Myelosuppression, Febrile Neutropenia and Cancer Related Infection Considerations

Question 1

Myelosuppression

Answer 1

• Myelosuppression is a condition in which the bone
  marrow activity is reduced, leading to fewer red blood
  cells, white blood cells, and platelets.
• Myelosuppression is a common side effect and dose
  limiting toxicity of chemotherapy (cytotoxic drugs).
• Myeloablation is a term used for SEVERE
  myelosuppression that is difficult to recover from
  without a stem cell infusion (example: when a
  lymphoma or myeloma patient is given HIGH DOSE
  chemotherapy as part of an autologous stem
  cell transplant conditioning/preparation protocol).
• Myelosuppression is NOT osteoporosis (weakening of
  the bones)

Question 2

cll type

Answer 2

Neutrophil 8 hours Kill bacteria using
enzyme rich granules
and endocytosis or
phagocytosis
Increased risk of
severe infections
very short life

Erythrocytes 120 days Carry O2 to tissues Fatigue, SOB

Thrombocytes
(platelets)
5-10 days Essential for normal
blood clotting
Bleeding

Question 3

Anemia

Answer 3

– Reduced erythrocytes (red blood cells)
– Monitor Hg levels
– If severe anemia and symptomatic (fatigue,
SOB), may need blood transfusion
* Remember – this is not from a
deficiency of iron, folate, or B12. This is
from damage to the bone marrow!

Question 4

Thrombocytopenia

– Awareness of easier bruising
– Soft toothbrush (gums can bleed easier)
– Blow nose gently (avoid a nose bleed)
– Avoid constipation and straining on the toilet (avoid anal fissures and
anal bleeding)
– Avoid use of (or be cautious when using) medications that can
increase the risk of bleeding (NSAIDs, ASA)
– Medical attention is required in the event of uncontrolled bleeding

Answer 4

• Thrombocytopenia
  – normal platelet range is 150-400 X 109
  /L
  – reduced platelets can lead to bruising,
  bleeding (major and minor) or a petechiae
  type rash
  – depending on the antineoplastic regimen,
  treatment delay or dosing may be adjusted if
  platelets are < 50-100 X 109
  /L
  – if platelets are critically low (<10 X 109
  /L),patient may be given a platelet transfusion

Question 5

Immune Function in Cancer Patients

Answer 5

Disease Factors Treatment Factors
Impaired Humoral Immunity?
Some hematologic malignancies can lead to
impaired humoral immunity (Example:
myeloma – issues with serum antibodies)
Chemotherapy
* Chemotherapy induced NEUTROPENIA
* Chemotherapy causes cell death in rapidly dividing cells (good and
bad)
* Affects neutrophil production in the bone marrow

Impaired Cell Mediated Immunity?
Some hematologic malignancies can lead to
impaired cell mediated immunity (Example: Tcell Lymphoma where T-cells are not functional to do their job)
Other Immunosuppressants
* Corticosteroids (prednisone, dexamethasone)
Radiation Therapy
* Example “TBI” (total body irradiation) with substantial impact on the
bone marrow

Question 6

• Chemotherapy Induced Neutropenia

Answer 6

– “Good Cells” impacted by cytotoxic drugs includes the neutrophils produced in the
bone marrow
– Neutrophil count will begin to fall occurs approximately 5-12 days after chemo
(depending on regimen)
– Dose related (think back to discussion of dose limiting toxicities)
– The lowest point is referred to as the “NADIR”
* When neutrophils are at their lowest number in the circulating blood

Response is dose related

The higher the dose of chemp or the more myelosuprpressive, the lower the nadir

Question 7

Infection “Portals” in Cancer Patients

Answer 7

Environmental
Exposure
“regular stuff”
Damage to Skin Damage to Mucous Membranes Medical Procedures
Droplet exposure IV access such as
Indwelling Catheter
Oral Mucositis (open wounds in the
mouth)
Endoscopy
Airborne exposure Antineoplastic adverse
effects (cracked, broken
skin)
Gastric Mucositis (inflammation or
ulceration of the membranes of GIT)
Bronchoscopy
Ingestion exposure Surgical wound Rectal Issues

Question 8

Infection Microbiology in Cancer Patients
Organisms colonizing the host (patient’s own flora) Organisms in the Environment Other Patient Specific
Factors

Answer 8

Skin Flora
* Usually gram positive
DAMAGE to SKIN: Skin flora can enter body through many mechanisms
Gut Flora
* Differs throughout the gut but gram positive, gram negative, and anaerobes are present
* MUCOSITIS - Gut flora can enter the blood through
injured gi mucosa

What is the patient’s recent environment?
* Community vs Hospital
* Recent outbreaks occurring?
* Travel history?
* Close contacts?

Resistance Risk?
* Frequent exposure to broad spectrum antibiotics (previous infections)
* Ongoing exposure to
prophylactic antibiotics

Question 9

BacteremiasBacteremias

Answer 9

– Isolation of gram positive more common than gram negative
– Gram negative associated with higher mortality than gram
positive(18% vs 5%)
* P. aeruginosa associated with very high mortality
– Possible drug resistant organism?
– Possible fungal/mold etiology?

Question 10

Indicators of Infection

Answer 10

• Usual signs and/or symptoms of infection may be absent or altered in
  neutropenic patients
  – Low number of leukocytes
  – Inability to mount a “normal” immune response
• Example: there may be no “pus”
• Neutropenic patients with bacteremia might exhibit NO signs or symptoms of infection other than FEVER
  Takes only a few neutophil cells to cause fever, often only sign
• A fever in a neutropenic cancer patient is assumed to be caused by
  infection until proven otherwise
• A fever in a neutropenic patient is an oncologic emergency

– Temperature of 38.3oC or greater, or a
sustained temperature of ≥38.0oC lasting
more than 1 hour.

Question 11

What is Neutropenia?

Answer 11

• Reduced number of neutrophils circulating in the peripheral
  blood.
• Normal neutrophil range is 2.0 to 8.0 x 109
  /L
  – In practice, infection concern is heightened at 0.5 X 109
  /L or less
• Often referred to “ANC” = Absolute Neutrophil Count
  – Sum of Neutrophils + Bands

Number of bands is suually small and doesnt change ANC all that much

concerned is heighted at 0.5 or less

Question 12

Febrile Neutropenia
* Definition (IDSA):

Answer 12

– Single oral temperature ≥38.3oC or sustained oral temperature ≥38.0oC for
more than 1 hour
– ANC < 0.5 X 109
/L or expected to fall to < 0.5 X 109
/L within the next 48
hours
* Oncologic and Medical Emergency
– High rate of mortality/morbidity if untreated
– Infection can progress rapidly and become life threatening quickly
– Prompt, empiric antibiotic therapy reduces mortality

Question 13

Patient Assessment and Workup

Answer 13

• Cultures and Sensitivities:
  – Blood, 2 sets - peripheral and central access (if applicable)
• DO ASAP BEFORE TREATMENT!

If central line is colonized w something,
It will be positivie
Peripheral line allows us to explore isolates in peripheral blood
Having both –> bloodstream infection source is likely a colonized line
2 bottles of blood for each set
- 1 for aerobic and 1 for anaerobic culture

Body fluids or other sites cultures
– Other possible sites of infection as indicated (examples: urine, wound, stool, sputum, NP swab)
* Laboratory Tests:
– CBC with differential
* Assess neutrophil count (don’t wait for results to treat)
– Chemistries:
* Electrolytes, Creatinine, BUN, hepatic transaminases, bilirubin
* Vital signs
– Patient stability and assessment for septic shock
* History
– Last chemo treatment, possible exposures
* Physical Exam
– Possible sites/sources of infection
* CVC site, Mucositis
* Other Diagnostic Tests as indicated
– Chest X-ray (respiratory symptoms)
* Consider COVID-19 test!

Question 14

Patient Risk Assessment
high risk

Answer 14

• Features of patients with HIGH RISK of complications or death
  – Prolonged (>7days) or profound (< 0.1 x 109
  /L) neutropenia
• Consider patient disease and chemotherapy received
  – Unstable
• Hypotension, neurologic changes, new onset abdominal symptoms, high
  fever
  – Significant medical/comorbid conditions
• Pneumonia, COPD, mucositis
• Admit high risk patients and initiate treatment with IV empiric
  therapy

Question 15

LOW RISK

Answer 15

Features of patients with LOW RISK of complications or death
– No focal findings of infection, hemodynamically and clinically stable
– Brief neutropenic period (<7 days)
– No or few comorbidities
* For low risk patients, initiate treatment with oral or IV empiric
treatment in clinic/hospital
– Consider transition to outpatient therapy:
* Oral antibiotics
* Home parenteral therapy program

Question 16

High vs Low Risk - Simplified

Answer 16

High Risk Low Risk
Expected prolonged or profound neutropenia (from the
chemotherapy or the disease)
Brief neutropenic time

Unstable (hypotension, neurologic changes, new onset
abdominal symptoms, high fever)
Hemodynamically and Clinically stable

Significant co-morbidities (COPD, mucositis, dehydration) Otherwise healthy

Worrisome infection (or suspected infection)
(pneumonia, bacteremia, SSTI)
and/or symptomatic (high fever, neurologic changes)
No focal source of infection and asymptomatic

Difficult access to urgent care Easy access to urgent care and able to take po med

Question 17

Concepts for Selecting Empiric Antimicrobial Therapy

Answer 17

• Prompt Treatment
• Start immediately after cultures
• Broad Spectrum:
• Cover gram negatives (including pseudomonas), gram
  positives, usually anaerobes
• Bactericidal preferred to Bacteriostatic
• Route of Administration
• Start with parenteral in most cases
• Oral may be appropriate for certain low-risk patients only
• Consideration of Patient Factors
• Allergies, organ function
• Previous antimicrobial exposure (including prophylaxis)
• Colonization or previous infections with resistant organisms
• Consideration of Institutional Factors:
• Infection patterns, antimicrobial susceptibility trends

wont wait till CBC comes back to confirm pt is neutropenic, give abx first

Question 18

FN - Empiric Treatment in Patients at
High Risk of Complications

Answer 18

• Initiation of empiric broad spectrum antibiotics
  – Monotherapy with anti-pseudomonal beta lactam such as:
  – Piperacillin+Tazobactam, Cefepime, Carbapenem (meropenem or
  imipenem+cilastatin)
  – Add additional gram positive coverage (vancomycin) IF risk of MRSA
  – Catheter related infections
  – Skin or Soft Tissue Infections (SSTI)
  – Pneumonia
  – Hemodynamic Instability
  – Known colonization with MRSA

Question 19

FN – Treatment Modifications

Answer 19

• Changes to treatment are guided by clinical and microbiological data
  – Cultures
• Use results to target treatment (around 48-72 hours)
  – Optimize antimicrobial therapy for isolated organism, site, and susceptibilities
• Sometimes no organism can be isolated
  – Patient Stability
• If patient remains febrile and is UNSTABLE, then broaden coverage:
• If patient has unexplained persistent fever but stable then modification in therapy
  rarely needed
• If patient clinically improving, then good indicator that spectrum of therapy is
  covering the pathogen (if one exists)

Question 20

FN – Treatment for Patients at
Low Risk for Complications

Answer 20

• Low risk Initial Empiric Treatment:
  – Initial treatment is given in Hospital or Clinic
• IV therapy as discussed in high risk
• Oral therapy with Ciprofloxacin + Amoxicillin/Clavulanate
  – Must be able to tolerate and absorb
• Avoid Ciprofloxacin if receiving quinolone prophylaxis
• Then can transition to outpatient care IF appropriate
  – Considerations:
• Low risk, stable, tolerating therapy
• Close proximity to medical care
• Ability to travel to medical centre
• Recovering neutrophil count (going up, not down)

Question 21

FN – Length of Therapy with Antimicrobials

Answer 21

• If stable and an infection source identified
  – Tailor treatment and duration to specific infection
• If stable and no source of fever identified:
  – Somewhat controversial but basic principles:
  – Treat until afebrile ≥ 2 days and neutrophils >0.5 and trending up
  – Usually minimum 7 day course for high risk patients
  – Consider longer course of therapy for patients with mucositis
  – Can consider step down to oral therapy in low risk patients

Question 22

Patient Education – Fever Monitoring

Answer 22

– Lack of evidence to develop a recommendation for how often
an ambulatory patient should check temperature when
asymptomatic/well.
– Patient should be educated regarding action plan in the event of
a fever
* What should they do? Who should they call? Where should they go?
– Standardized patient information in alignment with institution
or care team is important
– Cancer patients in the community receiving chemotherapy who
experience fever should seek urgent assessment
– If fever occurs outside of clinic hours, patients should be referred to
emergency department (or other designated urgent care centre)
– Be aware that antipyretics (acetaminophen) can mask a fever.
* Avoid acetaminophen if possible
* If unable to avoid acetaminophen, proper patient education and
monitoring strategies should be employed
* Avoid ibuprofen and ASA due to antiplatelet effects (increased risk
of bleeding)

Question 23

Thermometer Choice

Answer 23

• Some guidelines state “oral” temperature when defining Febrile Neutropenia
  – Avoid hot/cold food or beverages before taking oral temperature
• Tympanic membrane thermometry is a reasonable option
  – Follow manufacturers recommendations
  – When compared with rectal thermometry, both oral and tympanic thermometry have
  comparable specificity, positive predictive value, and negative predictive value.
  – Tympanic is more sensitive than oral or axillary
• Axillary thermometry shown in same study to be inferior to tympanic membrane and
  poor correlation with rectal temperature
• Avoid rectal thermometers
  – Infection and bleeding risk

Question 24

FN Prophylaxis

Answer 24

• Granulocyte-Colony Stimulating Factors (G-CSF)
  – G-CSF is a hematopoietic growth factor
• Regulates production and function of neutrophils
• Can accelerate neutrophil recovery after chemotherapy
  – Filgrastim or PEG-filgrastim
• Pros:
  – Reduced risk of febrile neutropenia
  – Reduction in infection related and all cause mortality
  – Improved relative dose intensity of chemotherapy delivered
  prevent dose reduction or delay in chemo
• Cons:
  – Costly, must consider insurance payer criteria
  – Adverse effects, bone pain
  – Subcutaneous administration of ambulatory patients has challenges

Question 25

Prophylaxis with Growth Factors
* Primary Prophylaxis

Answer 25

– Definition:
* The use of CSFs for prevention of FN starting with the first cycle of treatment
and continuing through subsequent cycles
– Generally recommended for patients with ≥20% risk of FN:
* Patient factors
* Disease factors
* Treatment related factors
– Chemotherapy protocols with high incidence of FN such as docetaxel for
breast cancer

Question 26

• What if patient gets FN without primary prophylaxis?

Answer 26

– A chemotherapy dose reduction or delay of next cycle is reasonable
when goal is palliation
– Secondary Prophylaxis
* Definition: initiation of FN prophylaxis with colony stimulating
factor for subsequent cycles of chemotherapy after an episode of
FN.
* Recommended for patients with:
– Patients who experienced a neutropenic complication from a
previous cycle of chemotherapy AND
– Dose reduction or treatment delay may compromise important
outcome (disease free or overall survival outcome), give it to them for the rest of the upcoming cycles so they dont get it again

Question 27

Filgrastim

Peg-filgrastim

Answer 27

– daily starting 1-5 days post chemo and continue 3-7 days
– 5mcg/kg/day
– Neupogen® (original product) is available as single use
vials
* no longer a benefit under Alberta Blue Cross (ABC).
* $300 per dose ($900-$2100 per cycle)
– Grastofil® (biosimilar) is available as pre-filled syringes
* now a benefit under ABC with special authorization
* $230 per dose ($700 to $1600 per cycle)
Round to the vial or syringe

– Brands:
* Neulasta® is original brand name product.
– Approximately $2500 per dose
* Biosimilars: Xiextenzo®, Fulphila®, Lapelga®
– Approximately $1900 per dose
– PEGylated! - One single 6 mg injection administered 1-3 days post chemo
– Peg-filgrastim is a benefit under ABC with special authorization
– ABC in process of transitioning to coverage only for biosimilar products

Question 28

FN Prophylaxis with Antimicrobials

Answer 28

– Quinolone (Ciprofloxacin or Levofloxacin)
* Consider for high risk patients expected to have prolonged and/or profound
neutropenia
– Benefits:
* May reduce the incidence of fever and documented infections (especially
gram negative infections)
– Risks:
* Possible increased risk of resistant infections:
– Quinolone resistant gram negative (example E.coli)
– C. difficile colitis

Question 29

Influenza Vaccination

Answer 29

• Increase in incidence and duration of influenza infections has been
  observed in immunosuppressed cancer patients.
• Annual inactivated influenza vaccine is indicated for MOST adult
  patients with cancer
  – Immunosuppressed patients should avoid intranasal (live) influenza vaccine
  – To allow patient opportunity for best antibody response, administer 2 weeks
  before chemo starts. If already receiving chemotherapy, administer between
  cycles once blood counts have recovered.
• Immunization of family members and health care providers who are in
  contact with cancer patients is recommended.
  – Inactivated preferred (not live nasal spray)

Do not get the intranasal one

Question 30

Which cancer patients should NOT receive flu vaccine?

Answer 30

– Rituximab or other B-cell depleting antibodies should have most immunizations
postponed until at least 6 months after the last dose of rituximab
– Patients receiving CTLA-4 inhibitors (ipilimumab) within the past 6 months should NOT receive flu vaccine due to a lack of safety information and potential risk for significant immune response
* NOTE: Patients receiving PD-1 or PD-L1 inhibitors may receive inactivated flu vaccine. Cannot be within 1 week of a ICI administration. Evidence suggests higher possibility of IMAE after influenza vaccine. Close monitoring is prudent. Best to have patient discuss with oncology
team.
– Patients on high dose systemic steroids should wait 4 weeks after discontinuation
* IMMUNIZATION OF CLOSE CONTACTS VERY IMPORTANT HERE!!!

Question 31

Vaccines and Stem-Cell Transplant (adults)

Answer 31

• Influenza Vaccine:
  – Immune system recovery post transplant is variable. Some may have
  antibody response at 6-24 months post transplant while others may be 24
  months or longer
  – Generally administered six months post transplant
• Non-Live Vaccines:
  – Usually encouraged to start immunization as per public health guidelines
  at 6 months after transplant
• Live Vaccines:
  – Contraindicated for at least 2 years

Question 32

COVID-19 Vaccination and Cancer
(Alberta: July 12, 2022)

Cancer patients and those on treatment may experience COVID-19
more severely

Answer 32

• All patients receiving cancer treatment should be vaccinated for COVID-19
  – Includes all patient receiveing chemotherapy (chemo), targeted therapy (TT), immune checkpoint inhibitors (ICI) and hormone
  therapies (HT).
  – Only one EXCEPTION – stem cell transplant in the past 4 months
• 4th dose should be given 5 months or more after the 3nd dose for:
  – Starting or currently on systemic therapy (chemo, TT, ICI)
  – Exceptions for 4th dose – TALK TO YOUR HEMATOLOGIST
• receiving chimeric antigen receptor (CAR-T) cell therapy
• hematologic cancers
• had a stem-cell transplant
• IMPORTANT: educate patients to still wear a mask, social distance, wash hands, etc as the extent of vaccine efficacy in this population is uncertain (example a patient receiving rituximab). Patients may have
  a false sense of protection once vaccinated.