Febrile Neutropenia in Hematologic Malignancies Authors
Myelodysplastic Syndromes (M Sekeres, Section Editor)
First Online: 29 August 2013 DOI:
Cite this article as: Keng, M.K. & Sekeres, M.A. Curr Hematol Malig Rep (2013) 8: 370. doi:10.1007/s11899-013-0171-4 Abstract
Febrile neutropenia (FN) can occur at any time during the course of a malignancy, especially hematologic malignancies, from diagnosis to end-stage disease. The majority of FN episodes are typically confined to the period of initial diagnosis and active treatment. Because of suppressed inflammatory responses, fever is often the sole sign of infection. As FN is a true medical emergency, prompt identification of and intervention in FN can prolong survival and improve quality of life. This article reviews FN in the setting of hematologic malignancies, specifically myelodysplastic syndromes and acute leukemias, providing an overview of the definition of fever and neutropenia, diagnostic approach, categories of risk/risk assessment, management in patients at low and high risk, and prophylaxis of infections.
Keywords Febrile neutropenia Neutropenic fever Neutropenia Fever Antibiotic prophylaxis Empiric Antibiotics Cancer Hematologic malignancies References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: Risks, consequences, and new directions for its management. Cancer. 2004;100:228–37.
Lyman GH, Dale D, Friedberg J, Crawford J, Fisher RI. Incidence and predictors of low chemotherapy dose intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol. 2004;22:4302–11.
Morrison VA, Picozzi, Scott S, et al. The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin's lymphoma receiving initial CHOP chemotherapy: a risk factor analysis. Clin Lymphoma. 2001;2(1):47–56.
Schwenkglenks M, Jackisch C, Constenla M, et al. Neutropenic event risk and impaired chemotherapy delivery in six European audits of breast cancer treatment. Support Care Cancer. 2006;14(9):901–9.
•• Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31(6):794–810.
This is the most recent FN guidelines, published by the American Society of Clinical Oncology. The manuscript reviews 43 studies on the topic of FN. The guideline primarily covers outpatient FN management, risk factors for FN, and Talcott’s group/MASCC scoring systems
Leibovici L, Paul M, Cullen M, et al. Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions. Cancer. 2006;107(8):1743–51.
Lyman GH. Guidelines of the National Comprehensive Cancer Center Network on the use of myeloid growth factors with cancer chemotherapy: a review of the evidence. J Natl Compr Cancer Netw. 2005;3:557–71.
Gafter-Gvili A, Fraser A, Paul M, et al. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005;142:979–95.
Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353:977–87.
Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med. 2005;353:988–98.
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47(1):8–32.
Wingard JR, Elmongy M. Strategies for minimizing complications of neutropenia: prophylactic myeloid growth factors or antibiotics. Crit Rev Oncol Hematol. 2009;72:144–54.
•• Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56–93.
This manuscript covers the most recent update for clinical practice guidelines of antimicrobial agents in the setting of neutropenic fever. It was published by the Infectious Diseases Society of America. It covers definitions of fever and neutropenia, all antimicrobial therapies (anti-bacterial, viral, and fungal agents) in the empiric, definitive, and prophylactic settings, and other precautions (growth factors, environmental exposures, and catheters)
• Legrand M, Max A, Peigne V, et al. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med. 2012;20(1):43–9.
This paper is a retrospective study that evaluates a French hospital’s experience with FN patients admitted to the intensive care unit. All of these FN patients meet the definition of severe sepsis or septic shock. The paper reviews patient demographics (especially oncologic diagnosis), site of infection, microbiological data, independent risk factors hospital mortality, and treatment in the high-risk, acute setting
Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637.
Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med. 1993;328:1323–32.
Bodey GP. The treatment of febrile neutropenia: from the dark ages to the present. Support Care Cancer. 1997;5:351–7.
Sundararajan V, Rubenstein EB, Rolston KV, et al. Controversies in new antibiotic therapy for ambulatory patients. Support Care Cancer. 1997;5:358–64.
Talcott JA, Finberg R, Mayer RJ, et al. The medical course of cancer patients with fever and neutropenia: clinical identification of a low-risk subgroup at presentation. Arch Intern Med. 1988;148:2561–8.
Talcott JA, Siegel RD, Finberg R, et al. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol. 1992;10:316–22.
Talcott JA, Whalen A, Clark J, et al. Home antibiotic therapy for low-risk cancer patients with fever and neutropenia: a pilot study of 30 patients based on a validated predication rule. J Clin Oncol. 1994;12(1):107–14.
Klastersky J, Paesmans M, Rubenstein EB, et al. The multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18:3038–51.
Klastersky J, Paesmans M, Georgala A, et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol. 2006;24:4129–34.
Elting LS, Lu C, Escalante CP, et al. Outcomes and cost of outpatient or inpatient management of 712 patients with febrile neutropenia. J Clin Oncol. 2008;26(4):606–11.
Talcott JA, Yeap BY, Clark JA, et al. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial. J Clin Oncol. 2011;29(30):3977–83.
Innes H, Marshall E. Outpatient therapy for febrile neutropenia. Curr Opin Oncol. 2007;19(4):294–8.
Teuffel O, Ethier MC, Alibhai SMH, et al. Outpatient management of cancer patients with febrile neutropenia: a systematic review and meta-analysis. Ann Oncol. 2011;22(11):2358–65.
EORTC International Antimicrobial Therapy Cooperative Project Group. Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. J Infect Dis. 1978;137:14–29.
Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6 degrees F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA. 1992;268:1578–80.
•• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2013.
(Accessed on July 1, 2013).
This is a comprehensive review, based on a panel of national experts, from the National Comprehensive Cancer Network regarding the prevention and treatment of cancer-related infections. The article provides an updated review of initial evaluation, risk stratification, and treatment (prophylactic, empiric, and definitive) in FN
Lyman GH, Lyman CH, Agboola O. Risk models for predicting chemotherapy-induced neutropenia. Oncologist. 2005;10:427–37.
Intragumtornchai T, Sutheesophon J, Sutcharitchan P, et al. A predictive model for life-threatening neutropenia and febrile neutropenia after the first course of CHOP chemotherapy in patients with aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2000;37:351–60.
Uys A, Rapoport BL, Anderson R. Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score. Support Care Cancer. 2004;12:555–60.
Paesmans M, Klastersky J, Maertens J, et al. Predicting febrile neutropenic patients at low risk using the MASCC score: does bacteremia matter? Support Care Cancer. 2011;19:1001–8.
de Naurois J, Novitzky-Basso I, Gill MJ, et al. Management of febrile neutropenia: ESMO clinical practice guidelines. Ann Oncol. 2010;21 Suppl 5:v252–6.
Lee JH, Lee KH, Lee JH, et al. Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome. Leuk Res. 2011;35:499–503.
Bow EJ. Neutropenic fever syndromes in patients undergoing cytotoxic therapy for acute leukemia and myelodysplastic syndromes. Semin Hematol. 2009;46(3):259–68.
Ray-Coquard I, Borg C, Bachelot T, et al. Baseline and early lymphopenia predict for the risk of febrile neutropenia after chemotherapy. Br J Cancer. 2003;88:181–6.
Pettengell R, Schwenkglenks M, Leonard R, et al. Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study. Support Care Cancer. 2008;16:1299–309.
Bow EJ, Kilpatrick MG, Scott BA, et al. Acute myeloid leukemia in Manitoba: The consequences of standard “7 + 3” remission-induction therapy followed by high dose cytarabine postremission consolidation for myelosuppression, infectious morbidity, and outcome. Cancer. 1994;74:52–60.
Bucaneve G, Micozzi A, Meichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353:977–87.
Agency for Healthcare Research and Quality. Emergency Severity Index (ESI): A Triage Tool for Emergency Department. Version 4.
(Accessed on July 1, 2013).
Vardakas KZ, Samonis G, Chrysanthopoulou SA, et al. Role of glycopeptides as part of initial empirical treatment of febrile neutropenic patients: a meta-analysis of randomised controlled trials. Lancet Infect Dis. 2005;5:431–9.
Paul M, Borok S, Fraser A, et al. Additional anti-Gram-positive antibiotic treatment for febrile neutropenic cancer patients. Cochrane Database Syst Rev. 2005;3, CD003914.
Dompeling EC, Donnelly JP, Deresinski SC, et al. Early identification of neutropenic patients at risk of gram positive bacteraemia and the impact of empirical administration of vancomycin. Eur J Cancer. 1996;32A:1332–9.
Peacock JE, Herrington DA, Wade JC, et al. Ciprofloxacin plus piperacillin compared with tobramycin plus piperacillin as empirical therapy in febrile neutropenic patients. A randomized, double-blind trial. Ann Intern Med. 2002;137(2):77–87.
Bliziotis IA, Michalopoulos A, Kasiakou SK, et al. Ciprofloxacin vs an aminoglycoside in combination with a beta-lactam for the treatment of febrile neutropenia: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2005;80(9):1146–56.
Eckmanns T, Ruden H, Gastmeier P. The influence of high-efficiency particulate air filtrationon mortality and fungal infection among highly immunosuppressed patients: a systematic review. J Infect Dis. 2006;193:1408–18.
van Tiel F, Harbers MM, Terporten PH, et al. Normal hospital and low-bacterial diet in patients with cytopenia after intensive chemotherapy for hematological malignancy: a study of safety. Ann Oncol. 2007;18:1080–4.
Pollyea DA, Brown JM, Horning SJ. Utility of influenza vaccination for oncology patients. J Clin Oncol. 2010;28:2481–90.
Bow EJ. Point: fluoroquinolone-based antibacterial chemoprophylaxis in neutropenic cancer patients works for defined outcomes in defined populations, but must be used wisely. J Natl Compr Cancer Netw. 2004;2(5):433–44.
Robenshtok E, Gafter-Gvili A, Goldberg E, et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol. 2007;25:5471–89.
Hachem R, Hanna H, Kontoyiannis D, et al. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer. 2008;112(11):2493–9.
Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068–75.
Kanda Y, Yamamoto R, Chizuka A, et al. Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials. Cancer. 2000;89(7):1611–25.
Bow EJ, Laverdière M, Lussier N, et al. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Cancer. 2002;94(12):3230–46.
Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356(4):348–59.
Wingard JR, Carter SL, Walsh TJ, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010;116(24):5111–8.
Vardakas KZ, Michalopoulos A, Falagas ME. Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta-analysis of randomised-controlled trials. Br J Haematol. 2005;131(1):22–8.
Glasmacher A, Prentice A, Gorschlüter M, et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J Clin Oncol. 2003;21(24):4615–26.
Lubel JS, Angus PW. Hepatitis B reactivation in patients receiving cytotoxic chemotherapy: diagnosis and management. J Gastroenterol Hepatol. 2010;25(5):864–71.
Firpi RJ, Nelson DR. Viral hepatitis: manifestations and management strategy. Hematology Am Soc Hematol Educ Program. 2006;375–80.
Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25(21):3158–67.
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187–205.
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;42(15):2433–53.
Bohlius J, Herbst C, Reiser M, et al. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008;CD003189.
Hartmann LC, Tschetter LK, Habermann TM, et al. Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia. N Engl J Med. 1997;336(25):1776–80.
Maher DW, Lieschke GJ, Green M, et al. Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial. Ann Intern Med. 1994;121(7):492–501.
Vellenga E, Uyl-de Groot CA, de Wit R, et al. Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia. J Clin Oncol. 1996;14(2):619–27.
Berghmans T, Paesmans M, Lafitte JJ, et al. Therapeutic use of granulocyte and granulocyte-macrophage colony-stimulating factors in febrile neutropenic cancer patients. A systematic review of the literature with meta-analysis. Support Care Cancer. 2002;10(3):181–8.
Kurderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258–66.
Thirumala R, Ramaswamy W, Chawla S. Diagnosis and management of infectious complications in critically ill patients with cancer. Crit Care Clin. 2010;26:59–91.
Klastersky J, Ameye J, Maertens J, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents. 2007;30S:S51–9.
CrossRef Copyright information
© Springer Science+Business Media New York 2013