BONE MARROW SUPRESSION AND

FEBRILE NEUTROPENIA

Pınar Çelik

12th ANNUAL CONGRESS OF THE TTD8-12 April 2009, Antalya

Hematopoietic Growth Factors Approved by FDA

Hematopoietic Growth Factor

Generic name Trade mark Molecular Impacts Hematopioetic Impacts

EPO Epoetin alfa Epogen, Procrit rHu EPO Red cell series

Darbepoetin Aranesp Variable glycosylated rHu EPO

Red cell series

G-CSF Filgrastim Neupojen rHu G-CSF Neutrophil series

Pegfilgrastim Neulasta Pegylated rHu G-CSF Neutrophil series

GM-CSF Sargramostim Leukine rHu GM-CSF Myeloid series

IL-11 Oprelvekin Neumega rHu IL-11 Megakaryocytes

Hematopoietic Growth Factors Available in Our Country

Hematopoietic Growth Factor

Generic name Trade mark Molecular Impacts Hematopioetic Impacts

EPO Epoetin alfaEpoetin beta

Eprex, Neorecormon

rHu EPO Red cell series

Darbepoetin Aranesp Variable glycosylated rHu EPO

Red cell series

G-CSF Filgrastim Neupojen rHu G-CSF Neutrophil series

Lenograstim Granulocyte Neutrophil series

GM-CSF Molgramostim Leucomax rHu GM-CSF Myeloid series

Is Hb value of the patientunder 10 g/dl ?

Is Hb value of the patient under 12 g/dl and over 10 g/dl?

Does the patient have increased risk for anemia complications ?

Stay away from recombinant eritropoetin

Consider recombinant eritropoetin

Yes

Yes

Yes

No

No

Eritropoetin Usage Algorithms for Chemotherapy Related Anemia According to ASCO and American Hematology Society Guidelines

EPO treatment

150 U/kg 3 times weekly for minimum 4 weeks

In case of unresponsiveness to the treatment, consider 300 U/kg dose

increse for additional 4-8 weeks

40 000 U/week administration is common

Similar results with 3 times a week

Optimal treatment period is not certain in patients who response

EPO usage

EPO decreases transfusion need and increases hematologic response

Improves quality of life

Increses venous thromboembolism

HT ?

Impact on overall survival and tumour response ?

Cost-effective ?

Need for more clinical trials in this area

Consider transfusion as a method, too

CSF usage

Primary prophylaxis Direct usage before neutropenia after termination of first cyclus CT

Secondary prophylaxis CSF usage to decrease the risk of FN, after termination of consequent CT cyclus due

to a prior FN period

For treatment To treat severe neutropenia or FN

FN risk > 20 % with CT regimen

Do long term results fit with decreased dose intensity ?

Does the patient have high risk for serious complications or death

due to FN? (ex: elderly, prior treatment, poor performance

status, etc.)

First CT cyclus without prophylactic CSF

Prophylactic CSF usage with first CT cyclusYes

Yes

Yes

No

No

No

Algorithm for Usage of Colony Stimulating Factors in CT Based Neutropenia for Primary Prophylaxis According to ASCO Recommended Guidelines

CSF

(category 1)

CSF

(category 1)

CSF

Consider CSF Consider CSF Consider CSF

Don’t use CSF Don’t use CSF Don’t use CSF

Symptom improvement/Quality of life

Identification of risk factors for febrile neutropenia following CTİn adult patients with solid tumours and nonmyeloid leukemia

• Disease• CT regimens * High dose therapy * Intense dose therapy * Standart dose therapy• Patient risk factors•Treatment intensity (palliative or curative)

High (>20 %)

Intermediate(10-20%)

Low (10 %)

Curative/Adjuvant

Prolonging survival/Quality of lifeRISK IDENTIFICATION FOR

FEBRILE NEUTROPENIA

EVALUATION

CT TREATMENT PURPOSE

NCCN GUIDELINES - v.1.2009

Primary Prophylaxis

Evaluate patient every cyclus

Consider decreasing the dose or changing the treatment regimen

Febrile neutropeniaor dose limited neutropenic event

No febrile neutropeniaor dose limited neutropenic event

With CSF usage

Without CSF usage Consider CSF

Repeat the interventionfor the next cyclus

NCCN GUIDELINES - v.1.2009

Secondary prophylaxis

Patient with FN

Patient with prophylactic CSF usage

NCCN GUIDELINES v.1.2009

Continue CSF

Risk factors absent

Risk factors present

Don’t use CSF

Consider CSF

CSF usage in FN

Patient without prophylactic CSF usage

Examples for CT regimens with Intermediate and High Risk FN

SCLC (Risk degree> 20%) Topotecan

SCLC (Risk degree 10-20 %) Etoposide/carboplatin

NSCLC (Risk degree 10-20 %) Cisplatin/paclitaxel Cisplatin/vinorelbine Cisplatin/docetaxel Cisplatin/irinotecan Cisplatin/etoposide Carboplatin/paclitaxel Docetaxel

NCCN GUIDELINES - v.1.2009

Risk Factors for FN Development

Elderly (especially over 65) Prior RT or CT Prior neutropenia or bone marrow involvement Prior status

Neutropenia Infection Recent surgical intervention

Poor performance status Renal functional impairment Hepatic functional impairment, especially high bilirubin levels

NCCN GUIDELINES - v.1.2009

Patient risk factors related with poor prognosis or complication development due to infection

Sepsis Age > 65 Severe neutropenia (ANC < 100/mm3) Neutropenia prediction for more than 10 days Pneumonia Invasive fungal infection Other clinically established infections Hospitalization during FN

CSF usage Filgrastim (category 1)

5 microgram/kg, until achieving normal or near normal labaratory levels

Pegfilgrastim (category 1) 6 mg for every cyclus Start 24-72 hours after termination of CT Treatment on the same day is not recommended

Sargramostim (category 2B) 250 microgram/m2/day Start 24-72 hours after termination of CT Treatment on the same day is not recommended

SP is recommended Prophylactic antibiotic usage is not recommended

NCCN GUIDELINES - v.1.2009

CSF usage FN is an important mortality and morbidity reason in patients receiving CT.

For the aim of prolonged survival, improved quality of life and curative, adjuvant treatment in

patients with FN risk > 20 %, it is recommended in category 1 level. It might be considered for

symptom palliation.

If FN risk is 10-20 % it is recommended in curative or adjuvant CT, however it should be

considered for prolonging survival and symptom palliation.

If FN risk is < 10 % CSF usage is not recommended.

If prophylactic CSF has been used in a patient with FN, continue; if it has not been used, use in

case of risk factors and don’t use if the patient doesn’t have any risk factors.

NCCN GUIDELINES - v.1.2009

FN Definition

Oral body temperature ≥38.3 °C or ≥38 °C for more than one hour

and accompanying

Neutrophils < 500/mm3 or 500-1000 mm3 and a tendency to decrease

CID 2002

Febrile Neutropenia

If neutrophil count < 500/mm3, infection risk increases 10 times

48-60 % hidden or undefined infection

If neutrophil count < 100/mm3 bacteriemia is present in 16-20 % cases

History

Underlying disease

Treatment protocol

Neutropenia duration

Prophylactic AB usage

Prior FN exacerbation and treatment protocol

Microorganisms causing FN in hospital and antibiotic susceptibilities

Examining other complaints other than fever (Localised pain, skin

eruption, diarhea, cough, drug allergy)

www.febrilnotropeni.net

Physical examination

Periodontium

Pharynx, oral mucosa

Lungs

Perineal region, anus

Skin (catheter access line, bone marrow aspiration regions, nails)

www.febrilnotropeni.net

First evaluation in a case with FN

Whole blood count

Routine biochemical tests: BUN, creatinine, electrolytes, SGOT, SGPT

Without considering patient charecteristics

At least two blood cultures from different veins (synchronous catheter culture)

Urine culture

Culture specimens for clinical microbiological examinations according to

patient’s symptom and signs (sputum, catheter access line, gaita, BOS, etc)

PA chest X-ray (In more than half of the FN patients with normal PA chest X-

ray pneumonia can be observed with HRCT)

Agents in febrile neutropenia

Agents can be determined in 30-50 % of FN patients

Microbiological agent spectrum has been changing recently

The most frequent FN agents are gram (–) bacteries, recently gram

(+) bacteries have been composing 60-70 % of whole agents

Low risk factors for FN patients Neutrophile count>100/mm3

Monocyte count>100/mm3

Normal chest X ray findings Near normal renal and hepatic function tests Neutropenia duration<7 days Expected neutropenia<10 days No catheter infection Remission in malignity < 39.0 °C fever No change in neurologic and mental status Absance of disease signs Absance of abdominal pain Absance of complications of comorbidities

CID 2002

MASCC (Multinational Association for Supportive Care in Cancer)

FN patients (score 26)

MASCC score ≥ 21 Low risk

MASCC score < 21 High risk

J Clin Oncol 2000

MASCC scoring system

Criteria Score

Symptoms associated with disease

Mild or no symptoms 5

Moderate severity symptoms 3

Hypotension absence 5

COPD absence 4

Underlying disease

Solid tumour presence 4

Hematologic disease without fungal infection 4

Dehydration absance 3

Fever onset outside the hospital 3

Age < 60 2

J Clin Oncol 2000

FN Treatment Recommendations

Assess risk status ,

Low Risk

Hospitalization or without hospitalization

Oral or IV treatment

High risk

Monotherapy

Combination treatment

Oral Treatment

Safe in low risk patients

Response rates similar with IV route

Ciprofloxacin/Levofloxacin + Amoxicillin clavulanate

Low prices, no need for hospitalization and IV catheter are

advantages

IV Monotherapy

Ceftazidime

Cefepime

Carbapenems

(Imipenem, meropenem)

Beta-lactam / betalactamase inhibitor

(piperacillin-tazobactam or cefaperazon-sulbactam)

Combination Treatment

Antipseudomonal cefalosporine + Aminoglycoside

Antipseudomonal carboxypenicillins or ureidopenicillins (ticarcillin

clavulanic acid or piperacillin tazobactam) + Aminoglycoside

Carbapenem + Aminoglycoside

Aminoglycoside (Amikacin, Tobramycin, Netilmicin, Gentamycin)

Antipseudomonal penicillins + ciprofloxacin may be used in patients

who haven’t received quinolone prophylaxis before

Combination Treatment

Advantages

Bactericidal activity increase

Potential sinergistic effect

Board antibacterial spectrum

Resistance development decrease

Disadvantages

Drug toxicity increase

Development of drug interactions

Increase in costs

Body temperature 38.3C + Neutropenia (< 500 neutrophil/mm3)

Low risk High risk

Oral IVNo need forvancomycin

Vancomycin necessary

Ciprofloxacin+Amoxicillin clavulanate

Monotherapy

•Piptazo

•Cefepime•Ceftazidime, •Carbapenem

Combination

Aminoglycoside+

•Antipseudomanal penicillin•Cefepime,•Ceftazidime or Carbapenem•Pip-tazobactam

Vankomycin+

Vankomycin+

Cefepime, Ceftazidime

orCarbapenem

aminoglycoside

Evaluate after 3-5 days

IDSA 2002

Indications for glycopeptide addition

Glycopeptide (teicoplanin, vancomycin) usage in FN is contraversial

Severe catheter infection Colonization with MRSA or penicillin +/- cephalosporin resistant S.

pneumonia Detection of gram (+) bacteria in blood cultures Hypotension – cardiac failure findings, shock and sepsis Severe mucosal injury, quinolone prophylaxis If these are absent and microbiological cultures are negative

glycopeptide is removed

New generation drugs (linezolid, quinupristin-dalfopristin) are recommended to be used only in vancomycine resistant enterococci infections

CID 2002, www.febrilnotropeni.net

No fever in the first 3-5 days of the treatment

Etiology undetermined Etiology determined

Low risk High risk Choose the most appropriate treatment

Change the treatmentCiprofloxocin

+ amoxicillin clavulanate

(Adults)

Continue with the same antibiotics

Externation

IDSA 2002

Reasons for ongoing fever

Nonbacterial infections

Resistent bacteria

Slow response to antibiotics

Presence of fungal infection

Drug fever

Inadequate tissue or serum levels

Ampirical antifungal treatment

Classical amphotericin deoxycholate

Liposomal amphotericin B

Variconazole

Caspofungin

Fever persists in the first 3-5 days of the treatment: Etiology unknown

Evaluate the patient in the 3-5th days again

Continue to antibiotherapy

Change the antibiotherapy

Antifungal treatment ±Change the antibiotherapy

Consider to stop vamcomycin

•Disease progression•Presence of criteria to use vancomycin

Fever persists in the first 5-7 days of the treatment and neutropeniais not expected to improve

IDSA 2002

Thank you