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ANTIFUNGAL PROPHYLAXIS IN PEDIATRIC ACUTE LEUKEMIA

ANTIFUNGAL PROPHYLAXIS IN PEDIATRIC ACUTE LEUKEMIA. By Dr. Tamer Hassan. Rationale for consideration of antifungal prophylaxis ?. WHY.

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ANTIFUNGAL PROPHYLAXIS IN PEDIATRIC ACUTE LEUKEMIA

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  1. ANTIFUNGAL PROPHYLAXIS IN PEDIATRIC ACUTE LEUKEMIA By Dr. Tamer Hassan Pediatric Oncology workshop- Zagazig university

  2. Rationale for consideration of antifungal prophylaxis? WHY Pediatric Oncology workshop- Zagazig university

  3. The difficulty in obtaining a timely diagnosis as well as the high morbidity and mortality associated with IFIs provide a rationale for consideration of antifungal prophylaxis.

  4. ❶ Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, especially among patients with acute myeloid leukemia (AML) and those who have undergone allogeneic hematopoietic stem cell transplantation. Pediatric Oncology workshop- Zagazig university

  5. Invasive fungal infections (IFIs) pose the most serious infectious risk to patients with hematologic malignancies and in those undergoing hematopoietic stem cell transplantation (HSCT). • Invasive candidiasis has an incidence of 8–18% and a mortality of 30–40% in various reports. • Invasive aspergillosis has an incidence of 4–15% and an even higher mortality of 60–85% cited in the published literature.

  6. ❷ Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy.

  7. 50% of patients with autopsy-proven invasive candidiasis did not have positive blood cultures prior to death. • The culture-based methods most commonly used today (Bactec Mycosis IC/F medium) can detect disseminated candidiasis in only 60% of cases within 2–5 days of incubation. • Respiratory secretions have poor yields for pulmonary aspergillosis and blood cultures are rarely positive in cases of hematogenous aspergillosis or Zygomycosis. • Tissue biopsies for histopathologic or culture-based diagnosis of visceral fungal infections, including pulmonary mold infections, are often challenging to obtain in this patient population group due to thrombocytopenia in many instances. • High resolution-computed tomographic scans of the chest remain the most sensitive way to diagnose IA.

  8. There have been advances in non-culture based methods of diagnosis such as the use of the double-sandwich enzyme-linked immunosorbent assay (ELISA) for serum galactomannan antigen, which is a major component of the cell wall ofAspergillusreleased during invasive infection, and beta-d-glucan which detectsCandida, Aspergillus, and several other fungal genera. • The sensitivity of the serum galactomannan antigen assay ranged from 61% to 71%, the specificity was 89–93%, the negative predictive value was 95–98%, and the positive predictive value was 26–53%. Therefore, the serum galactomannan assay has moderate sensitivity in confirming IA . • Beta-d-glucan is a cell wall component of many fungi, with notable exceptions ofCryptococcusand Zygomycetes species. The sensitivity and specificity of this test for the diagnosis of IFIs is 93% and 77%, respectively, but studies have been limited. • The use of the polymerase chain reaction to detect fungi-specific deoxyribonucleic acid (DNA) and nucleic acid sequence-based amplification of fungal-specific messenger ribonucleic acid (mRNA) for the diagnosis of IFIs have not yet been defined. • Therefore, despite the availability of two nonculture-based methods of diagnosis and others in development, there is difficulty in obtaining accurate and timely diagnosis of IFIs.

  9. Risk factors for IFIs • Protracted granulocytopenia Granulocytopenia > 7 days after onset of fever has been associated with increased risk for IFIs Gerson et al reported that granulocytopenia > 21 days was the single most significant risk factor for IFIs in ANLL. • Chemotherapy type and intensity, AML> ALL. • Refractory and relapsed acute leukemia > newly diagnosed. • Use of broad spectrum antibacterial agents. Schwarz et al reported that use of broad spectrum antibiotics was an important risk factor for development of invasive candidiasis in AML patients. • Corticosteroids • Central venous catheters • Mucosal injury • Patient's health status

  10. Brief overview of antifungal compounds • Azoles e.g. Fluconazole , Itraconazole, Voriconazole, posaconazole • Polyene macrolidese.g. amphotericin B & liposomal amphotericin B • Echinocandins e.g. Caspofungin • Synthetic fluorinated pyrimidine e.g. Flu cytosine

  11. Pediatric Oncology workshop- Zagazig university 4/18/2010 Infectious Diseases Society of America and United States Public Health Service grading system for ranking recommendations Strength of recommendation A : Good evidence to support a recommendation for use B: Moderate evidence to support a recommendation for use C: Poor evidence to support a recommendation D: Moderate evidence to support a recommendation against use E: Good evidence to support a recommendation against use Quality of evidence I : Evidence from ≥ 1 properly randomized, controlled trial II: Evidence from ≥ 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from 1 center); from multiple-time series; or from dramatic results from uncontrolled experiments III: Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

  12. Evaluation of antifungal agents for prophylaxis ❶ Fluconazole • Fluconazole is the most extensively studied triazole. • Acts by inhibiting fungal ergosterol biosynthesis. • Pediatric dose ( for prophylaxis ): 3-12 mg/kg per day. • Fluconazole has a favorable safety profile and patient compliance is good. • Grade and quality of evidence Prophylaxis in acute leukemia: ECIL-3, 2009: CI Prophylaxis in allogeneic BMT: ECIL-3, 2009: Neutropenic phase: AI GVHD phase: C1 Pediatric Oncology workshop- Zagazig university

  13. Drawbacks of Fluconazole • Ineffective against molds and Candida krusei, and its activity against Candida glabrata is dose-dependent. • Several large studies indicate breakthrough infections. • In a large survey on 106 centers by the European Confederation of Medical Mycology , Candida albicans was responsible for only 35% of candidemia in hematological malignancies and the rest(65%) was caused by non-albicans Spp. This shift was explained by the prophylactic use of fluconazole with emergence of fluconazole resistant candida spp.

  14. Evaluation of antifungal agents for prophylaxis Pediatric Oncology workshop- Zagazig university ❷Itraconazole Acts by inhibiting fungal ergosterol biosynthesis. Itraconazole is an agent suitable for oral (capsules and suspension) and intravenous administration. Its spectrum of action includes non-albicans Candida species and molds. Many fluconazole resistant strains of candida are sensitive to itraconazole. Mechanism of resistance is not common in both drugs. Oral bioavailability is markedly higher in oral solution than capsules. Pediatric dose ( for prophylaxis ): 5 mg/kg 4/18/2010

  15. Drawbacks of Itraconazole • Grade and quality of evidence Prophylaxis in acute leukemia: ECIL-3, 2009: CI Prophylaxis in allogeneic BMT: ECIL-3, 2009: Neutropenic phase: BI GVHD phase: B1 • Unpleasant taste • Longer time to achieve higher plasma levels( capsule form only) • Severe paralytic ileus in some cases( mostly ALL). • - ve inotropic effect

  16. Voriconazole 3 • Acts by inhibiting fungal ergosterol biosynthesis. • Broad spectrum antifungal activity including fusarium spp. • May be active against fluconazole and itraconazole resistant Candida spp. • May be active against itraconazole and amphotericin B resistant Aspergillus spp. • Available in oral and intravenous formulations. • The Bone Marrow Transplant Clinical Trials Network (BMT CTN) in the United States performed a multicenter, randomized double-blind trial of extended prophylaxis with either voriconazole 200 mg twice a day given either by mouth or intravenously versus fluconazole 400 mg a day, also administered either by mouth or intravenously after myeloablative allogeneic HSCT. 7 cases of IA in voriconazole arm 16 cases of IA in fluconazole arm

  17. Grade and quality of evidence Prophylaxis in acute leukemia: ECIL-3, 2009:--------- Prophylaxis in allogeneic BMT: ECIL-3, 2009: Neutropenic phase: Provisional AI GVHD phase: Provisional AI Drawbacks of Voriconazole Safety concern; Visual disturbance, Hepatic side effects Not used as a prophylactic antifungal agent in acute leukemia till now.

  18. Amphotericin B 4 • Amphotericin B has the broadest spectrum of activity of all antifungal agents available. • Acts by binding the sterol in the fungal cell membrane with a resultant change in membrane permeability which allows leakage of intracellular components. • It is in widespread use as an oral suspension (1.5-3 g/d). Local amphotericin B administration as lozenges or suspension reduces colonization and lowers the incidence of superficial fungal infections (level BI). However, there is no evidence that oral administration can prevent invasive pulmonary aspergillosis. • Pediatric dose( for prophylaxis): 0.1- 0.2 mg/kg/day

  19. Grade and quality of evidence Prophylaxis in acute leukemia: ECIL-3, 2009: Ampho iv : CI Inhaled Liposomal Ampho+ fluconazole oral : BI Prophylaxis in allogeneic BMT: ECIL-3, 2009: Neutropenic phase: CI GVHD phase: CI Drawbacks of Amphotericin B Saftey concerns regarding infusion related reactions, hypokalemia nephrotoxicity.

  20. liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol thus maximizes drug delivery to reach higher concentration.

  21. Posaconazole 5 • Acts by inhibiting fungal ergosterol biosynthesis. • Posaconazole is an extended spectrum oral azole with a wide range of activity againstCandidaspecies,Aspergillus,Fusariumand Zygomycetes, with an acceptable adverse event profile. • Posaconazole has a similar drug interaction profile to itraconazole since posaconazole is a substrate for the CYP450 enzymes. • Dose: 5 ml(200 mg) three times/ day in Children≥13 years. • In a randomized open-label study of patients with high risk neutropenia from chemotherapy given for acute myelogenous leukemia or myelodysplastic syndrome, the safety and efficacy of posaconazole prophylaxis was compared to that of fluconazole or itraconazole . ► IFI was 2% with posaconazole versus 8% with fluconazole/ itraconazole ► IA was 1% with posaconazole versus 7% with fluconazole/ itraconazole ► Fungal related mortality was 2% with posaconazole versus 5% with fluconazole/ itraconazole ►Serious adverse events, possibly or probably related to treatment, were reported in 6% with posaconazole versus 2% with fluconazole/ itraconazole. ????? deleterious interaction of posaconazole with the chemotherapy( Still an open question) (Cornely et al .,2007)

  22. Grade and quality of evidence Prophylaxis in acute leukemia: ECIL-3, 2009: AI Prophylaxis in allogeneic BMT: ECIL-3, 2009: Neutropenic phase: -------- GVHD phase: AI Drawbacks of Posaconazole • Posaconazole is relatively well tolerated. In clinical trials the most common adverse effects have been nausea and headache. Rash, dry skin, nausea, taste disturbance, abdominal pain, dizziness and flushing can occur. Posaconazole can cause abnormalities in liver function.

  23. Caspofungin 6 • Acts by inhibiting the synthesis of (1,3)-D- glucan, an integral component of the fungal cell wall of susceptible Aspergillus and Candida spp. (1,3)-D- glucan is not present in mammalian cells. • Potent against candida including fluconazole resistant candida • Moderate activity against Aspergillus spp. • 70 mg/m2 once then 70 mg/m2 thereafter. • Grade and quality of evidence Prophylaxis in acute leukemia: ECIL-3, 2009: insufficient data Prophylaxis in allogeneic BMT: ECIL-3, 2009: insufficient data

  24. Drawbacks of Caspofungin • Safety and efficacy of doses>70 mg have not been adequately studied in Candida infection • Safety information on treatment duration longer than 4 weeks is limited • Clinical hepatic abnormalities have occurred . • Renal toxicity, hypokalemia and infusion related reactions but the incidence is relatively low compared to Amphotericin B. • Flushing, facial edema and flu like symptoms.

  25. Recommended prophylactic regimens and their levels of evidence according to an earlier study by Oliver et al.,2003 Oliver et al., 2003 Pediatric Oncology workshop- Zagazig university

  26. UPDATE ECIL-3 2009 • Primary antifungal prophylaxis in acute leukemia( Induction, high risk patients) ►Posaconazole: AI ► Itraconazole: CI (close monitoring of serum drug level) ► Fluconazole: CI ( not in centers with high incidence of mould infections and not having HEPA filtered rooms) ► Amphotericin B iv: CI ► Inhaled Liposomal Ampho+ fluconazole oral : BI • Primary antifungal prophylaxis in allogenic BMT ( Neutropenic phase) ► Fluconazole: AI ► Voriconazole: Provisional AI ► Itraconazole: BI ► Amphotericin B iv: CI ►Inhaled Liposomal Ampho+ fluconazole oral : BII • Primary antifungal prophylaxis in allogenic BMT ( GVHD phase) ► Posaconazole: AI ► Voriconazole: Provisional AI ► Itraconazole: BI ► Fluconazole: CI ► Amphotericin B iv: CI

  27. UPDATE ECIL-3 2009 • Secondary antifungal prophylaxis: AII Previously documented and fully resolved IFI plus new episode of prolonged neutropenia or severe myelosuppression( usually Tx) no drug specific recommendations

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