Management of Confirmed Aspergillosis · Management of Confirmed Aspergillosis Oliver A. Cornely 1Department I for Internal Medicine Haematology / Oncology / Infectious Diseases

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)


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)


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


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,


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


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


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.

Documents

Management of Confirmed Aspergillosis · Management of Confirmed Aspergillosis Oliver A. Cornely 1Department I for Internal Medicine Haematology / Oncology / Infectious Diseases