Fungal infections in high-risk haematology-oncology patients

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Fungal infections in high-risk haematology-oncology patients

  1. 1. Axel Glasmacher Treatment of invasive fungal infection in the immunocompromised patient The Association of Clinical Pathologists – International Scientific Meeting – June 2006
  2. 2. 0% 2% 4% 6% 8% 10% 12% 14% 16% Polyenes/no prophylaxis Rateofinvasivefungalinfections Proven Proven / suspected Data from the control arms of RCTs on antifungal prophylaxis, n=3597 (Glasmacher et al., JCO 2003) Incidence of invasive fungal infections in neutropenic patients with haematological malignanciesIncidenceinautopsies 0% 5% 10% 15% 20% 25% 1978-82 1983-87 1988-92 Invasive mycoses: • 76% responsible for death • 25% of patients with AML • 19% of patients with AIDS Frankfurt (Germany), Groll et al. 1996 Candida spp. 49%, Aspergillus spp. 51%
  3. 3. Improvement of overall survival in AML patients Appelbaum,Roweetal.ASHEducational2001 ECOG, since 1973 Years
  4. 4. Mortality from invasive Aspergillus infections 0 10 20 30 40 50 60 70 80 90 100 Leuk./Lymph. alloSCT Kidney-Tx Lung/Heart-Tx Liver-Tx AIDS/HIV Linetal.,CID2001;32:358 %
  5. 5. Mortality from invasive Candida infections 0 10 20 30 40 50 60 70 80 90 100 Surgery ICU Solid tumor Haem. Malig. HIV Premature birth Tortoranoetal.,EJCMID2004;23:317 %
  6. 6. Development of antifungals mod. nach R. Lewis, ICAAC 2002 Amphotericin B Abelcet Amphotec liposomales Nystatin Ketoconazol Fluconazol Voriconazol PosaconazolRavuconazol AmBisome 5-Flucytosin Itraconazol Micafungin Caspofungin Nystatin PyrimidinanalogaPolyene Azole Echinocandine Anidulafungin Amphotericin B Abelcet Amphotec liposomales Nystatin Ketoconazol Fluconazol PosaconazolRavuconazol AmBisome 5-Flucytosin Micafungin Nystatin PyrimidinanalogaPolyenes Azoles Echinocandins Anidulafungin
  7. 7. GeorgopapadakouNH,WalshT.Nature1994;264:371 The (small) world of antifungals Membrane function: Amphotericin B Cellwall synthesis: Echinocandins Ergosterol synthesis: Azoles
  8. 8. Antifungal Activity (█ > 75% sensible, █ ≤ 50%, █ < 5%; mixed colours: differing results; modified after O'Brien et al., ASH Edu 2003) Erreger AmB Fluco Itra Vori Caspo Flucyt. C. albicans C. parapsilosis C. tropicalis C. glabrata C. krusei A. fumigatus A. flavus A. terreus Zygomycetes Fusarium spp.
  9. 9. Presentation overview Risk stratification Antifungal prophylaxis Empirical antifungal therapy Therapy of proven invasive mycoses
  10. 10. Risk groups for invasive fungal infections in cancer patients Low risk Autologous bone marrow /stem cell transplant (SCT) Childhood ALL (except for P. jirovecii) Lymphoma Intermediate – low – risk Moderate neutropenia 0.1-0.5 G/l < 3 weeks Lymphocytes < 0.5 G/l + antibiotics Older age  Central venous catheter Intermediate – high – risk Colonized > 1 site OR heavy at one site Neutropenia < 0.5 to > 0.1 G/l >3 to <5 weeks AML  TBI  Allogeneic matched sibling donor SCT High risk Neutrophils <0.1 G/l > 3 weeks OR <0.5 G/l > 5 weeks Colonized by Candida tropicalis Unrelated or mismatched donor SCT  GVHD Corticosteroids: > 1mg/kg & neutroph. < 1 G/l >1 week Corticosteroids: > 2mg/kg > 2 weeks High-dose cytarabine  Fludarabine? PrenticeHG,KibblerCC,PrenticeAG,BJH2000;110:273
  11. 11. Evaluation of risk groups for invasive fungal infections in cancer patients 0% 5% 10% 15% 20% 25% 30% 35% 40% High (n=51) Inter high (n=100) Inter low (n=53) Risk group (Prentice et al., 2000) PCR + EAT IFI McLintockLAetal.,BJH2004;124:403 PCR+: 2 consecutive positive pan-fungal PCR results; EAT: empirical antifungal therapy; IFI: invasive fungal infections EORTC/MSG (proven: 3, probable: 9, possible 10)
  12. 12. Presentation overview Risk stratification Antifungal prophylaxis Empirical antifungal therapy Therapy of proven invasive mycoses
  13. 13. Prophylaxis is unselective Diseases desperate grown By desperate appliance are relieved, Or not at all. William Shakespeare (1564-1616) Hamlet 4.3.9-11: Claudius to his lords
  14. 14. Other antifungal drugs for prophylaxis  Fluconazole (Meta-analysis: Kanda et al., Cancer 2000)  Not effective after myelosuppressive treatment for acute leukaemia but only in early phase after allogeneic stem cell transplantation  Effective only against Candida (albicans)  Effective only in higher doses (400 mg/d)  Amphotericin B (Meta-analysis: Bow et al., Cancer 2002)  Toxic, no full doses used  Not effective against invasive Aspergillus infections (in prophylaxis)
  15. 15. Incidence of proven invasive fungal infections Test for heterogeneity (13 trials), Χ²=10.87, P=0.54 n=3597; OR = Peto odds ratio Reduction = Relative risk reduction Overall: 40% reduction - BDD < 110 mg/d 8% reduction - BDD > 200 mg/d 53% reduction p=0.049 Glasmacher et al., JCO 2003; 21: 4615event Odd =  no event odd A Odds ratio =  odd B Citation Treated Control OR PValue BDD < 110 27 / 517 28 / 495 .92 .770 BDD > 200 32 / 1295 66 / 1290 .47 <.001 Combined 59 / 1812 94 / 1785 .60 .002 0.1 0.2 0.5 1 2 5 10 Favors ITRA Favors control BDD = bioavailable daily dose Odds ratio Odds ratio 95% Confidence Interval Line of equivalence
  16. 16. Incidence of proven invasive yeast infections Glasmacheretal.,JCO2003;21:4615 Citation Treated Control OR PValue BDD < 110 8 / 373 12 / 362 .63 .30 BDD > 200 11 / 1247 28 / 1250 .40 .005 Combined 19 / 1620 40 / 1612 .47 .004 0.1 0.2 0.5 1 2 5 10 Favors ITRA Favors control (C) BDD = bioavailable daily dose Efficacy of prophylaxis in different species: Prevention of C. albicans: RR = 0.54 [0.23-1.24] Prevention of non-albicans Candida spp.: RR = 0.49 [0.26-0.92] Test for heterogeneity (11 trials), Χ²=8.48, P=0.58 n=3320; OR = Peto odds ratio Reduction = Relative risk reduction Overall: 54% reduction - BDD < 110 mg/d 36% reduction - BDD > 200 mg/d 61% reduction p=0.38
  17. 17. Incidence of proven invasive Aspergillus infections Glasmacheretal.,JCO2003;21:4615 BDD = bioavailable daily dose Citation Treated Control OR PValue BDD < 110 9 / 238 5 / 227 1.74 .31 BDD > 200 18 / 1247 34 / 1250 .52 .02 Combined 27 / 1485 39 / 1477 .68 .12 0.1 0.2 0.5 1 2 5 10 Favors ITRA Favors control Test for heterogeneity (10 trials), Χ²=9.42, P=0.40 n=3320; OR = Peto odds ratio Reduction = Relative risk reduction Overall: 31% reduction - BDD < 110 mg/d 74% increase - BDD > 200 mg/d 46% reduction p=0.05
  18. 18. Other evidence  Mortality:  Significantly reduced fungal-infection-associated mortality  No difference in overall mortality (studies neither powered nor conducted to find such a difference due to short follow-up)  Drug discontinuation:  Higher in studies with itraconazole oral solution  Hypokalemia:  Clearly more frequent with itraconazole  Other toxicity:  Renal and liver toxicity in one trial with itraconazole con-comittant to high-dose cyclophosphamide (Marr et al., Blood 2004) Glasmacheretal.,JCO2003;21:4615
  19. 19. Posaconazole vs. "Standard" Azole  Patients with AML or MDS and intensive chemotherapy  Prophylaxis during all courses  Posaconazole (600 mg/d) vs fluconazole (400 mg/d) or itraconazole (400 mg/d OS) Posaconazole "Standard" Azole P N 304 298 IFI during Tx 2% 8% 0.0009 IA during Tx 1% 7% 0.0001 IFI ≤ 100d 5% 11% 0.0031 Cornelyetal.,ASH2005,#1844 IFI = invasive fungal infection, IAI = invasive Aspergillus infection OR = odds ratio
  20. 20. Posaconazole vs. Fluconazole in the Prophylaxis of Invasive Mycoses  Patients with allogeneic stem cell transplantation, duration ≤ 112 d  Posaconazole (600 mg/d) vs fluconazole (400 mg/d) Posaconazole Fluconazole OR P N 301 299 IFI at any time 7% 14% 0.43 0.003 IFI ≤ 112 d 5% 9% 0.56 0.07 AI ≤ 112 d 2% 7% 0.31 0.006 Ullmannetal.,ICAAC2005,#M-716 IFI = invasive fungal infection, IAI = invasive Aspergillus infection OR = odds ratio
  21. 21. Recommendations – Antifungal prophylaxis  Patients with intermediate high or high risk:  Antifungal prophylaxis with itraconazole is indicated  Patients with intermediate low risk:  Indication should be determined according to local incidence rates and individual risk  At least 200 mg/d bioavailable itraconazole are necessary for a reduction of the incidence  of invasive fungal infections including  invasive Aspergillus infections  Posaconazole may be an alternative – depending on full reports and cost-effectiveness
  22. 22. Presentation overview Risk stratification Antifungal prophylaxis Empirical antifungal therapy Therapy of proven invasive mycoses
  23. 23. Why do we need empirical antifungal therapy?  High incidence and fatality rates for invasive fungal infections  Insufficient diagnostics  Culture-based methods  Helpful only with Candida, but even then 10% false negative  Almost never diagnostic for invasive Aspergillus infections  Non-culture based methods (GM, PCR)  Still high false negative rate  Many invasive fungal infections are diagnosed too late or only at autopsy  Late treatment greatly reduces success rates
  24. 24. Development of empirical antimycotic therapy  Period I (1982-1988)  Conventional amphotericin B vs. no therapy / placebo  Pizzo et al. 1982, EORTC 1988  Significant reduction of breakthrough infections if both studies combined  Period II (1993-1998)  Conventional amphotericin B vs. fluconazole or liposomal AmB  Defervescence as main outcome, mostly no statistically signif. differences  Only one study (Prentice 1997) with a significant difference  Period III (1998-2001)  Introduction of the composite outcome score (Walsh et al., COS)  Conventional AmB vs. liposomal AmB, fluconazole, itraconazole, ABCD  No significant differences  Period IV (2000-today)  Continued use of the composite outcome score (COS)  Liposomal AmB vs. ABLC, voriconazole, caspofungin
  25. 25. Empirical antimycotic therapy Period III + IV: Composite Study Endpoint AmB Altern. better Incidence of invasive fungal infections: 3-10% No differences!
  26. 26. Overview of Trials for Empirical Antifungal Prophylaxis Walsh et al., NEJM 1999 Walsh et al., NEJM 2002 Walsh et al., NEJM 2004 Comparators LipoAmB ConvAmB LipoAmB Vori- conazole LipoAmB Caspo- fungin N 344 343 415 422 556 539 Design Double blind Unblinded Double blind Intervention 3 mg/kg/d 0.6 mg/kg/d 3 mg/kg/d 126 mg/kg/d 3 mg/kg/d 70 50 mg/d
  27. 27. Empirical Antimycotic Therapy: Successful Therapy of Base Line Invasive Fungal Infections Successful treatment of baseline invasive fungal infection
  28. 28. Empirical Antimycotic Therapy: Other Components of Composite Outcome
  29. 29. Caspofungin: Overall survival Caspofungin (N=556) LipoAmB (N=539) Log Rank, P=0.044 0 7 14 21 28 35 42 49 56 63 STUDY DAY 0 10 20 30 40 50 60 70 80 90 100 Survival(%) NEJM 2004; 351: 1391
  30. 30. Incidence of Nephrotoxicity in Clinical Trials for Empirical Antifungal Therapy Nephrotoxicity: Creatinine ≥ 2 x baseline RateofNephrotoxicity 34% 19% 42% 14% 24% 5% 7% 8% 12% 3% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% ABLC cAmB L-AmB Azoles Caspo Walsh, 1999 Wingard, 2000 Boogaerts, 2001 Walsh, 2002 Walsh, 2003
  31. 31. Incidence of Hepatotoxicity in Clinical Trials of Empirical Antifungal Therapy 8% 12% 12% 5% 11% 3% 7% 10% 10% 5% 0% 2% 4% 6% 8% 10% 12% 14% ABLC cAmB L-AmB Azoles Caspo Walsh, 1999 Wingard, 2000 Boogaerts, 2001 Walsh, 2002 Walsh, 2003 Rateofbilirubin>2xbaseline
  32. 32. Empirical Antimycotic Therapy: Nephro- & Hepatotoxicity Nephrotoxicity (> 2 times base line value) NNT for CAS versus L-AmB: 1:11 Hepatotoxicity (hyperbilirubinemia)
  33. 33. Towards a recommendation of drugs for empirical antifungal therapy Efficacy proven IFI Broad spectrum Evidence EAT trials Toxicity liver Toxicity kidney Drug interact. Conv. AmB ABLC Lipo AmB Itra- conazole Vori- conazole Caspo- fungin
  34. 34. Presentation overview Risk stratification Antifungal prophylaxis Empirical antifungal therapy Therapy of proven invasive mycoses
  35. 35. Definition of proven infections EORTC/MSG criteria:  Proven: Culture / histology from a normally sterile body site  Probable: Requires host, clinical AND microbiological factors  E.g.: Neutropenic patient with a typical lesion in HR-CT AND two positive galactomannan antigen results  Possible: Requires host, clinical OR microbiological factors  E.g.: Same patient without two positive GM antigen results These criteria are made for clinical trials and should not be used for clinical decision making (or reimbursement issues)  Of 22 patients with IPA at autopsy only 2 were classified as proven, 6 as probable, 13 as possible. 64% had no microbiological or major clinical criteria before death (Subira et al., AH 2003).
  36. 36. Invasive Candida Infections (mostly non-neutropenic patients) Response rate, according to study criteria STAND = Standard therapy, OR = Peto odds ratio, cAmB = conventional amphotericin B, FCZ = Fluconazole AG, 2004 Citation STAND ALT Standard Alternative Rex I cAmB Fluconazole 73 / 103 81 / 103 Anaissie cAmB Fluconazole 66 / 75 58 / 67 Philips cAmB Fluconazole 24 / 42 26 / 42 Tuil FCZ Itraconazole 64 / 96 67 / 97 Rex II FCZ FCZ+cAmB 73 / 107 58 / 104 Mora-Duarte cAmB Caspofungin 79 / 109 71 / 115 Kullberg cAmB+FCZ Voriconazole 76 / 185 76 / 185 Combined (7) 455 / 717 437 / 713 0,1 0,1 0,2 0,2 0,5 0,5 1 1 2 2 5 5 10 10 Favors STAND Favors ALT
  37. 37. Proportion of non-albicans Candida spp. in these studies 0% 10% 20% 30% 40% 50% 60% 70% Rex I Anaissie Phillips Rex II Mora-Duarte Kullberg %non-albicansCandida AmB AmB/Flu Fluco Caspo Vori
  38. 38. Micafungin vs. liposomal Amphotericin B in invasive Candida infections  Invasive Candida infections, Candidemia  Micafungin (100 mg/d) versus liposomal Amphotericin B (3 mg/kg/d) Micafungin Liposomal AmB N 202 190 Overall success 90% 90% C. albicans 88% 89% Non-albicans Candida 90% 89% Ruhnke et al., ICAAC 2005, #M-722c
  39. 39. Invasive Aspergillus infections Response rate, according to study criteria All comparisons made to cAmB as standard therapy OR = Peto odds ratio, cAmB = conventional amphotericin B lipoAmB = liposomal amphotericin B Study ALTernative N OR P van-t Wout Itraconazole 32 .778 .719 Verweij cAmB+Flucytosin 28 1.599 .622 Leenders lipoAmB 66 1.495 .418 Ellis lipoAmB 87 .539 .148 Bowden ABCD 103 .753 .559 Herbrecht Voriconazole 277 2.297 .001 593 0,1 0,2 0,5 1 2 5 10 Favors cAmB Favors ALT AG, 2003
  40. 40. AmbiLOAD-Study: Favorable Overall Response 0% 10% 20% 30% 40% 50% 60% 70% 80% Aspergillosis (all cases) Neutropenia at Baseline 3 mg/kg/d 10 mg/kg/d No differences are statistically Cornely et al., ASH 2005, #2322
  41. 41. Antifungal Therapy in Neutropenic Patients with Aspergillus Infections 0% 10% 20% 30% 40% 50% 60% 70% 80% Caspofungin Voriconazole L-AmB Second line First line Herbrecht et al. 2002Betts et al., Cancer 2006 Glasmacher, JAC 2005 Cornely et al. 2005 N=65 N=65 Definition of neutropenia: Neutrophils < 500 at start of therapy or in the 2 weeks before N=107 Responserate(95%CI)
  42. 42. Treatment indication according to risk groups for invasive fungal infections Low risk No primary antifungal prophylaxis Empirical antimycotic therapy rarely necessary Treat proven / probable infections Intermediate – low – risk No primary antifungal prophylaxis (in most circumstances) Empirical antimycotic therapy usually indicated Intermediate – high – risk Antifungal prophylaxis recommended Empirical antimycotic therapy recommended High risk

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