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Supplements Clinical Advance in the Management of Febrile Neutropenia

Guidelines in the Management of Febrile Neutropenia for Clinical Practice

    Treatment is necessary until the patient is afebrile for at least 48 hours, clinically stable with resolution of neutropenia (ANC of at least 500 cells per microliter), and has negative blood cultures.4,5 For patients with documented » infections, the duration of treatment is decided by the organism and site of infection, and treatment should continue until resolution of neutropenia.4

If a patient is clinically unstable, such as if they present with persistent fever, signs of infection, or positive blood cultures, a broad-coverage antibiotic therapy should be considered. Patients with persistent fever are at a high risk of developing complications and need prompt consultation from an infectious diseases physician. If high fever persists for more than 4 to 6 days, then empiric antifungal therapy may be necessary. Treatment with antibiotics can be discontinued in patients with an ANC of less than 500 cells per microliter who have maintained an afebrile state for 5 to 7 days without any complications. High-risk patients, such as those with acute leukemia and those who have recently had high-dose cytotoxic chemotherapy, may require treatment with antibiotics for up to 10 days or until the resolution of neutropenia.1,4,5

Prophylaxis for FN

The recommended initial treatment for patients who are considered high risk for complications of FN, and who are expected to have an extended period of profound neutropenia lasting longer than 7 days defined by no more than 100 cells per microliter, is fluoroquinolone prophylaxis. Both ciprofloxacin and levofloxacin are recommended to treat patients at high risk for FN; however, levofloxacin is the preferred agent for patients with an increased risk of Streptococcus-mediated oral mucositis.4,5 The IDSA guidelines do not recommend treatment with prophylaxis in low-risk patients, nor do they recommend the addition of an antibiotic against gram-positive infections with prophylaxis.4,5

Patients who are considered high risk for invasive fungal infection, such as candidiasis from allogeneic hematopoietic stem cell transplant or from intensive remission induction or salvage-induction chemotherapy for acute leukemia, are strongly recommended to be initiated on antifungal prophylaxis with fluconazole, itraconazole, voriconazole, posaconazole, micafungin, or caspofungin. Patients who are considered high risk for aspergillus are aged 13 years or older, and/or are undergoing intensive chemotherapy for acute myeloid leukemia or myelodysplastic syndrome are strongly recommended to initiate posaconazole for prophylaxis. Low-risk patients are not required to have antifungal prophylaxis.4

Prophylaxis with Granulocyte Colony-Stimulating Factor

Granulocyte colony-stimulating factor (G-CSF)—filgrastim, filgrastim-sndz, tbo-filgrastim, or pegfilgrastim—is indicated for the prevention of chemotherapy-induced neutropenia in patients with nonmyeloid malignancies.5 As a prophylactic treatment, G-CSF is used to reduce infection in patients with nonmyeloid malignancies who are undergoing myelosuppressive chemotherapy associated with severe FN. Treatment with a G-CSF reduces the time to neutrophil recovery and decreases the duration of FN.6

The NCCN recommends that patients with solid and nonmyeloid malignancies are evaluated for risk factors of chemotherapy-induced FN prior to the first cycle of chemotherapy.7 The intensity of the chemotherapy regimen administered is associated with the severity of neutropenia. Patients are assessed for factors including disease type, chemotherapy regimen, treatment intent, and patient risk factors that may lead to the development of FN (Table 37).1,7 Patients who are at low risk of developing FN (<10%) and patients who do not present with risk factors should not initiate prophylaxis with G-CSF. Patients with intermediate risk for FN (10%-20%) need to be evaluated for additional patient risk factors, which are summarized in Table 3.7 After assessment, patients who present with at least 1 of these risk factors for FN is recommended for treatment with a G-CSF. Prophylaxis with G-CSF is initiated in patients who are at high risk for FN (>20%) to reduce the risks of FN, hospitalization, and intravenous antibiotic use during the course of treatment.7


As cytotoxic chemotherapy-induced FN may lead to serious complications of infection and mortality, initiating antimicrobial therapy is recommended for this patient population. Before initiating antibiotic therapy, it is crucial to perform a risk assessment to determine whether the therapy should be oral or intravenous, inpatient or outpatient, and patient needs for the duration of therapy. Risk assessment also plays a key role in determining whether G-CSF should be initiated for primary prophylaxis. Guidelines suggest that G-CSF may be needed to boost the immune system of high-risk patients, but G-CSF should initially be avoided in low-risk patients. In cases of intermediate risk, additional patient risk factors need to be weighed.

1. Klastersky J, de Naurois J, Rolston K, et al; ESMO Guidelines Committee. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016;27(suppl 5):v111-v118.
2. Neutropenia and risk of infection. CDC website. Accessed August 2, 2017.
3. Vanderpuye-Orgle J, Sexton Ward A, Huber C, Kamson C, Jena AB. Estimating the social value of G-CSF therapies in the United States. Am J Manag Care®. 2016;22(10):e343-e349.
4. Freifeld AG, Bow EJ, Sepkowitz KA, et al; Infectious Diseases Society of America. 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(4):e56-e93. doi: 10.1093/cid/cir073.
5. NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections, version 2. 2017. National Cancer Comprehensive Network website.  Published February 21, 2017. Accessed September 27, 2017.
6. Mehta HM, Malandra M, Corey SJ. G-CSF and GM-CSF in neutropenia. J Immunol. 2015;195(4):1341-1349. doi: 10.4049/jimmunol.1500861.
7. NCCN Clinical Practice Guidelines in Oncology. Myeloid Growth Factors, version 1.2017. National Cancer Comprehensive Network website. Published April 28, 2017. Accessed August 2, 2017.
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