Treatment of invasive fungal infection in the immunocompromised patient

1
Treatment of invasive fungal infection in the
immunocompromised patient
The Association of Clinical Pathologists
International Scientific Meeting June 2006
2
Incidence of invasive fungal infections in
neutropenic patients with haematological
malignancies
Candida spp. 49, Aspergillus spp. 51
3
Improvement of overall survivalin AML patients
Appelbaum, Rowe et al. ASH Educational 2001
4
Mortality from invasive Aspergillus infections

Lin et al., CID 2001 32 358
5
Mortality from invasive Candida infections

Tortorano et al., EJCMID 2004 23 317
6
Development of antifungals
mod. nach R. Lewis, ICAAC 2002
7
The (small) world of antifungals
Georgopapadakou NH, Walsh T. Nature 1994 264 371
8
Antifungal Activity( gt 75 sensible, ? 50,
lt 5 mixed colours differing results
modified after O'Brien et al., ASH Edu 2003)
9
Presentation overview

• Risk stratification
• Antifungal prophylaxis
• Empirical antifungal therapy
• Therapy of proven invasive mycoses

10
Risk groups for invasive fungal infections in
cancer patients
Prentice HG, Kibbler CC, Prentice AG, BJH 2000
110 273
11
Evaluation of risk groups for invasive fungal
infections in cancer patients
McLintock LA et al., BJH 2004 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
Presentation overview

• Risk stratification
• Antifungal prophylaxis
• Empirical antifungal therapy
• Therapy of proven invasive mycoses

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
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
Meta-Analysis of Itraconazole Antifungal
Prophylaxis Methods

• Inclusion criteria
• Randomized controlled trials of neutropenic
  patients with haematological malignancies
• Comparators none, placebo, oral polyenes,
  fluconazole
• Outcome
• Only proven invasive fungal infections
• Calculation of the bioavailable daily dose (BDD)
  in neutropenic patients
• Capsules 22 BDD 0.22 (daily dose from
  capsules)
• Solution 55 BDD 0.55 (daily dose from oral
  solution)

Glasmacher et al., JCO 2003 21 4615
16
Meta-Analysis of Itraconazole Antifungal
Prophylaxis Included Studies (13 trials, N3597)
BDD lt 110 mg/d
Glasmacher et al., JCO 2003 21 4615
BDD gt 200 mg/d
Daily doses in mg/d, if not stated otherwise.
BDD bioavailable daily dose, Caps itraconazole
capsules, Sol itraconazole oral solution,
Fluco fluconazole (oral), AmB amphotericin B
(oral) i.n. intranasal
17
Incidence of proveninvasive fungal infections
event Odd ???? no event
odd A Odds ratio ???? odd B
Glasmacher et al., JCO 2003 21 4615
Test for heterogeneity (13 trials), ?²10.87,
P0.54 n3597 OR Peto odds ratio Reduction
Relative risk reduction
18
Incidence of proveninvasive yeast infections
Glasmacher et al., JCO 2003 21 4615
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), ?²8.48,
P0.58 n3320 OR Peto odds ratio Reduction
Relative risk reduction
19
Incidence of proveninvasive Aspergillus
infections
Glasmacher et al., JCO 2003 21 4615
Test for heterogeneity (10 trials), ?²9.42,
P0.40 n3320 OR Peto odds ratio Reduction
Relative risk reduction
20
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)

Glasmacher et al., JCO 2003 21 4615
21
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)

Cornely et al., ASH 2005, 1844
IFI invasive fungal infection, IAI invasive
Aspergillus infection OR odds ratio
22
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)

Ullmann et al., ICAAC 2005, M-716
IFI invasive fungal infection, IAI invasive
Aspergillus infection OR odds ratio
23
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

24
Presentation overview

• Risk stratification
• Antifungal prophylaxis
• Empirical antifungal therapy
• Therapy of proven invasive mycoses

25
Which antimycotic drug for empirical therapy?
26
Why do we need empiricalantifungal 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

27
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

28
Efficacy Evaluation in Trials of Empirical
Antimycotic Therapy

• Favorable Overall Response required meeting a
  5-part composite endpoint (Walsh et al.
  1999-2004)

Survival to 7 days posttherapy
Fever resolution for 48 hours during the period
of neutropenia
Successful treatment of baseline IFI
No discontinuation due to lack of efficacy or
study drug toxicity
Prevention of breakthrough IFI up to 7 days
posttherapy
29
Empirical antimycotic therapy Period III IV
Composite Study Endpoint
No differences!
Incidence of invasive fungal infections 3-10
AmB Altern. better
30
Overview of Trialsfor Empirical Antifungal
Prophylaxis
31
Empirical Antimycotic TherapySuccessful Therapy
of Base Line Invasive Fungal Infections
Successful treatment of baseline invasive fungal
infection
32
Empirical Antimycotic TherapyOther Components
of Composite Outcome
33
Caspofungin Overall survival
100
90
80
70
Caspofungin (N556) LipoAmB (N539) Log Rank,
P0.044
60
50
Survival ()
40
30
20
10
0
0
7
14
21
28
35
42
49
56
63
STUDY DAY
NEJM 2004 351 1391
34
Caspofungin Cause of death


13 (2)
22 (4)
NEJM 2004 351 1391
35
Incidence of Nephrotoxicity in Clinical Trials
for Empirical Antifungal Therapy
36
Empirical Antimycotic Therapy (Walsh et al.,
2004)Proportion of Patients with Changes of GFR
Glasmacher, Kartsonis et al., unpublished
observations
37
Incidence of Hepatotoxicity in Clinical Trials
of Empirical Antifungal Therapy
Rate of bilirubin gt 2x baseline
38
Empirical Antimycotic TherapyNephro-
Hepatotoxicity
Nephrotoxicity (gt 2 times base line value) NNT
for CAS versus L-AmB 111
Hepatotoxicity (hyperbilirubinemia)
39
Criteria for choosing drugsfor empirical
antifungal therapy

• Efficacy / EMEA criteria
• Documentation of efficacy in proven infections
• Broad spectrum of activity in relevant organisms
• Clinical trials with adequate endpoints
• Toxicity
• Kidney, liver, CNS
• Cross resistance
• Drug interactions
• Cost

40
Towards a recommendation of drugsfor empirical
antifungal therapy
41
Presentation overview

• Risk stratification
• Antifungal prophylaxis
• Empirical antifungal therapy
• Therapy of proven invasive mycoses

42
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).

43
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
44
Proportion of non-albicans Candida spp. in these
studies
45
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)

Ruhnke et al., ICAAC 2005, M-722c
46
Invasive Aspergillus infections
AG, 2003
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
47
AmbiLOAD-Study Favorable Overall Response
Cornely et al., ASH 2005, 2322
No differences are statistically significant
48
Antifungal Therapy in Neutropenic Patients with
Aspergillus Infections
Definition of neutropenia Neutrophils lt 500 at
start of therapy or in the 2 weeks before
Response rate (95 CI)
Betts et al., Cancer 2006Glasmacher, JAC 2005
Herbrecht et al. 2002
Cornely et al. 2005
Second line
First line
49
Treatment indication according to risk groups for
invasive fungal infections
50
German Case Documentation on Caspofungin(Glasmach
er et al., JAC 2006)
51
Case-Documentation Methods

• Summer 2001 to January 2003 (mostly prelicense)
• Structured, standardized questionnaire (20 pages)
• EORTC/MSG (1999) criteria for diagnosis
• Predefined response criteria
• No selection
• Invitation to all major treatment centers in
  Germany
• Open to all patients who received caspofungin in
  Germany outside of a clinical trial
• No exclusion of received data from safety analysis

52
Response to Caspofungin without Neutrophils

• Patients with proven/probable invasive fungal
  infections who were persistingly neutropenic (lt
  500/µl) at start and at end of caspofungin
  therapy
• Betts et al., Response 6/28 (21)
• Candoni et al., Response 2/13 (15)
• Glasmacher et al., Response 3/10 (30)
• TOTAL Response 11/51 (22 95CI 14-32)
• No data in Herbrecht et al. 2002

53
German Caspofungin Case Documentation
Glasmacher et al., JAC 2006
54
Efficacy of Caspofungin in neutropenic patients
with proven/probable infections
95CI 45-76
95CI 38-61
Pretreated, 1Betts et al. Cancer in press
2Glasmacher et al. JAC in press
55
Summary of EMEA criteria for empirical antifungal
therapy in neutropenic patients
Criteria for the approval of antifungals for
empiric antifungal therapy
A. Glasmacher, 2004