Oliver A. Cornely. Department I for Internal Medicine Haematology / Oncology / Infectious Diseases / Intensive Care 2. Centre for Clinical Research

Transcription

1 Management of Confirmed Aspergillosis Oliver A. Cornely 1 Department I for Internal Medicine Haematology / Oncology / Infectious Diseases / Intensive Care 2 Centre for Clinical Research University of Cologne

2 Global the Aspergillus Study Group and the

3 Successful Response Rate Voriconazole n = 144 c-amb n = 133 Week 12 (95% CI 10-33%) 76 (53%) 42 (32%) Voriconazole is superior to amphotericin B deoxycholate.

4 Overall Survival 100% Voriconazole 80% 71% % surv vival 60% 40% log rank, p = % Amphotericin B 20% 0% Weeks Number of patients at risk Voriconazole c-amb

5 What do European Guidelines Propose? Herbrecht R et al. EJC 2007; S49-59.

6 ECIL-1 Products Rating Voriconazole Amphotericin B deoxycholate Liposomal amphotericin B Amphotericin B lipid complex Amphotericin B colloidal dispersion Caspofungin Itraconazole Combination therapy AI DI BI BII DI CIII CIII DIII Herbrecht et al., Eur J Cancer Supplement, 2007;

7 Cornely O. et al. Clinical Infectious Diseases 2007; Cornely 44: et al. CID ; 44:

8 AmBiLoad Trial Design Invasive Filamentous Fungal Infection Randomization L-AmB d1-14 L-AmB 3 mg/kg double-blind 10 mg/kg L-AmB 3mg/kg Cornely O. et al. Clinical Infectious Diseases 2007; 44:

9 Patient probable ALL Steroids Neutropenia Fever >72h? Galactomannan 1

10 Probable Invasive Aspergillosis AML Neutropenia Fever >72h Cough Dyspnea yp Pleuritis Galactomannan 1

11 Baseline Characteristics AmBi-3mg N=107 AmBi-10mg N=94 Age (mean, yrs) [range] 50.9 [15-76] 50.4 [2-78] Sex: M/F (%) 57/43 67/33 Hematological Malignancies 1 99 (93) 87 (93) Controlled 36/99 (36) 26/85 (31) Uncontrolled 2 63/99 (64) 59/85 (69) Allo-SCT 17 (16) 18 (19) Auto-SCT 1 (1) 4 (4) Solid Organ Transplant 1 (1) 0 HIV 2 (2) 2 (2) Neutropenia at baseline 76 (71) 71 (76) Cornely O. et al. Clinical Infectious Diseases 2007; 44:

12 Overall Response at EOT N (%) L-AmB 3mg N=107 L-AmB 10mg N=94 Favorable 53 (50) 43 (46) CR 1 (1) 2 (2) PR 52 (49) 41 (44) Unfavorable Stable 8 (7) 5 (5) Failure 36 (34) 36 (38) Not evaluable 10 (9) 10 (11) Cornely O. et al. Clinical Infectious Diseases 2007; 44:

13 Conclusions In a highly immunocompromised population 93% hematological malignancies 42% neutropenia persisting at EOT 1. L-AmB 3mg/kg as 1st line treatment for aspergillosis resulted in a 50% success rate 72% 12 week survival rate 2. L-AmB 10 mg/kg did not improve response or survival was associated with higher rates of toxicity Cornely O. et al. Clinical Infectious Diseases 2007; 44:

14 What do US Guidelines Propose? Walsh T, et al. Clinical Infectious Diseases 2008; 46: Walsh TJ et al. CID 2008; 46:

15 IDSA Guidelines : Primary Therapy of Invasive Aspergillosis i IDSA Guidelines 2000 Amphotericin B Liposomal amphotericin B Voriconazole Amphotericin B has been the standard of treatment in invasive aspergillosis, particularly for life-threatening and severe infections. In well-characterized patients, the overall response rate has been 37% (range, 14% 83%) The lipid based formulations are indicated for patients with invasive aspergillosis who develop nephrotoxicity while receiving amphotericin IDSA Guidelines 2008 Preferred therapy-voriconazole ole is recommended for the primary treatment of invasive aspergillosis in most patients Rating AII 1 Rating AI 2,3 Liposomal amphotericin B Alternative-A ti Arandomized d trial comparing two dosages of liposomal amphotericin B showed similar efficacy in both arms, suggesting that liposomal therapy could be considered as alternative primary therapy in some patients AI 2,3 1 Stevens D, et al. Clinical Infectious Diseases 2000;30: Patterson W, et al. IDSA IA guidelines 2007, ICAAC Walsh T, et al. Clinical Infectious Diseases 2008; 46:

16 Survival and Sub-group Analyses from the AmBiLoad Trial New Insights

17 Survival Was Similar in Both Treatment Groups Cum mulative % of patient ts 100% 80% 60% 40% 20% 94% 91% 93% 88% Log rank p= % 69% 72% 59% 0% Weeks L-AMB 3 mg/kg, g, n=107 L-AMB 10 mg/kg, g, n=94 Cornely O. et al. Clinical Infectious Diseases 2007; 44:

18 Favorable Overall Response with L-AMB by Baseline Neutropenia Status t 3 mg/kg g per day 10 mg/kg g per day 100% % of patie ents 80% 60% 40% 43% 42% 67% 57% 20% 0% Neutropenia No neutropenia Cornely O, et al. Poster P122. 2nd Advances Against Aspergillosis, Athens, Greece, Feb 2006.

19 Stepwise Logistic Regression Analysis 12 Week Survival

20 Patients with Allo SCT Had a Lower Survival at 12 Weeks 80% 71%* survival f patients % o 60% 40% 20% 40% 0% No Allo SCT Allo SCT *P<0.001 Cornely O, et al. Poster P122. 2nd Advances Against Aspergillosis, Athens, Greece, Feb 2006.

21 Patients with Uncontrolled Malignancy Had a Lower Survival with L-AmB at 12 Weeks Uncontrolled Malignancy Controlled Malignancy Heme Malignancy (all) 54% 81% * Leukemias (all) 57% 82% * 82% Acute Leukemias * 63% Lymphomas 41% 100% * 0% 20% 40% 60% 80% 100% 120% % of patients survival * P < 0.05 Cornely O, et al. Poster P122. 2nd Advances Against Aspergillosis, Athens, Greece, Feb 2006.

22 Does Prior Antifungal Therapy Affect Outcomes with Liposomal Amphotericin B Therapy? Cornely O, et al. Poster #M-885, ICAAC 2006.

23 Response and Survival with L-AMB Was Not Affected by Prior Azole or Voriconazole Use 100% Favorable Response 100% Survival 80% 80% 64% 66% 72% 64% % of patie ents 60% 40% 49% 50% 46% 36% % of patie ents 60% 40% 20% 20% 0% Prior Az No prior Az Prior Vori No Prior Vori 0% Prior Az No prior Az Prior Vori No Prior Vori Cornely O, et al. Poster #M-885, ICAAC 2006.

24 Overall Mortality Time to Death 1.00 Proba bility of Surviva l Posaconazole Standard azoles P =.003* Days after Randomization Censoring time is last contact or day 100.

25 Overall Mortality Time to Death 1.00 l Surviva bility of log rank, P =.035 Proba 0.25 Posaconazole Standard azoles Days after Randomization Censoring time is last contact or day 100.

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27 Survival until Day 7 post EOT (MITT) 100% % surv vival 90% 80% 70% p=0.044 Caspofungin, n=556 L-AmB, n=539 60% 50% Days on study

28 Global the Aspergillus Study Group and the

29 Patients with Satisfactory Treatment Response Categorized by Baseline CT Findings (adapted from Tom Patterson) Sati isfactory Response (CR/PR) All Patients Definite Probable Probable (Radiology alone) Pr reemptive Non-MITT Voriconazole Amphotericin B Herbrecht R et al NEJM 2002;347:408-15; Patterson TF et al, Clin Infect Dis 2005;41: ; Greene R et al. ECCMID 2003

30 Cornely et al. CID ; 44:

31 Favorable Overall Response: No Significant Differences between Treatment Groups Preemptive No differences are statistically significant Cornely O. et al. Blood 2005; 106:900a, Abstract 3222.

32 Caspofungin for IA in Hematological Patients (EORTC) Multicenter, open, phase II First-line therapy Probable and proven invasive aspergillosis First study to apply strict EORTC/MSG diagnostic criteria Response rate (%) in the 30s.

33 Conclusions Voriconazole and liposomal amphotericin B both are AI recommended for 1st line treatment of IA. Diagnostic options are still very limited, making overtreatment clinical practice. Early treatment yields the highest rates in response and survival. The clinical field moves away from treating proven/probable IA.