fungal infections in high-risk haematology-oncology patients

Axel Glasmacher

Treatment of invasive fungal infection in the immunocompromised patient

The Association of Clinical Pathologists – International Scientific Meeting – June 2006

0%

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Polyenes/no prophylaxisRa

te o

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un

ga

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ns 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 malignancies

Inci

denc

e in

aut

opsi

es

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 AIDSFrankfurt (Germany), Groll et al. 1996 Candida spp. 49%, Aspergillus spp. 51%

Improvement of overall survivalin AML patients

App

elba

um, R

owe

et a

l. A

SH E

duca

tion

al 2

001

ECOG, since 1973

Years

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

Lin

et a

l., C

ID 2

001;

32:

358

%

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 Tor

tora

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23:

317

%

Development of antifungals

mod. nach R. Lewis, ICAAC 2002

Amphotericin B

Abelcet Amphotec

liposomalesNystatin

Ketoconazol

Fluconazol

Voriconazol

PosaconazolRavuconazol

AmBisome

5-Flucytosin

Itraconazol

Micafungin

Caspofungin

Nystatin

PyrimidinanalogaPolyene Azole Echinocandine

Anidulafungin

Amphotericin B

Abelcet Amphotec

liposomalesNystatin

Ketoconazol

Fluconazol

PosaconazolRavuconazol

AmBisome

5-Flucytosin

Micafungin

Nystatin

PyrimidinanalogaPolyenes Azoles Echinocandins

Anidulafungin

Geo

rgop

apad

akou

NH

, Wa l

s h T

. Nat

u re

1994

; 264

: 371

The (small) world of antifungals

Membrane function:Amphotericin B

Cellwall synthesis:Echinocandins

Ergosterol synthesis:Azoles

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.

Presentation overview

Risk stratificationAntifungal prophylaxisEmpirical antifungal therapyTherapy of proven invasive mycoses

Risk groups for invasive fungal infections in cancer patients

Low riskAutologous 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 weeksLymphocytes < 0.5 G/l + antibioticsOlder age Central venous catheter

Intermediate– high – risk

Colonized > 1 site OR heavy at one siteNeutropenia < 0.5 to > 0.1 G/l >3 to <5 weeksAML TBI Allogeneic matched sibling donor SCT

High risk

Neutrophils <0.1 G/l > 3 weeks OR <0.5 G/l > 5 weeksColonized by Candida tropicalis Unrelated or mismatched donor SCT GVHDCorticosteroids: > 1mg/kg & neutroph. < 1 G/l >1 week Corticosteroids: > 2mg/kg > 2 weeksHigh-dose cytarabine Fludarabine?

Pren

tice

HG

, Kib

bler

CC

, Pre

ntic

e A

G, B

JH 2

000;

110

: 273

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

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ck L

A e

t al.,

BJH

200

4; 1

24: 4

03

PCR+: 2 consecutive positive pan-fungal PCR results; EAT: empirical antifungal therapy; IFI: invasive fungal infections EORTC/MSG (proven: 3, probable: 9, possible 10)

Prophylaxis is unselective

Diseases desperate grownBy desperate appliance are relieved,Or not at all.

William Shakespeare (1564-1616)Hamlet 4.3.9-11: Claudius to his lords

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)

Incidence of proveninvasive fungal infections

Test for heterogeneity (13 trials), ²=10.87, P=0.54n=3597; OR = Peto odds ratioReduction = 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: 4615 event Odd =

no event

odd AOdds ratio =

odd B

Citation Treated Control OR PValue

BDD < 110 27 / 517 28 / 495 .92 .770BDD > 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

Incidence of proveninvasive yeast infections

Gla

smac

her e

t al.,

JC

O 2

003;

21:

461

5


BDD < 110 8 / 373 12 / 362 .63 .30BDD > 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)


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]


Overall: 54% reduction- BDD < 110 mg/d 36% reduction- BDD > 200 mg/d 61% reduction p=0.38

Incidence of proveninvasive Aspergillus infections

Gla

smac

her e

t al.,

JC

O 2

003;

21:

461

5



BDD < 110 9 / 238 5 / 227 1.74 .31BDD > 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


Overall: 31% reduction- BDD < 110 mg/d 74% increase- BDD > 200 mg/d 46% reduction p=0.05

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)

Gla

smac

her e

t al.,

JC

O 2

003;

21:

461

5

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

Cor

nely

et a

l., A

SH 2

005,

#18

44

IFI = invasive fungal infection, IAI = invasive Aspergillus infectionOR = odds ratio

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

Ullm

ann

et a

l., IC

AA

C 2

005,

#M

-716

IFI = invasive fungal infection, IAI = invasive Aspergillus infectionOR = odds ratio

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

Why do we need empiricalantifungal therapy?

High incidence and fatality rates for invasive fungal infections Insufficient diagnostics

Culture-based methodsHelpful only with Candida, but even then 10% false negativeAlmost 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

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

Empirical antimycotic therapy Period III + IV: Composite Study Endpoint

AmB Altern. better

Incidence of invasive fungal infections: 3-10%

No differences!

Overview of Trialsfor 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

Intervention3

mg/kg/d0.6

mg/kg/d3

mg/kg/d126

mg/kg/d3

mg/kg/d70 50mg/d

Empirical Antimycotic Therapy:Successful Therapy of Base Line Invasive Fungal Infections

Successful treatment of baseline invasive fungal infection

Empirical Antimycotic Therapy:Other Components of Composite Outcome

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

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40

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70

80

90

100

Su

rviv

al (

%)

NEJM 2004; 351: 1391

Incidence of Nephrotoxicity in Clinical Trials for Empirical Antifungal Therapy

Nephrotoxicity: Creatinine ≥ 2 x baseline

Rat

e of

Nep

hrot

oxic

ity

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

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, 1999Wingard, 2000Boogaerts, 2001Walsh, 2002Walsh, 2003

Rat

e of

bili

rubi

n >

2x b

asel

ine

Empirical Antimycotic Therapy:Nephro- & Hepatotoxicity

Nephrotoxicity (> 2 times base line value) NNT for CAS versus L-AmB: 1:11

Hepatotoxicity (hyperbilirubinemia)

Towards a recommendation of drugsfor 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- conazoleCaspo- fungin

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).

Invasive Candida Infections(mostly non-neutropenic patients)

Response rate, according to study criteriaSTAND = 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 / 103Anaissie cAmB Fluconazole 66 / 75 58 / 67Philips cAmB Fluconazole 24 / 42 26 / 42Tuil FCZ Itraconazole 64 / 96 67 / 97Rex II FCZ FCZ+cAmB 73 / 107 58 / 104Mora-Duarte cAmB Caspofungin 79 / 109 71 / 115Kullberg 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

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

% n

on-a

lbic

ans

Can

dida

AmB

AmB/Flu

Fluco

Caspo

Vori

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

Invasive Aspergillus infections

Response rate, according to study criteriaAll comparisons made to cAmB as standard therapyOR = Peto odds ratio, cAmB = conventional amphotericin BlipoAmB = liposomal amphotericin B

Study ALTernative N OR P

van-t Wout Itraconazole 32 .778 .719Verweij cAmB+Flucytosin 28 1.599 .622Leenders lipoAmB 66 1.495 .418Ellis lipoAmB 87 .539 .148Bowden ABCD 103 .753 .559Herbrecht Voriconazole 277 2.297 .001

593

0,1 0,2 0,5 1 2 5 10

Favors cAmB Favors ALT

AG, 2003

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 significant

Cornely et al., ASH 2005, #2322

Antifungal Therapy in Neutropenic Patients with Aspergillus Infections

0%

10%

20%

30%

40%

50%

60%

70%

80%

Caspofungin Voriconazole L-AmBSecond line First line

Herbrecht et al. 2002Betts et al., Cancer 2006Glasmacher, 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=107Res

pons

e ra

te (9

5% C

I)

Treatment indication according to risk groups for invasive fungal infections

Low risk

No primary antifungal prophylaxisEmpirical antimycotic therapy rarely necessaryTreat proven / probable infections

Intermediate– low – risk

No primary antifungal prophylaxis (in most circumstances)Empirical antimycotic therapy usually indicated

Intermediate– high – risk

Antifungal prophylaxis recommendedEmpirical antimycotic therapy recommended

High risk

fungal infections in high-risk haematology-oncology patients

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