect size, were applicable. As a result, certainty of evidence was appraised through structured qualitative judgment rather than formal GRADE rating.\u003c/p\u003e \u003cp\u003eMeta-analysis\u003c/p\u003e \u003cp\u003eA meta-analysis was undertaken to estimate the pooled incidence of febrile neutropenia during remission-induction chemotherapy for acute myeloid leukaemia. Three eligible studies reporting febrile neutropenia incidence were included [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Study-level proportions were transformed using the logit function and combined with a DerSimonian\u0026ndash;Laird random-effects model to account for between-study variability. A continuity correction of 0.5 was applied to studies with proportions of 0 or 1. Heterogeneity was quantified using the I\u0026sup2; statistic, and sensitivity analyses were performed by sequentially excluding each study.\u003c/p\u003e \u003cp\u003eUse of artificial intelligence tools\u003c/p\u003e \u003cp\u003eAn artificial intelligence language model (ChatGPT, OpenAI, San Francisco, CA, USA) was used solely to assist with language editing and clarification. The tool was not used for study design, data extraction, data analysis, interpretation of results, or generation of scientific content. All methodological decisions, analyses, interpretations, and conclusions are the sole responsibility of the authors.\u003c/p\u003e \u003cp\u003eThe detailed search strategies for all databases are provided in Additional file 1. The extracted dataset used for the meta-analysis is available in Additional file 3.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eStudy Selection\u003c/p\u003e \u003cp\u003eThe PRISMA flow process yielded 3 eligible studies from 4489 records identified across databases [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. After removing duplicates (1,590 unique records), 737 titles/abstracts were screened, 75 full-text articles were reviewed, and 3 studies met all criteria (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 1 \u0026ndash; PRISMA Flow Diagram for study selection\u003c/b\u003e \u003c/p\u003e\n\u003ch3\u003eRisk of bias assessment\u003c/h3\u003e\n\u003cp\u003eWhile all studies contributed relevant incidence data, the overall risk-of-bias assessment revealed methodological limitations across all three studies (Fig.\u0026nbsp;2). Vaezi et al was rated as having some concerns, primarily due to insufficient detail on randomization and lack of blinding, although outcome measurement was considered low risk. Penthinapong et al were judged to be at high risk of bias due to confounding inherent in its retrospective design and limited adjustment for prognostic variables, despite low risk in outcome measurement. Kato et al were rated as having some concerns overall, with particular issues related to incomplete data capture, potential confounding, and reporting bias in its registry-based cohort.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 2. Risk of bias assessment of included studies\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStudy characteristics\u003c/p\u003e \u003cp\u003eVaezi et al and Penthinapong et al defined febrile neutropenia using standard National Comprehensive Cancer Network (NCCN)/ Infectious Diseases Society of America (IDSA) criteria [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], whereas Kato et al applied a narrower definition restricted to fever of unknown origin (FUO) without documented infection [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePenthinapong et al. conducted a retrospective single-center cohort study of 141 patients treated with idarubicin/cytarabine. FN was reported as a primary endpoint with detailed microbiological data and timing. Vaezi et al conducted a prospective randomized trial of 114 patients comparing daunorubicin 60 mg/m\u0026sup2; vs 80 mg/m\u0026sup2;, and FN incidence and infectious complications were prospectively followed up. Kato et al was a multicenter surveillance study across a national protocol enrolling 980 patients and reported microbiologically documented infections separately. This study was included only in the sensitivity analysis due to a narrow FN definition. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarises study characteristics.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDesign\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSample size (N)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatient demographics (Age, Sex %)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eStudy period\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eInduction chemotherapy regimen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFN definition used\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKato et al., 2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRetrospective analysis of national multicenter trial cohort (JALSG AML201)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e980\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMedian age 47 years; 60% male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2001\u0026ndash;2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eJALSG AML201 protocol: standard anthracycline\u0026thinsp;+\u0026thinsp;cytarabine induction (equivalent to 3\u0026thinsp;+\u0026thinsp;7 based on Japanese leukemia trial standards)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003efever of unknown origin (FUO) without documented infection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePenthinapong et al., 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThailand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRetrospective cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMean age 40.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4; 58.2% female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2008\u0026ndash;2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIdarubicin\u0026thinsp;+\u0026thinsp;cytarabine, either 3\u0026thinsp;+\u0026thinsp;7 (82.3%) or 2\u0026thinsp;+\u0026thinsp;5 (17.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNCCN\u0026thinsp;+\u0026thinsp;IDSA definitions: Temp\u0026thinsp;\u0026ge;\u0026thinsp;38.3\u0026deg;C once OR\u0026thinsp;\u0026ge;\u0026thinsp;38\u0026deg;C\u0026thinsp;\u0026gt;\u0026thinsp;1 h and ANC\u0026thinsp;\u0026lt;\u0026thinsp;500/mm\u0026sup3; or expected to fall\u0026thinsp;\u0026lt;\u0026thinsp;500/mm\u0026sup3; in 24\u0026ndash;48 h\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaezi et al., 2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIran\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProspective randomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMean age 42 years; 62% male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2011\u0026ndash;2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCytarabine 100 mg/m\u0026sup2; \u0026times; 7 days\u0026thinsp;+\u0026thinsp;daunorubicin 60 mg/m\u0026sup2; \u0026times;3 days (Arm 1) or 80 mg/m\u0026sup2; \u0026times;3 days (Arm 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNCCN\u0026thinsp;+\u0026thinsp;IDSA definitions: Temp\u0026thinsp;\u0026ge;\u0026thinsp;38.3\u0026deg;C once OR\u0026thinsp;\u0026ge;\u0026thinsp;38\u0026deg;C\u0026thinsp;\u0026gt;\u0026thinsp;1 h and ANC\u0026thinsp;\u0026lt;\u0026thinsp;500/mm\u0026sup3; or expected to fall\u0026thinsp;\u0026lt;\u0026thinsp;500/mm\u0026sup3; in 24\u0026ndash;48 h\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: Study Characteristics of included studies\u003c/p\u003e \u003cp\u003eIncidence and Timing of Febrile Neutropenia\u003c/p\u003e \u003cp\u003eAll studies confirmed FN as an almost universal complication of induction chemotherapy. Penthinapong et al documented FN in 125/141 (88.7%) patients, with a median onset on day six (IQR, 7) from the initiation of chemotherapy. The median duration of fever was 14 days, while neutropenia persisted for a median of 21 days, and antibiotic therapy was administered for a median of 27 days. Vaezi et al reported that 100% (114/114) of patients developed febrile neutropenia irrespective of daunorubicin dose. The median duration of antibiotic use was 20 days in both arms, and neutrophil recovery was observed on day 20 (60 mg/m\u0026sup2;) compared to day 22 (80 mg/m\u0026sup2;) (p\u0026thinsp;=\u0026thinsp;0.469). Kato etal, with its narrow definition, reported FN in 786/980 (80.2%) of patients during induction.\u003c/p\u003e \u003cp\u003eThe overall FN incidence in studies using standard-definition was very high, with febrile episodes characteristically occurring between day five and seven, coinciding with the expected neutrophil nadir.\u003c/p\u003e \u003cp\u003eMicrobiological Profile\u003c/p\u003e \u003cp\u003eIn the selected cohorts, the microbial pathogens of febrile neutropenia during induction chemotherapy were characterized by a predominance of gram-positive organisms and a significant incidence of invasive fungal infections.\u003c/p\u003e \u003cp\u003ePenthinapong et al confirmed a microbiological source in 43.2% of febrile neutropenia episodes, with gram-positive bacteria accounting for 60.5% of isolates. Enterococcus faecium was the most frequently identified pathogen, and pneumonia represented the predominant clinical focus (28.0% of cases). Fungal infections were also documented, and Aspergillus spp. accounted for the majority of fungal infections.\u003c/p\u003e \u003cp\u003eVaezi et al reported invasive fungal infections in 32.7% of patients treated with daunorubicin 60 mg/m\u0026sup2; and 49.1% of those receiving 80 mg/m\u0026sup2;. However, this difference did not show statistical significance. The bacterial aetiology was not documented for this study.\u003c/p\u003e \u003cp\u003eIn kato etal pulmonary infections occurred in 10.3% of patients, and Blood culture positivity for bacteria or fungi was reported in 8.3%. Invasive pulmonary aspergillosis was reported as a major complication. This study also did not provide a detailed microbiological profile. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u0026ndash; summarises the microbiological profile. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarises the microbiological profiles\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of microbiological profiles of included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMicrobiological Source Identified\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBacterial Profile\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFungal Profile\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMost Common Infection Site\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePenthinapong et al., 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.2% of FN episodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGram-positive 60.5%; most common: Enterococcus faecium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAspergillus spp. identified in invasive fungal infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePneumonia (28.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaezi et al., 2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNot detailed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInvasive fungal infections in 32.7% (60 mg/m\u0026sup2;) and 49.1% (80 mg/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKato et al., 2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBacteremia/fungemia in 8.3% of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGram-positive 65.1%; most common: Staphylococcus epidermidis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInvasive pulmonary aspergillosis reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePulmonary infections (10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUse of Antimicrobial Prophylaxis, empirical therapy, and Granulocyte colony-stimulating factor (G-CSF)\u003c/p\u003e \u003cp\u003eThe use of antimicrobial prophylaxis, empirical treatment, and granulocyte colony-stimulating factor (G-CSF) during induction chemotherapy was reported variably.\u003c/p\u003e \u003cp\u003ePenthinapong et al primarily focused on the incidence and outcomes of febrile neutropenia, but did not provide details regarding prophylactic or empirical antimicrobial regimens or G-CSF use. Similarly. Vaezi et al did not disclose any details on the above. In contrast, Kato et al documented data from a multicentre registry and reported institutional practices. For antibacterial prophylaxis, 52% of hospitals used fluoroquinolones and 30% used trimethoprim\u0026ndash;sulfamethoxazole. Oral fluconazole was noted as the antifungal prophylaxis commonly used. Reported empiric choices for FN included anti-pseudomonal cephalosporin monotherapy (29%) or carbapenem monotherapy (21%), as well as combination regimens with an aminoglycoside. In later surveys, more institutions had moved to monotherapy regimens, with either antipseudomonal cephalosporins or carbapenems.\u003c/p\u003e \u003cp\u003eMeta-Analysis of Febrile Neutropenia Incidence\u003c/p\u003e \u003cp\u003eAcross the three included studies, the incidence of FN during remission induction ranged from 80% to 100%. The pooled febrile neutropenia incidence was 0.88 (95% CI 0.76\u0026ndash;0.95) under a random-effects model, indicating that nearly nine in ten patients experienced FN during induction therapy. Substantial heterogeneity was observed (I\u0026sup2; = 85%), primarily reflecting differences in chemotherapy regimens and supportive-care practices. Leave-one-out sensitivity analysis produced pooled estimates between 0.85 and 0.93, confirming the robustness of the overall result.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 3. Forest plot of the pooled incidence of febrile neutropenia with the random effect model assumption\u003c/b\u003e \u003c/p\u003e \u003cp\u003eReporting biases\u003c/p\u003e \u003cp\u003eAcross the included studies, febrile neutropenia incidence was reported in a manner consistent with the described methods, and no obvious evidence of selective non-reporting of the primary outcome was identified. Nevertheless, given the small evidence base, the possibility of unpublished or unreported results cannot be excluded.\u003c/p\u003e \u003cp\u003eCertainty of evidence\u003c/p\u003e \u003cp\u003eBased on the qualitative certainty assessment, the overall certainty of evidence for the primary outcome (incidence of febrile neutropenia) was considered limited. Although all included studies reported the primary outcome using comparable definitions, certainty was reduced by methodological heterogeneity and differences in study design. The randomized controlled trial contributed higher internal validity, whereas the retrospective cohort and national registry studies were subject to potential residual confounding. Variability in sample size and event rates across studies also contributed to imprecision. Taken together, these factors resulted in a cautious interpretation of the pooled estimate, with findings considered informative but subject to uncertainty.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis review confirms febrile neutropenia as an inevitable outcome of intensive induction chemotherapy for acute myeloid leukaemia. The reviewed cohorts, spanning geographical regions across both high-income and low- to middle-income countries, consistently reported a high incidence of febrile neutropenia. This is a consequence of profound iatrogenic neutropenia, induced by the intensity of the induction chemotherapy regimens used, to eradicate leukemic blasts [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The timing of febrile neutropenia in the cohorts coincides with the neutrophil nadir, and the prolonged duration of the neutropenia observed during AML induction justifies the extended duration of antibiotic therapy reported across the studies, in keeping with current Infectious Diseases Society of America (IDSA) and European Society for Medical Oncology (ESMO) guidelines that recommend continuation of empiric antibiotics until neutrophil recovery [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe microbiological findings in these studies highlight the epidemiological shift of microbial agents in neutropenic AML patients. The observed predominance of gram-positive bacterial infections is in keeping with the epidemiological trend from past decades [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Historically, Gram-negative bacilli dominated, attributed to chemotherapy-induced mucosal damage with subsequent gut translocation of enteric flora. It is postulated that the widespread use of fluoroquinolone prophylaxis and the frequent use of central venous catheters have led to a rise in Gram-positive infections [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. While Gram-positive organisms emerge in numbers, the most severe infections leading to neutropenic sepsis and mortality are still accounted for by Gram-negative infections [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This reinforces the fact that, irrespective of the aetiology, FN in AML patients should be treated as a high-risk clinical entity.\u003c/p\u003e \u003cp\u003eWe also noted a significant burden of invasive fungal infections across the studies, particularly pulmonary infections with \u003cem\u003eAspergillus\u003c/em\u003e species. These findings align with both current evidence and recommendations for mold-specific antifungal prophylaxis during AML induction [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study also highlights the impact of the definitional variations on the incidence of FN. The narrow febrile neutropenia definition substantially lowered the reported incidence (80% vs 95%). Therefore, it is imperative to implement a standard FN definition both in research and clinical settings to ensure uniformity of clinical decision-making and data interpretation. While adhering to standard FN definition criteria, the selective reporting of clinically or microbiologically documented infections separately will allow for more scientific comparison between studies in the future.\u003c/p\u003e \u003cp\u003eWe noted several limitations among the included studies that may affect the strength and generalizability of the pooled estimates. One of the important limitations was geographical and resource-level limitations. There were only three studies, and all three studies were from the Asian continent (Japan, Iran, Thailand), belonging to high and upper-middle income levels, which may affect the generalizability of the findings. The limited eligible study number reflects the limited literature specifically reporting febrile neutropenia incidence during the induction cycle for newly diagnosed AML. While the absence of Western and low-income categories may reflect stricter eligibility criteria, inconsistent outcome reporting, or publication bias, during the literature review and article screening stages of this review, the authors noticed that, over the last decade, western countries have focused more on alternating induction regimes, including low-intensity and immune-targeted therapies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This may also have led to the absence of data from the western part of the world. In contrast, limited access to diagnostics, research funding, and underreporting are likely to have caused the underrepresentation of data from resource-limited settings [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother important limitation was the heterogeneous definitions of febrile neutropenia. While Penthinapong et al and Vaezi et al used standard definitions, Kato et al applied a narrower definition. This heterogeneity hindered direct comparability, which necessitated sensitivity analyses to overcome the definitional variations.\u003c/p\u003e \u003cp\u003eFurther, two of the studies (Penthinapong et al., Kato et al.) were observational, and the other (Penthinapong et al) was single-center and retrospective, which may lead to potential selection and information bias. Only Vaezi et al. was a randomized controlled trial, though even this had methodological concerns, such as a lack of blinding and incomplete reporting of allocation procedures. Standardized protocols for febrile neutropenia diagnosis and supportive care were not utilized by any of the studies.\u003c/p\u003e \u003cp\u003eIn addition, key factors and important outcomes related to febrile neutropenia, such as infection-related mortality, microbiological profiles, prophylactic and supportive care practices, and intensive care admissions, were either partially documented or entirely omitted. For example, although Vaezi et al reported overall 30-day mortality failed to specify infection-related deaths or intensive care admissions. Similarly, empirical antibiotic regimens were not detailed in Penthinapong or Vaezi et al. Only Kato et al systematically documented institutional antimicrobial and supportive care practices. This limited the assessment of adherence to guideline-based practices.\u003c/p\u003e \u003cp\u003eAlthough this review was designed and conducted according to PRISMA 2020 guidelines, several limitations in the review process need to be acknowledged. The review included only English-language publications indexed in major databases. While this ensured methodological rigor and easy accessibility, it may have excluded relevant non-English literature or regional repositories, introduced language and indexed bias. Further, we have excluded literature such as conference abstracts, case reports, or clinical trial registries. As a consequence, evolving data from ongoing trials or institution-level reports may have been missed, leading to potential publication bias and limiting insight into real-world febrile neutropenia management practices. Although we employed a broader search strategy, it may have been insufficient to capture febrile neutropenia data within larger AML treatment studies. Some prospective multicentre trials or national registries may collect febrile neutropenia outcomes but do not report them as standalone endpoints, and therefore may have been overlooked.\u003c/p\u003e \u003cp\u003eThis review unravels a new research dimension in AML treatment. Instead of focusing on febrile neutropenia and associated risk factors, future research should move forward to identifying and risk-stratifying patients who develop febrile neutropenia before they go on to severe neutropenic sepsis, including the development and validation of risk-stratification tools. Researchers should also focus on the identification of changing microbial profiles and monitoring antibiotic resistance patterns to improve evidence-based care.\u003c/p\u003e \u003cp\u003eIn conclusion, this systematic review and meta-analysis highlight febrile neutropenia as an inevitable complication of intensive induction chemotherapy in AML patients. While Gram-positive organisms have overtaken Gram-negative infections, invasive fungal infections pose a substantial risk, reinforcing the need to treat these patients under a high-risk category with broad-spectrum antibiotics and Mold-active prophylaxis. The universal occurrence of febrile neutropenia with the absence of reliable predictors of its occurrence brings out the unmet need in research and clinical practice to focus on improving outcomes after the onset of febrile neutropenia. Therefore, by shifting focus to early recognition and prevention of consequences of febrile neutropenia, like severe sepsis, multiorgan failure, and death, we can hope to ensure more patients will survive intensive induction therapy to achieve complete remission.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAML\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcute myeloid leukaemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eANC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAbsolute neutrophil count\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESMO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEuropean Society for Medical Oncology\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFebrile neutropenia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFUO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFever of unknown origin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCSF\u0026ndash;Granulocyte colony\u0026ndash;stimulating factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGRADE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGrading of Recommendations Assessment, Development and Evaluation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensive care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIDSA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInfectious Diseases Society of America\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eI\u0026sup2;\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eI\u0026ndash;squared statistic (measure of heterogeneity)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMeSH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMedical Subject Headings\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNCCN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNational Comprehensive Cancer Network\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRISMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta\u0026ndash;Analyses\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePROSPERO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Prospective Register of Systematic Reviews\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRoB 2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk of Bias 2 tool\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROBINS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eI\u0026ndash;Risk of Bias in Non\u0026ndash;randomized Studies of Interventions\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This study is a systematic review and meta-analysis based entirely on previously published studies. It did not involve the collection or analysis of individual-level human data, human tissue, or animal subjects, and therefore did not require ethical approval or informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript does not contain any person\u0026rsquo;s data, images, videos, or identifiable information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary information files. Extracted datasets are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUMW conceptualized the study, developed the protocol, registered the study in PROSPERO, conducted the literature search, performed data extraction and statistical analysis, interpreted the results, and drafted the manuscript. PMN and IW independently screened studies for eligibility, contributed to data extraction, and assessed risk of bias. PPRS served as the content expert, resolved conflicts during study selection and data extraction, and contributed to methodological oversight, interpretation of findings, and critical revision of the manuscript for important intellectual content. SS contributed to methodological design, data interpretation, contextualization of findings within the current literature, and critical review of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHansen BA, Wendelbo \u0026Oslash;, Bruserud \u0026Oslash;, Hauk\u0026aring;s E, Reikvam H. Febrile neutropenia in acute leukemia: epidemiology, etiology, pathophysiology, and treatment. Mediterr J Hematol Infect Dis. 2020;12(1):e2020009.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou Y, Huang G, Cai X, Liu Y, Qian B, Li D, et al. Global burden of acute myeloid leukemia, 1990\u0026ndash;2021: a systematic analysis for the Global Burden of Disease Study 2021. Biomark Res. 2024;12:101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi L, Zhou Y, Chen X, et al. Burden of acute myeloid leukemia, 1990\u0026ndash;2019: estimates from the Global Burden of Disease study. JCO Glob Oncol. 2023;9:e2200404.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026ouml;hner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of acute myeloid leukemia in adults: 2022 ELN recommendations from an international expert panel. Blood. 2022;140(12):1345\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFreifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. 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Outpatient management of fever and neutropenia in adults treated for malignancy: 2022 update of the IDSA clinical practice guideline. Clin Infect Dis. 2022;74(8):e220\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016;27(Suppl 5):v111\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWasylyshyn AI, Sykes AG, Okogbule-Wariso I, et al. Invasive fungal disease in patients with newly diagnosed acute myeloid leukemia. J Fungi (Basel). 2021;7(9):761.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Comprehensive Cancer Network (NCCN). Prevention and treatment of cancer-related infections. Version 1.2024. NCCN Clinical Practice Guidelines in Oncology. 2024. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nccn.org\u003c/span\u003e\u003cspan address=\"https://www.nccn.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 21 Dec 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePenthinapong T, Tantiworawit A, Trakoonchai D, Sornsong T, Yoodee J. Incidence and risk factors associated with febrile neutropenia in acute myeloid leukemia patients during induction phase. Thai J Pharm Sci. 2023;47(4):e2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaezi M, Zakerinia M, Arasteh MM, et al. Comparison of 60 mg/m\u0026sup2; vs 80 mg/m\u0026sup2; daunorubicin in induction therapy of acute myeloid leukemia. Hematol Oncol. 2017;35(1):101\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKato H, Fujita H, Akiyama N, Kimura SI, Hiramoto N, Hosono N, et al. Infectious complications in adults undergoing intensive chemotherapy for acute myeloid leukemia in 2001\u0026ndash;2005 using the JALSG AML201 protocol. Support Care Cancer. 2018;26(12):4187\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Cancer Institute. Common Toxicity Criteria, Version 2.0. Bethesda (MD): Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. 1999. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ctep.cancer.gov\u003c/span\u003e\u003cspan address=\"https://ctep.cancer.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 21 Dec 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzerefegne EF, Azibte GT, Bekele FS, Kotiso KS, Abera BM, Molla BA, et al. Clinical profile, treatment, and outcomes of febrile neutropenia in hematologic disorders: a look at 30-day mortality predictors. Sci Rep. 2025;15(1):23905. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-025-06787-z\u003c/span\u003e\u003cspan address=\"10.1038/s41598-025-06787-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, et al. CPX-351 versus 7\u0026thinsp;+\u0026thinsp;3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukemia: 5-year results of a randomized phase 3 trial. Lancet Haematol. 2021;8(7):e481\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMontesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRonnacker J, Muller PJ, Mikesch JH, Zukunft S, Weinbergerov\u0026aacute; B, Šr\u0026aacute;mek J, et al. Gemtuzumab ozogamicin in first-line treatment of core-binding factor acute myeloid leukemia: insights from a retrospective multicenter analysis. Leukemia. 2025;39(9):2174\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhoja A, Kazim F, Ali NA. Barriers to conducting clinical trials in developing countries. Ochsner J. 2019;19(4):294\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acute Myeloid Leukaemia, Febrile Neutropenia, Induction Chemotherapy Neutropenia, Infection, Systematic Review, Meta-Analysis, Immunocompromised Host, Bacterial Infections, Fungal Infections","lastPublishedDoi":"10.21203/rs.3.rs-8456536/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8456536/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFebrile neutropenia (FN) is a life-threatening complication of intensive induction chemotherapy for acute myeloid leukaemia (AML) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is the leading cause of treatment-related mortality and adversely affects remission as well as overall survival. The reported incidence of febrile neutropenia is high and heterogeneous. This systematic review and meta-analysis aim to estimate the pooled incidence of FN during AML induction and to characterize associated infections to enhance optimal management of these high-risk patients.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024628474) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies included adults (\u0026ge;\u0026thinsp;18 years) with newly diagnosed AML patients undergoing intensive induction (7\u0026thinsp;+\u0026thinsp;3-like anthracycline\u0026ndash;cytarabine regimens). We searched PubMed, Embase, Scopus, and Web of Science for the last 10 years from 1st of December 2024. Febrile neutropenia incidence proportions were pooled using a Der Simonian\u0026ndash;Laird random-effects model after logit transformation. Heterogeneity was assessed with the I\u0026sup2; (I-squared) statistic, and leave-one-out sensitivity analyses were conducted to evaluate result robustness. An artificial intelligence language model (ChatGPT, OpenAI) was used solely to assist with language editing and clarification.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThree studies were included in the final analysis, all conducted in Asian countries classified as high- or upper-middle-income settings. The pooled incidence of febrile neutropenia during induction chemotherapy was 88% (95% CI, 76%\u0026ndash;95%). Considerable heterogeneity was observed (I\u0026sup2; = 85%), due to differences in definitions of febrile neutropenia, chemotherapy protocols, and supportive care practices. One study with a narrow febrile neutropenia definition was included only in sensitivity analyses to maintain methodological consistency. However, the pooled estimates remained stable (ranging from 85% to 93%) upon sequential exclusion of individual studies. Gram-positive cocci were the predominant pathogens, and Aspergillus species accounted for the majority of fungal infections. All included studies had moderate to high risk of bias, mainly due to inconsistent febrile neutropenia definitions and limited microbiological documentation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFebrile neutropenia occurs at a very high frequency during AML induction, highlighting the importance of vigilant infection prophylaxis and prompt empirical therapy. Adoption of the standard febrile neutropenia definition and supportive care planning is recommended to improve treatment outcomes in AML induction.\u003c/p\u003e","manuscriptTitle":"Incidence of Febrile Neutropenia in Newly Diagnosed Acute Myeloid Leukaemia Patients during Intensive Induction Chemotherapy: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-07 06:16:15","doi":"10.21203/rs.3.rs-8456536/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c24c3a68-e646-47fa-92e6-2c58ac0b595b","owner":[],"postedDate":"January 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-26T09:11:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-07 06:16:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8456536","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8456536","identity":"rs-8456536","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}