A presentation I gave during an internship/Advanced Pharmacy Practice Experience (APPE) in oncology at a hospital.

1. Febrile Neutropenia: A Review
Paul Pasco, PharmD Candidate
UTHSC College of Pharmacy
ppasco@uthsc.edu
Monday, August 30, 2021 1

2. Objectives
› Describe the morphology and physiology of neutrophils.
› Review the process of hematopoiesis.
› Explain the terms “febrile neutropenia” and “fever” in the setting of neutropenia.
› Develop an understanding of the pathophysiology of febrile neutropenia.
› Understand the epidemiology of febrile neutropenia.
› Outline the clinical presentation of febrile neutropenia.
› Identify models used for risk stratification of febrile neutropenia.
› Elucidate the evidence-based management of febrile neutropenia.
› List selected chemotherapeutic regimens where there is a high risk for febrile
neutropenia.
› Recognize the utility of granulocyte colony-stimulating factors (G-CSFs) in febrile
neutropenia.
› Delineate strategies for primary and secondary prophylaxis for febrile
neutropenia, as well as other potential indications/contraindications for use based
on the current guidelines.
2

3. Background
3

4. What Are Neutrophils?
› A type of leukocyte (white blood cell, WBC)
› Also called polymorphonuclear leukocytes (PMNs)
– Sometimes called “polys”, segmented neutrophils, or “segs”
› Protect the host against bacterial and fungal infections
› Arise from the myeloid lineage in hematopoiesis
› Granulocytic
› Multilobed, horseshoe-shaped nucleus
– Typically, 2 to 5 lobes connected by thin strands
– Number increases with age
› Most numerous WBC
– 60-70% of WBCs in the body
4

5. Hematopoiesis
5
Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 15th ed. Langara College; 2017. Accessed August 22, 2021. Vitalsource.com

6. Hematopoiesis of Neutrophils
6

7. What is Febrile Neutropenia?
› The suffix “-penia” comes from the ancient Greek “penía” for
“poverty, lack”
› Neutropenia = ↓ # neutrophils
– The # neutrophils = the absolute neutrophil count (ANC)
– Febrile neutropenia (FN) = neutropenia with an evident fever
› Causes:
– Radiation exposure
– Chemotherapeutic exposure
– Vitamin B12 deficiency
– Systemic lupus erythematosus (SLE)
› Clinical significance:
– Risk of infection ↑ with ↑ depth and ↑ duration of neutropenia
– Febrile neutropenia is an oncologic EMERGENCY!
7

8. Pathophysiology of Febrile Neutropenia
› Bone marrow ➔ rapidly dividing cells that ultimately differentiate into
neutrophils
› Direct toxicity/inhibition
– Chemotherapeutics exhibit toxicity to rapidly dividing cells ➔ neutropenia
› Immune-mediated reaction
– Often related to exposure to haptens
› May be due to other mechanisms (e.g., rituximab)
› Haptens are antigenic but non-immunogenic small molecules that can ultimately cause an
immune reaction (e.g., hypersensitivity)
– Anti-hapten antibodies may form after exposure to certain pharmacotherapeutics
› Penicillins (PCNs)
› Trimethoprim/sulfamethoxazole (TMP/SMX)
› Vancomycin
– Anti-hapten antibodies destroy neutrophil precursors => neutropenia
8
Bhatt V, Saleem A, Annals of Clinical & Laboratory Science. Drug-Induced Neutropenia – Pathophysiology, Clinical Features, and Management. Annals of Clinical & Laboratory Science.
2004;34(2):131-137. Accessed August 24, 2021. http://www.annclinlabsci.org/content/34/2/131.full.pdf+html
Curtis BR, Immunohematology. Drug-induced immune neutropenia/agranulocytosis. Immunohematology. 2014;30(2):95-101. Accessed August 24, 2021.
https://pubmed.ncbi.nlm.nih.gov/25247619/

9. What Constitutes a Fever in the Setting of
Neutropenia?
› A single oral temperature of ≥ 38.3 °C (101 °F) OR
› A temperature of ≥ 38.0 °C (100.4 ° F) sustained over an hour
› Fever is NOT always present
– A high degree of clinical suspicion is recommended
› May be below this threshold if it is present
› Medications commonly administered in the setting of cancer
may mask fever
– Acetaminophen
– Glucocorticosteroids (e.g., prednisone, dexamethasone)
9
IDSA, ASCO, Taplitz RA, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: ASCO and IDSA Clinical Practice Guideline
Update. Idsociety.org. Published May 1, 2018. Accessed August 24, 2021. https://www.idsociety.org/practice-guideline/fever-and-neutropenia-in-adults-with-cancer/

10. Epidemiology of Febrile Neutropenia
10

11. Epidemiology of FN: Morbidity and Mortality
› Morbidity
– The rate of major complications from FN is 25-30%
– Major complications include:
› Hypotension
› Acute renal, respiratory, and cardiac failure
› Mortality
– Mortality rate ranges up to 11%
– In the setting of inpatient sepsis, mortality rates may reach 50%
11
IDSA, ASCO, Taplitz RA, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: ASCO and IDSA Clinical Practice Guideline
Update. Idsociety.org. Published May 1, 2018. Accessed August 24, 2021. https://www.idsociety.org/practice-guideline/fever-and-neutropenia-in-adults-with-cancer/

12. Epidemiology of FN: Overview of Risk Factors
› Intravenous access
– Port
– Central line
› Impaired barrier defenses
– Mucositis
› Surgery
› Healthcare exposure
– Multidrug resistant organisms (MDROs), including methicillin-
resistant staphylococcus aureus (MRSA) and vancomycin-resistant
enterococci (VRE)
› Pharmacotherapeutics
– Many drugs implicated
12
Family L, Li Y, Chen LH, Page J, Klippel ZK, Chao C. Risk factors for febrile neutropenia in cancer patients treated with chemotherapy. Journal of Clinical Oncology.
2016;34(15_suppl):6559-6559. doi:10.1200/jco.2016.34.15_suppl.6559

13. Epidemiology of FN: Risk Factors with Selected
Pharmacotherapies
› Chemotherapeutics
– Alkylating agents
› Cisplatin
› Carboplatin
– Anthracyclines (topoisomerase 2 inhibitors)
› Doxorubicin
– Antimetabolites
› Fludarabine
› Cytarabine
› 5-FU
– Camptothecins (topoisomerase 1 inhibitors)
› Topotecan
– Epipodophyllotoxins (topoisomerase 2 inhibitors)
› Tenoposide
– Taxanes (microtubule inhibitors)
› Paclitaxel
– Vinblastine (vinca alkaloid, microtubule inhibitor)
13
› Antimicrobials
– PCNs
› Oxacillin
› PCN G
– Folate inhibitors
› TMP/SMX
– Glycopeptides
› Vancomycin
– Sulfones
› Dapsone
› Psychotropics
– Clozapine (antipsychotic)
– Lamotrigine (mood stabilizer)
› Antiarrhythmics
– Procainamide
– Quinidine
Moore DC, Pharmacy & Therapeutics: A Peer-Reviewed Journal for Managed Care and Hospital Formulary Management. Drug-Induced Neutropenia: A Focus on Rituximab-Induced Late-Onset Neutropenia. P & T : a peer-reviewed
journal for formulary management. 2016;41(12):765-768. Accessed August 24, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132417/

14. Presentation of Febrile Neutropenia
14

15. How does Febrile Neutropenia Present?
› Signs
– Fever
› ≥ 38.3 °C (101 °F) OR of ≥ 38.0 °C (100.4 ° F) sustained for an hour or more
– Rigors
– Diaphoresis
– Hypotension
– Altered mental status
– Tachycardia
– Tachypnea
› Symptoms
– Chills
› Risk for infection varies based on ANC of the patient
15
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 IDSA. Clinical
Infectious Diseases. 2011;52(4):e56-e93. doi:10.1093/cid/cir073

16. How is the Absolute Neutrophil Count
Determined?
›𝐴𝑁𝐶
𝑐𝑒𝑙𝑙𝑠
𝑚𝑚3 = 𝑊𝐵𝐶 𝑥 (
% 𝒏𝒆𝒖𝒕𝒓𝒐𝒑𝒉𝒊𝒍𝒔∗ + % 𝒃𝒂𝒏𝒅𝒔
100
)
– Bands = immature neutrophils
– *May be reported as % neutrophils, % mature neutrophils,
% segmented neutrophils, % segs, % polymorphonuclear cells, % PMNs,
or % polys by laboratories
16

17. ANC Grading and Infection Risk
17
NUMBER OF
NEUTROPHILS/mcL
RISK OF INFECTION
1500 – 2000 No significant risk
1000 – 1500 Minimal risk
500-1000 Moderate risk
< 500 Severe risk
< 100 PROFOUND RISK

18. Diagnostic Criteria for FN
› Neutropenia is either:
– ANC < 500 neutrophils/mcL OR
– ANC < 1000 neutrophils/mcL AND an expected decline to < 500
neutrophils/mcL over the next 48-hours
– If diagnosis of neutropenia is presumed to be secondary to
chemotherapeutic exposure, consider:
› Nadir occurs 10-14 days after treatment (typically)
– Neutrophil recovery tends to occur in 3-4 weeks after treatment
› Exceptions to this include mitomycin, carmustine, and lomustine
– Neutrophil recovery tends to occur 6-8 weeks after treatment
› Guidelines recommend strong clinical suspicion of FN within 6 weeks of
receiving chemotherapy
18
Moore DC, Pharmacy & Therapeutics: A Peer-Reviewed Journal for Managed Care and Hospital Formulary Management. Drug-Induced Neutropenia: A Focus on Rituximab-Induced Late-
Onset Neutropenia. P & T : a peer-reviewed journal for formulary management. 2016;41(12):765-768. Accessed August 24, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132417/

19. Common Microbial Pathogens in FN
› Gram +
– Coagulase negative staphylococci
› Staphylococcus aureus, including MRSA
› Enterococcus, including VRE
› Streptococcus viridans
› Gram –
– Escherichia coli
– Klebsiella spp.
– Enterobacter spp.
– Pseudomonas aeruginosa
– Acinetobacter spp.
– Stenotrophomonas maltophilia
19
› Fungi
– Common in high-risk patients
only
– Candida
– Aspergillus
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 IDSA. Clinical Infectious
Diseases. 2011;52(4):e56-e93. doi:10.1093/cid/cir073

20. Models for Risk Stratification of FN at Diagnosis
› Multinational Association for Supportive Care in Cancer
(MASCC)
– Assesses the probability of chemotherapy-associated complications
– Validated
› 71% sensitive, 68% specific, 91% positive predictive value
– Consists of 8 factors
– Maximum score is 26; higher score = better
– MASCC ≥ 21: LOW risk of febrile neutropenia
› Treat as OUTPATIENT with ORAL, broad-spectrum antibiotics
› 91% chance of resolution without an adverse outcome
– MASCC < 21: HIGH risk of febrile neutropenia
› Treat as INPATIENT with IV, broad-spectrum antibiotics
› 64% chance of resolution without an adverse outcome if treated appropriately
› Clinical Index of Stable Febrile Neutropenia (CISNE)
– Stratifies risk into low-, intermediate-, and high-risk groups
20
IDSA, ASCO, Taplitz RA, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: ASCO and IDSA Clinical Practice Guideline
Update. Idsociety.org. Published May 1, 2018. Accessed August 24, 2021. https://www.idsociety.org/practice-guideline/fever-and-neutropenia-in-adults-with-cancer/

21. Multinational Association for Supportive Care in
Cancer (MASCC) Criteria for Febrile Neutropenia
21

22. Management of Febrile Neutropenia
22

23. Initial Management of Febrile Neutropenia
23
IDSA, ASCO, Taplitz RA, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: ASCO and IDSA Clinical Practice Guideline
Update. Idsociety.org. Published May 1, 2018. Accessed August 24, 2021. https://www.idsociety.org/practice-guideline/fever-and-neutropenia-in-adults-with-cancer/

24. Important Tests During Triage of FN
24
› History & Physical
– Previous healthcare exposure ➔ MDROs?
› Complete Blood Count w/differential
› Comprehensive Metabolic Panel
› Cultures
– Blood cultures x 2 (different anatomical sites)
– Other cultures as clinically indicated (e.g., urine, CSF, stool, wound)
› Imaging (if s/sx of lower respiratory tract infection)
– Chest X-ray for lower respiratory tract infections (e.g., pneumonia)
› Rapid influenza test (if s/sx of respiratory illness)
– Potentially other respiratory virus panels
› Procalcitonin?
– Insufficient evidence
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 IDSA. Clinical Infectious
Diseases. 2011;52(4):e56-e93. doi:10.1093/cid/cir073

25. To Admit or Not to Admit?
25
IDSA, ASCO, Taplitz RA, et al. Outpatient Management of Fever and Neutropenia in
Adults Treated for Malignancy: ASCO and IDSA Clinical Practice Guideline Update.
Idsociety.org. Published May 1, 2018. Accessed August 24, 2021.
https://www.idsociety.org/practice-guideline/fever-and-neutropenia-in-adults-with-cancer/

26. Potential Contraindications to Outpatient
Management
› Consider these contraindications for outpatient treatment
when triaging (even with MASCC score ≥ 21)
– Uncontrolled arrhythmias
– Pericardial effusion
– VTE (DVT, PE)
– Ascites
– LFTs > 5x ULN
– Altered mental status
– Pneumothorax
– Pleural effusion
– Pregnant or nursing
– MRSA, VRE, Stenotrophomonas maltophilia colonization
26
IDSA, ASCO, Taplitz RA, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: ASCO and IDSA Clinical Practice Guideline
Update. Idsociety.org. Published May 1, 2018. Accessed August 24, 2021. https://www.idsociety.org/practice-guideline/fever-and-neutropenia-in-adults-with-cancer/

27. Outpatient Management: LOW Risk
› Oral, broad-spectrum, combination, and bactericidal empiric therapy
is recommended
– Strong Gram+, Gram-, and anti-PA coverage
– Assess antibiogram (if available)
› Within 1 hour of presentation, initiate any of these three regimens
(AFTER cultures have been taken):
– Ciprofloxacin + amoxicillin/clavulanate
– Levofloxacin + amoxicillin/clavulanate
– Ciprofloxacin + clindamycin (PCN allergy only)
– Levofloxacin + clindamycin (PCN allergy only)
› Do NOT use FQ monotherapy
› Do NOT use these regimens if the patient has received prior FQ
therapy (e.g., for prophylaxis in high-risk patients)
› If fever does not dissipate within 2-3 days of antimicrobial therapy,
reevaluate for admission to the hospital
27
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 IDSA. Clinical
Infectious Diseases. 2011;52(4):e56-e93. doi:10.1093/cid/cir073

28. Inpatient Management: HIGH Risk
› Monotherapy backbone with an antipseudomonal ẞ-lactam is
recommended
– Piperacillin-tazobactam
– Cefepime
– Carbapenem (meropenem or imipenem-cilastatin, NOT ertapenem)
› May consider adding an aminoglycoside, FQ, and vancomycin for
complications that arise, in the case of resistance, or when certain
risk factors are present (e.g., MDRO colonization)
– MRSA ➔ add vancomycin, linezolid, or daptomycin
– ESBLs ➔ early use of a carbapenem
– Except as noted, adding an aminoglycoside is otherwise NOT beneficial (only
increases toxicity)
– C. difficile ➔ consider metronidazole
– Fungi ➔ consider antifungal coverage if no response to antibiotics after 4-7
days and expected duration of neutropenia > 7 days
28
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 IDSA. Clinical
Infectious Diseases. 2011;52(4):e56-e93. doi:10.1093/cid/cir073

29. Selected Chemotherapeutic Regimens with a High
Risk* of FN
› In general, all dose-dense regimens
› Non-Hodgkins lymphoma
– ICE
– HyperCVAD
› Colorectal cancer
– FOLFOXFIRI
› Multiple myeloma
– DT-PACE
› SCLC
– Topotecan
* > 20% risk 29
› Pancreatic cancer
– FOLFIRINOX
› Kidney cancer
– Doxorubicin/gemcitabine
› Bladder cancer
– Dose dense MVAC
› Ovarian cancer
– Topotecan
– Docetaxel
NCCN. Hematopoietic Growth Factors. Nccn.org. Published May 20, 2021. Accessed August 25, 2021.
https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf

30. Role of G-CSFs in Febrile Neutropenia
› What is granulocyte colony-stimulating factor (G-CSF)?
– Endogenous glycoprotein that stimulates production of neutrophils
› Granulocyte colony-stimulating factors
– Exogenous glycoprotein pharmacotherapeutics
– MOA
› Binds to receptors on precursors (increased differentiation and proliferation) and
mature neutrophils (increased survival)
› Stimulates the myeloid line of bone marrow to produce neutrophil precursors, which
ultimately differentiate into neutrophils
– Reduce both depth and duration of neutropenia
› Available agents include:
– Pegfilgrastim
– Filgrastim
– tbo-filgrastim
– Filgrastim-sndz
30
Yang B-B, Kido A. Pharmacokinetics and Pharmacodynamics of Pegfilgrastim. Clinical Pharmacokinetics. 2011;50(5):295-306. doi:10.2165/11586040-000000000-00000

31. Summary of Primary Prophylaxis with G-CSFs
› Primary prophylaxis
– Start with first cycle
– Continue through all subsequent cycles
› Multiple factors should be considered to evaluate a patient's
candidacy for primary prophylaxis
– Assess risk for FN
› High risk vs. low risk
› Use if risk of FN is ≥ ~20%
– Evaluate clinical factors
› Consider in diffuse aggressive lymphoma if ≤ 65 years AND treated with curative
therapy (CHOP-R)
– Consider neutropenic potential of treatment
› Intensity of chemotherapeutic regimen (e.g., dose dense)
31
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical
Oncology. 2015;33(28):3199-3212. doi:10.1200/jco.2015.62.3488

32. Summary of Secondary Prophylaxis with G-CSFs
› Secondary prophylaxis
– An episode of FN in the absence of G-CSF treatment has occurred
already
– Therapy with G-CSFs has been initiated to prevent a recurrence
› Similar criteria for initiating as with primary prophylaxis
– Assess risk for FN
› High risk vs. low risk
– Evaluate clinical factors
– Consider neutropenic potential of treatment
› Intensity of chemotherapeutic regimen (e.g., dose dense)
– Assess if dose reduction or delay of therapy would adversely affect
treatment outcomes (e.g., overall survival, disease-free survival)
32
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical
Oncology. 2015;33(28):3199-3212. doi:10.1200/jco.2015.62.3488

33. Summary of Other Guidelines for Use of G-CSFs
› Other recommendations
– Recommend against routine use as prophylaxis in neutropenic patients who
are afebrile
– Recommend administration of G-CSFs after autologous stem cell
transplants to reduce the duration of severe neutropenia
– Recommend consideration of G-CSFs after allogeneic stem cell transplants
to reduce the duration of severe neutropenia
– Recommend against the use of G-CSFs as adjunctive therapy in febrile
patients receiving antibiotics who become neutropenic
› Consider if a high risk of infection-related complications or presence of poor
prognostic markers (e.g., sepsis syndrome)
– Recommend against the use of G-CSFs in patients receiving chemoradiation,
especially with radiation of the mediastinum
› May consider in radiation alone if a prolonged delay in recovery secondary to
neutropenia is anticipated
33
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of
Clinical Oncology. 2015;33(28):3199-3212. doi:10.1200/jco.2015.62.3488

34. Questions?
34

35. Febrile Neutropenia: A Review
Paul Pasco, PharmD Candidate
UTHSC College of Pharmacy
ppasco@uthsc.edu
Monday, August 30, 2021 35