3/6/2016 1 Febrile Neutropenia in Cancer Lela Hall, Pharm.D. PGY-2 Oncology Pharmacy Resident Baptist Hospital of Miami March 13, 2016 www.fshp.org Disclosure • Nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation Objectives • Pharmacist – Define febrile neutropenia and the risk factors for developing an infection – Identify the different prophylactic treatment options for high risk patients – Recognize appropriate empiric therapy for initial treatment, based on guideline recommendations • Technician – Identify patients who are at risk of developing febrile neutropenia – Indicate the time frame in which febrile neutropenia treatment should be initiated – Recognize healthcare worker actions that may reduce febrile neutropenia occurrence Guidelines • NCCN: National Comprehensive Cancer Network – Cancer Related Infections: Prevention & Treatment – Myeloid Growth Factors • ASCO: American Society of Clinical Oncology – Febrile Neutropenia: Prophylaxis & Outpatient Management – WBC Growth Factors • IDSA: Infectious Diseases Society of America – Neutropenic Patients with Cancer: Antimicrobial Agent Use
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3/6/2016
1
Febrile Neutropenia in Cancer
Lela Hall, Pharm.D.
PGY-2 Oncology Pharmacy Resident
Baptist Hospital of Miami
March 13, 2016
www.fshp.org
Disclosure
• Nothing to disclose concerning possible
financial or personal relationships with
commercial entities (or their competitors)
that may be referenced in this presentation
Objectives• Pharmacist
– Define febrile neutropenia and the risk factors for developing an infection
– Identify the different prophylactic treatment options for high risk patients
– Recognize appropriate empiric therapy for initial treatment, based on guideline recommendations
• Technician
– Identify patients who are at risk of developing febrile neutropenia
– Indicate the time frame in which febrile neutropenia treatment should be initiated
– Recognize healthcare worker actions that may reduce febrile neutropenia occurrence
Guidelines
• NCCN: National Comprehensive Cancer Network– Cancer Related Infections: Prevention & Treatment
– Myeloid Growth Factors
• ASCO: American Society of Clinical Oncology– Febrile Neutropenia: Prophylaxis & Outpatient Management
– WBC Growth Factors
• IDSA: Infectious Diseases Society of America– Neutropenic Patients with Cancer: Antimicrobial Agent Use
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Abbreviations
• ANC: Absolute Neutrophil Count
• CSF: Colony Stimulating Factor
• MDS: Myelodysplastic Syndrome
• AML: Acute Myeloid Leukemia
• ALL: Acute Lymphocytic Leukemia
• NHL: Non-Hodgkin’s Lymphoma
• HL: Hodgkin’s Lymphoma
• MM: Multiple Myeloma
• PS: Performance Status
• CVC: Central Venous Catheter
• CBC: Complete Blood Cell
• CMP: Complete Metabolic Panel
• FN: Febrile Neutropenia
• PPI: Proton Pump Inhibitor
• HSCT: Hematopoietic Stem Cell Transplant
• GVHD: Graft vs. Host Disease
• HSV: Herpes Simplex Virus
• VZV: Varicella Zoster Virus
• CMV: Cytomegalovirus
• HBV: Hepatitis B Virus
• MRSA: Methicillin Resistant S. Aureus
• VRE: Vancomycin Resistant Enterococcus
• KPC: K. pneumoniae carbapenemase
• ESBL: Extended Spectrum Beta Lactamase
• PCP: Pneumocystis jirovecii
• MASCC: Multinational Association for
Supportive Care in Cancer
• ECOG: Eastern Cooperative Oncology
Group
Febrile Neutropenia
• Fever• Single temperature ≥38.3⁰ C (101⁰ F)
• Sustained temperature ≥38.0⁰ C (100.4⁰ F) ≥1 hour
• Neutropenia• ANC <500/mcL
• ANC <1000/mcL & expect a fall to <500/mcL within 48 hours
NCCN. Prevention and Treatment of Cancer Related Infections.
Epidemiology
• Incidence Varies • Dependent on Risk Factors
• Solid Tumors 10-50%
• Hematologic Malignancy >80%
• Clinically Documented Infection• 20-30% of Febrile Neutropenia Cases
Freifeld AG, et al. IDSA. 2011.
Etiology
• Bacteremia• 10-20% of Patients with a Prolonged ANC <100/mcL
• Common Infection Sites• GI Tract
• Sinus• Lung
• Skin
• Aspergillosis• Life Threatening • Sinus/Lung
• Primarily Neutropenia ≥ 2 Weeks
• Mucositis• Candida • Bacterial
Freifeld AG, et al. IDSA. 2011.http://media-cache-ak0.pinimg.com/736x/cf/61/91/cf6191da9107d52763900294823d98b5.jpg
http://image.slidesharecdn.com/acuteinflamation-140220065049-phpapp01/95/acute-inflamation-5-638.jpg?cb=1392879172NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.
Risk Factors
• . Patient
Age ≥65 years
Poor PS ≥2
Albumin <35g/L
Comorbidities• Single 27%
• Two 67%
• Three (+) 125%
FN History
Cancer
Diagnosis
• AML
• MDS
• NHL
• MM
• Germ Cell
• Soft Tissue
Incomplete Response• Persistent/Refractory
• Progressive
• Remission Unattained
Stage ≥2
Treatment
Medication• >85% Dose Admin
• Purine Analogs
• Alemtuzumab
• Steroids
• High Dose Chemo
Mucositis grade ≥3
Neutropenia ≥7 days
Procedures• HSCT
• Splenectomy
• Radiation
Flowers CR, et al. ASCO. 2012. NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.
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Cancer Diagnosis & Risk90
27 26 2316
12 105.5 4.6 4.4
0
10
20
30
40
50
60
70
80
90
100
Re
po
rte
d F
N R
ate
Cancer Diagnosis
Flowers CR, et al. ASCO. 2012.
Chemotherapy Regimens
FN Risk ≥20%
• .Hematologic
ALL
• Induction
HL
• BEACOPP
NHL• ICE
• RICE
• CHOP-14
• MINE
• DHAP
• ESHAP• HyperCVAD/Rituximab
Solid Tumor
Bladder Ovarian
• MVAC • Topotecan
• Paclitaxel
Breast • Docetaxel• Docetaxel/Trastuzumab
• Dose Dense AC/T Soft Tissue Sarcoma
• TAC • MAID
• Doxorubicin
Gastro/Esophageal • Ifosfamide/Doxorubicin
• DCFSmall Cell Lung Cancer
Renal • Topotecan
•Doxorubicin/Gemcitabine
Testicular
Melanoma • BEP • VeIP• Dacarbazine Based • TIP • VIP
† † Itraconazole Suspension: Take on Empty Stomach
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Antifungal Prophylaxis
Echinocandin Dose Coverage Considerations
Micafungin 50-100 mg IV Daily Candida
Aspergillus
Hepatic Dosing
Sirolimus Interaction
Caspofungin 50 mg IV Daily Candida
Aspergillus
Hepatic Dosing
Cyclosporine, Tacrolimus &
Dexamethasone Interaction
Polyene Dose Coverage Considerations
Amphotericin B
Lipid (ABLC)
2.5 mg/kg IV TIW
Candida
Aspergillus
Dimorphic Fungi
Pre-Medicate:
NSAID +/- Diphenhydramine
OR
APAP + Diphenhydramine/HC
Less Renal Toxicity than Non-
Lipid/Liposomal
Amphotericin B
Liposomal (LAmB)
3 mg/kg IV TIW
NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.Mattiuzzi GN, Kantarjian H, Fader lS, et al. Amphotericin B lipid complex as prophylaxis of invasive fungal infections
in patients with AML or MDS undergoing induction chemotherapy. Cancer. 2004; 100(3)581-589.
Aspergillus
Aspergillus fumigatus Isolates: October 2011-2013
http://wwwnc.cdc.gov/eid/article/20/9/14-0142-f1
Antiviral Prophylaxis
Criteria Virus Prophylaxis Duration
Solid Tumor
Standard Chemo
HSV If Prior HSV Active Therapy + While Neutropenic
Autologous HSCT
Lymphoma
Multiple Myeloma
CLLPurine Analog
HSV
VZV
Acyclovir
Famciclovir
Valacyclovir
Active Therapy + While Neutropenic
Post HSCT: Minimum 30 Days
Autologous 6-12 Months
Acute Leukemia
-Induction
-Consolidation
HSVAcyclovir
Famciclovir
ValacyclovirActive Therapy + While Neutropenic
Proteasome Inhibitor VZV
Allogeneic HSCT
GVHD + Steroids
Alemtuzumab
HSV
VZV
Acyclovir
Famciclovir
Valacyclovir-
HSV
HSV: Active Therapy +
While Neutropenic +
Post HSCT Minimum 30 Days
VZV: Post HSCT 12 Months
NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.
Antiviral Prophylaxis Agents
Drug Dose Coverage Considerations
Acyclovir
HSV: 400-800 mg PO BID
VZV: 800 mg PO BID
CMV: 800 mg PO QID
HSV
VZV
CMV
Nephrotoxic
Hydration
IBW for IV dosing
Famciclovir HSV/VZV: 250 mg PO BID HSV
VZV
No Oncologic Data
Valacyclovir HSV/VZV: 500 mg PO BID or TID
CMV: 2 gm PO QID
HSV
VZV
Thrombocytopenia
HUS
Ganciclovir CMV: 5-6 mg/kg/Day IV
5 Days/Week
100 Days Post HSCT
CMV
HSV
VZV
HHV-6
Myelosuppression
Preemptive Regimen -Asymptomatic
-CMV ReactivationValganciclovir CMV: 900 mg PO Daily
CMV
HSV
VZV
HHV-6
NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.
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Pneumonia Prophylaxis
Infection Criteria Prophylaxis
PCP
HSCT
ALL
Steroids ≥20 mg/Day ≥1 month
Purine AnalogsAlemtuzumab
Temozolomide + Radiation
Trimethoprim-Sulfamethoxazole
Sulfa Allergy:
• Dapsone• Atovaquone
• Pentamidine
Pneumococcal Allogeneic HSCT
Chronic GVHD -On Immunosuppressants
Penicillin
• 3 Months to ≥1 Year Post HSCT
• Regardless of Vaccination Status
PCV13 Vaccine
• 6-12 Months Post HSCT
PSV23 Vaccine
• 12 Months Post HSCT
NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.
PCP Prophylaxis Agents
Drug Dose Considerations / Interactions
Trimethoprim-
Sulfamethoxazole
-SS or DS PO Daily
-DS PO TIW
Renal Dosing
CYP3A4, CYP2C9,
Methotrexate & Leucovorin
Dapsone -100 mg PO Daily
-50 mg PO BID
CYY3A4
CYP2C9
Atovaquone -1500 mg PO Daily Hepatic Dosing
With Food
Pentamidine -300 mg via Nebulizer
Q 3-4 Weeks
Renal Dosing
QT Prolongation
Nebulized
NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.
Influenza
Prophylaxis Drug Considerations
Patients ≥6 Months-Not Receiving
• Anti-B Cell Ab• Induction/Consolidation
Household MembersHealthcare Providers
Trivalent InactivatedVaccine
-Annually-Chemotherapy or Immunotherapy
• Vaccinate ≥2 Weeks Prior to Therapy-HSCT
• Vaccinate 4-6 Months Post HSCT
Exposure or Outbreak -Oseltamivir
75 mg PO DailyTake with Food
-Zanamivir 2 PO Inhalations Daily
May Cause Bronchospasm
Treatment Drug Considerations
Influenza A or B Positive Result
-Oseltamivir 75-100 mg PO BID
FDA Approved: 5 DaysImmunocompromised:10 Days/Resolution
-Zanamivir 2 PO Inhalations BID
Duration Based on Exposure
NCCN. Prevention and Treatment of Cancer Related Infections. 2.2015.
References• Cau DP, Riess E, Hagen F, et al. Passive Surveillance for Azole-Resistant Aspergillus
fumigatus, United States 2011-2013. CDC. 2014; 20(9)
http://wwwnc.cdc.gov/eid/article/20/9/14-0142-f1
• CDC. Cover Your Cough. CDC 2016; http://www.cdc.gov/flu/protect/covercough.htm
• 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. ASCO. 2012.
• 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. CID. 2011; 52(2):e56-93.
• NCCN Clinical Practice Guidelines in Oncology. Myeloid Growth Factors. NCCN. 2015.
Version 2.2015
• NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-
Related Infections. NCCN. 2015. Version 2.2015
• 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. JCO. 2015; 33.