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BONE MARROW SUPRESSION AND FEBR I LE NEUTROPENIA

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

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BONE MARROW SUPRESSION AND FEBR I LE NEUTROPENIA

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  1. BONE MARROW SUPRESSION AND FEBRILE NEUTROPENIA Pınar Çelik 12th ANNUAL CONGRESS OF THE TTD 8-12 April 2009, Antalya

  2. Hematopoietic Growth Factors Approved by FDA

  3. Hematopoietic Growth Factors Available in Our Country

  4. Is Hb value of the patient under 10 g/dl ? Yes Consider recombinant eritropoetin Is Hb value of the patient under 12 g/dl and over 10 g/dl? No Stay away from recombinant eritropoetin Yes Yes No Does the patient have increased risk for anemia complications ? Eritropoetin Usage Algorithms for Chemotherapy Related Anemia According to ASCO and American Hematology Society Guidelines

  5. 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

  6. 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

  7. 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

  8. FN risk > 20 % with CT regimen Yes No Do long term results fit with decreased dose intensity ? Prophylactic CSF usage with first CT cyclus Yes No Does the patient have high risk for serious complications or death due to FN? (ex: elderly, prior treatment, poor performance status, etc.) Yes No First CT cyclus without prophylactic CSF Algorithm for Usage of Colony Stimulating Factors in CT Based Neutropenia for Primary Prophylaxis According to ASCO Recommended Guidelines

  9. Primary Prophylaxis CT TREATMENT PURPOSE Symptom improvement/ Quality of life Prolonging survival/ Quality of life Curative/ Adjuvant RISK IDENTIFICATION FOR FEBRILE NEUTROPENIA EVALUATION High (>20 %) Intermediate (10-20%) Low (10 %) • Disease • CT regimens * High dose therapy * Intense dose therapy * Standart dose therapy • Patient risk factors • Treatment intensity • (palliative or curative) Identification of risk factors for febrile neutropenia following CT İn adult patients with solid tumours and nonmyeloid leukemia NCCN GUIDELINES - v.1.2009

  10. With CSF usage Febrile neutropenia or dose limited neutropenic event Without CSF usage Consider CSF No febrile neutropenia or dose limited neutropenic event Repeat the intervention for the next cyclus Secondary prophylaxis Consider decreasing the dose or changing the treatment regimen Evaluate patient every cyclus NCCN GUIDELINES - v.1.2009

  11. CSF usage in FN Patient with prophylactic CSF usage Continue CSF Patient with FN Don’t use CSF Risk factors absent Patient without prophylactic CSF usage Consider CSF Risk factors present NCCN GUIDELINES v.1.2009

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Physical examination Periodontium Pharynx, oral mucosa Lungs Perineal region, anus Skin (catheter access line, bone marrow aspiration regions, nails) www.febrilnotropeni.net

  21. 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)

  22. 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

  23. 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

  24. 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

  25. 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

  26. FN Treatment Recommendations Assess risk status , Low Risk Hospitalization or without hospitalization Oral or IV treatment High risk Monotherapy Combination treatment

  27. 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

  28. IV Monotherapy Ceftazidime Cefepime Carbapenems (Imipenem, meropenem) Beta-lactam / betalactamase inhibitor (piperacillin-tazobactam or cefaperazon-sulbactam)

  29. 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

  30. 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

  31. IDSA 2002 Body temperature  38.3C + Neutropenia (< 500 neutrophil/mm3) Low risk High risk No need for vancomycin Vancomycin necessary Oral IV Ciprofloxacin + Amoxicillin clavulanate Vankomycin+ Combination • Monotherapy • Piptazo Vankomycin + • Cefepime • Ceftazidime, • Carbapenem Aminoglycoside + Cefepime, Ceftazidime or Carbapenem  aminoglycoside • Antipseudomanal • penicillin • Cefepime, • Ceftazidime or Carbapenem • Pip-tazobactam Evaluate after 3-5 days

  32. 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

  33. No fever in the first 3-5 days of the treatment Etiology undetermined Etiology determined Choose the most appropriate treatment Low risk High risk Change the treatment Ciprofloxocin + amoxicillin clavulanate (Adults) Continue with the same antibiotics Externation IDSA 2002

  34. Reasons for ongoing fever Nonbacterial infections Resistent bacteria Slow response to antibiotics Presence of fungal infection Drug fever Inadequate tissue or serum levels

  35. Ampirical antifungal treatment Classical amphotericin deoxycholate Liposomal amphotericin B Variconazole Caspofungin

  36. Fever persists in the first 3-5 days of the treatment: Etiology unknown Evaluate the patient in the 3-5th days again Fever persists in the first 5-7 days of the treatment and neutropenia is not expected to improve Continue to antibiotherapy Change the antibiotherapy Consider to stop vamcomycin • Disease progression • Presence of criteria to use • vancomycin Antifungal treatment ± Change the antibiotherapy IDSA 2002

  37. Thank you

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