Management of Confirmed AspergillosisManagement of Confirmed Aspergillosis
Oliver A. Cornely
1Department I for Internal MedicineHaematology / Oncology /
Infectious Diseases / Intensive Care
2Centre for Clinical ResearchUniversity of CologneUniversity of Cologne
andthe
Global Aspergillus Study the p g y
Group
Successful Response RateSuccessful Response Rate
Voriconazolen = 144
c-AmBn = 133
Week 12 (95% CI 10 - 33%) 76 (53%) 42 (32%)
Voriconazole is superior to amphotericin B deoxycholate.
Overall SurvivalOverall Survival
80%
100%
71%
Voriconazole
60%
80%
viva
l
71%
40%
% s
urv
58%
Amphotericin Blog rank, p = 0.015
0%
20%
0 2 4 6 8 10 12Weeks
Number of patients at riskVoriconazole 144 131 125 117 111 107 102c-AmB 133 117 99 87 84 80 77
What do European Guidelines Propose?What do European Guidelines Propose?
Herbrecht R et al. EJC 2007; S49-59.
ECILECIL--11
ProductsRating
Voriconazole AI
Amphotericin B deoxycholate DI
Liposomal amphotericin B BI
Amphotericin B lipid complex BII
Amphotericin B colloidal dispersion DI
Caspofungin CIII
Itraconazole CIII
Combination therapy DIII
Herbrecht et al., Eur J Cancer Supplement, 2007; http://www.ichs.org
Cornely et al. CID 2007. 2007; 44:1289–97.Cornely O. et al. Clinical Infectious Diseases 2007; 44:1289–97.
AmBiLoad AmBiLoad –– Trial DesignTrial Design
Invasive Filamentous Fungal Infection
RandomizationRandomization
LL--AmBAmB L-AmBd1-143 mg/kg3 mg/kg 10 mg/kgdouble-blind
LL--AmBAmB3 mg/kg3 mg/kg3 mg/kg3 mg/kg
Cornely O. et al. Clinical Infectious Diseases 2007; 44:1289–97.
Patient 1001 Patient 1001 -- probableprobable
ALLSteroidsNeutropeniaNeutropeniaFever >72h
Galactomannan ?•
Galactomannan ?
1
•
• ••• • ••
• • • •
Probable Invasive AspergillosisProbable Invasive Aspergillosis
AMLAMLNeutropeniaFever >72hFever >72hCoughDyspneay pPleuritis
Galactomannan
• • •
Galactomannan
1•
• • • ••
Baseline CharacteristicsBaseline Characteristics
AmBi-3mgN=107
AmBi-10mgN=94
Age (mean yrs) [range] 50 9 [15-76] 50 4 [2-78]Age (mean, yrs) [range] 50.9 [15-76] 50.4 [2-78]
Sex: M/F (%) 57/43 67/33
Hematological Malignancies1 99 (93) 87 (93)
Controlled 36/99 (36) 26/85 (31)
Uncontrolled2 63/99 (64) 59/85 (69)
Allo-SCT 17 (16) 18 (19)
Auto-SCT 1 (1) 4 (4)
Solid Organ Transplant 1 (1) 0Solid 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; 44:1289–97.
Overall Response at EOTOverall Response at EOT
N (%)L-AmB 3mg
N=107L-AmB 10mg
N=94
Favorable 53 (50) 43 (46)
CR 1 (1) 2 (2)
PR 52 (49) 41 (44)
UnfavorableUnfavorable
Stable 8 (7) 5 (5)
F il 36 (34) 36 (38)Failure 36 (34) 36 (38)
Not evaluable 10 (9) 10 (11)
Cornely O. et al. Clinical Infectious Diseases 2007; 44:1289–97.
ConclusionsConclusions
In a highly immunocompromised population93% hematological malignancies42% neutropenia persisting at EOT42% neutropenia persisting at EOT
1. L-AmB 3mg/kg as 1st line treatment for aspergillosis resulted in a
50% success rate72% 12 week survival rate72% 12 week survival rate
2. L-AmB 10 mg/kgdid not improve response or survivalwas associated with higher rates of toxicity
Cornely O. et al. Clinical Infectious Diseases 2007; 44:1289–97.
What do US Guidelines Propose?What do US Guidelines Propose?
Walsh TJ et al. CID 2008; 46: 327-60.Walsh T, et al. Clinical Infectious Diseases 2008; 46:327–60.
IDSA Guidelines 2000→2008: IDSA Guidelines 2000→2008: P i Th f I i A ill iP i Th f I i A ill iPrimary Therapy of Invasive AspergillosisPrimary Therapy of Invasive Aspergillosis
IDSA Guidelines 2000
Amphotericin B has been the standard of treatment in invasive aspergillosis, particularly for life-threatening and
Amphotericin B Liposomal amphotericin B
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
RatingAII1
with invasive aspergillosis who develop nephrotoxicity while receiving amphotericin
IDSA Guidelines 2008Preferred therap Voricona ole is recommended for the
Voriconazole
Preferred therapy-Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients
RatingAI2,3
Alt ti A d i d t i l i t d f
Liposomal amphotericin B
Alternative-A randomized 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
AI2,3
1Stevens D, et al. Clinical Infectious Diseases 2000;30:696–7092Patterson W, et al. IDSA IA guidelines 2007, ICAAC 20073Walsh T, et al. Clinical Infectious Diseases 2008; 46:327–60.
Survival and SubSurvival and Sub--group Analyses from the group Analyses from the AmBiLoad Trial AmBiLoad Trial oad aoad a
New Insightsg
Survival Was Similar in Both Treatment GroupsSurvival Was Similar in Both Treatment Groups
94%
80%
100%
ts
72%91%
94%93%
76%
60%
80%
% o
f pat
ient
59%
88%
69%
40%
mul
ativ
e %
Log rank p= 0.089
0%
20%Cum
0 2 4 6 8 10 12Weeks
L-AMB 3 mg/kg, n=107 L-AMB 10 mg/kg, n=94g g, g g,
Cornely O. et al. Clinical Infectious Diseases 2007; 44:1289–97.
Favorable Overall Response with LFavorable Overall Response with L--AMB AMB b B li N t i St tb B li N t i St tby Baseline Neutropenia Statusby Baseline Neutropenia Status
3 mg/kg per day 10 mg/kg per day
100%
g g p y g g p y
67%57%60%
80%
ents
43% 42%40%
60%
% o
f pat
ie
0%
20%
Neutropenia No neutropenia
Cornely O, et al. Poster P122. 2nd Advances Against Aspergillosis, Athens, Greece, Feb 2006.
Stepwise Logistic Regression Analysis Stepwise Logistic Regression Analysis 12 Week Survival12 Week Survivalee Su aee Su a
Patients with Allo SCT Patients with Allo SCT H d L S i l t 12 W kH d L S i l t 12 W kHad a Lower Survival at 12 WeeksHad a Lower Survival at 12 Weeks
71%*80%
40%
60%
surv
ival
40%40%
f pat
ient
s
0%
20%
% o
No Allo SCT Allo SCT
*P<0.001
Cornely O, et al. Poster P122. 2nd Advances Against Aspergillosis, Athens, Greece, Feb 2006.
Patients with Uncontrolled Malignancy Patients with Uncontrolled Malignancy H d L S i l ith LH d L S i l ith L A B t 12 W kA B t 12 W kHad a Lower Survival with LHad a Lower Survival with L--AmB at 12 WeeksAmB at 12 Weeks
54%81%
Heme Malignancy (all)
Uncontrolled Malignancy Controlled Malignancy
*
57%
54%
82%Leukemias (all)
g y ( )
*
63%82%
Acute Leukemias *
100%41%Lymphomas *
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.
Does Prior Antifungal Therapy Affect Does Prior Antifungal Therapy Affect Outcomes with Liposomal Amphotericin B Outcomes with Liposomal Amphotericin B Outco es t poso a p ote cOutco es t poso a p ote c
Therapy?Therapy?
Cornely O, et al. Poster #M-885, ICAAC 2006.
Response and Survival with LResponse and Survival with L--AMB AMB Was Not Affected by Prior Azole or Voriconazole UseWas Not Affected by Prior Azole or Voriconazole UseWas Not Affected by Prior Azole or Voriconazole UseWas Not Affected by Prior Azole or Voriconazole Use
Favorable Response Survival
80%
100%
80%
100%Favorable Response Survival
49% 50%60%
80%
ents
64% 66%72%
64%60%
80%
ents
49% 46%
36%
50%
40%% o
f pat
ie
40%% o
f pat
ie
20% 20%
0%Prior Az No prior
AzPriorVori
No PriorVori
0%Prior Az No prior
AzPriorVori
No PriorVori
Cornely O, et al. Poster #M-885, ICAAC 2006.
Overall Mortality Overall Mortality –– Time to DeathTime to Deathl
1.00
P 003*
Surv
iva
0.75P = .003*
bilit
y of
0.50
Prob
a
0.25 PosaconazoleStandard azolesPosaconazoleStandard azolesPosaconazoleStandard azoles
0.00 0 20 40 60 80 100
Censoring time is last contact or day 100.
Days after Randomization
Overall Mortality Overall Mortality –– Time to DeathTime to Deathl
1.00
Surv
iva
0.75
log rank, P = .035
bilit
y of
0.50
Prob
a
0.25 PosaconazoleStandard azolesPosaconazoleStandard azolesPosaconazoleStandard azoles
0.00 0 20 40 60 80 100
Censoring time is last contact or day 100.
Days after Randomization
Survival until Day 7 post EOT (MITT)Survival until Day 7 post EOT (MITT)
90%
100%
80%
90%
viva
l Caspofungin, n=556L-AmB, n=539
p=0.044
70%
% s
urv
50%
60%
0 10 20 30 40 50 60Days on study
andthe
Global Aspergillus Study the p g y
Group
Patients with Satisfactory Treatment ResponsePatients with Satisfactory Treatment ResponseCategorized by Baseline CT FindingsCategorized by Baseline CT FindingsCategorized by Baseline CT FindingsCategorized by Baseline CT Findings
(adapted from Tom Patterson)(adapted from Tom Patterson)
6780
100
(CR
/PR
)
5345
6067
4432 37
4460
Res
pons
e
3219
3723
20
40
isfa
ctor
y R
reem
ptiv
e
0All Patients Definite Probable Probable
(RadiologyNon-MITT
Sati Pr
( gyalone)
Voriconazole Amphotericin B
Herbrecht R et al NEJM 2002;347:408-15;Patterson TF et al, Clin Infect Dis 2005;41:1448-52;Greene R et al. ECCMID 2003
Cornely et al. CID 2007. 2007; 44:1289–97.
Favorable Overall Response:Favorable Overall Response:No Significant Differences between Treatment GroupsNo Significant Differences between Treatment GroupsNo Significant Differences between Treatment GroupsNo Significant Differences between Treatment Groups
Preemptive
No differences are statistically significantNo differences are statistically significant
Cornely O. et al. Blood 2005; 106:900a, Abstract 3222.
Caspofungin for IA in Hematological Patients (EORTC)Caspofungin for IA in Hematological Patients (EORTC)
Multicenter, open, phase II
First line therapyFirst-line therapy
Probable and proven invasive aspergillosisProbable and proven invasive aspergillosis
First study to apply strict EORTC/MSG diagnostic criteria
Response rate (%) in the 30s.
ConclusionsConclusions
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.