bone marrow supression and febr i le neutropenia
DESCRIPTION
BONE MARROW SUPRESSION AND FEBR I LE NEUTROPENIA. Pınar Çelik 12 th ANNUAL CONGRESS OF THE TTD 8-12 April 2009, Antalya. Hematopoietic Growth Factors Approved by FDA. Hematopoietic Growth Factors Available in Our Country. Is Hb value of the patient under 10 g/dl ?. Yes. Consider - PowerPoint PPT PresentationTRANSCRIPT
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