Transcript Document

Optimal Antifungal Prophylaxis
The Case for Posaconazole
Oliver A. Cornely, MD, FIDSA
Dep. I for Internal Medicine
Hematology - Oncology
Infectious Diseases – Intensive Care
Center for Clinical Trials
BMBF 01KN0706
University of Cologne
Sources of information
• 2 RCT
• Institutional data
Leukemia Treatment Path
Newly diagnosed = Uncontrolled leukemia
Induce remission by „induction chemotherapy“
Remission achieved ?
No
Yes
Consolidate remission by „consolidation chemotherapy“
Posaconazole
3x 200 mg
Fluconazole
1x 400 mg
or
Itraconazole
2x 200 mg
Number of Induction Chemotherapies
POS
(n = 304)
FLU/ITZ
(n = 298)
1
174 (57)
182 (61)
2
96 (32)
89 (30)
≥3
34 (11)
27 (9)
n (%)
Time to Systemic Antifungal Use
% with systemic antifungal
100
75
50
Kaplan-Meier analysis of the time to empiric systemic antifungal use
within the 100-day phase showed a significant difference in favor of
POS (P = .0235)
25
0
0
20
40
60
80
Time From Randomization
Posaconazole
Other azole
Posaconazole – censored
Other azole – censored
Censoring time is the minimum of the last contact date and day 100
100
Posaconazole Prophylaxis Effectively
Prevented Invasive Fungal Infections
Incidence of IFIs (%)
P =.0009
12%
10%
8%
8%
6%
4%
2%
0%
2%
7
7/304
25
25/298
IFI During Prophylaxis
Posaconazole
FLU/ITZ
Clinical Success and Reasons for Failure
Posaconazole
(n = 304)
Standard
Azoles
(n = 298)
Clinical success
195 (64)
160 (54)
Clinical failure*
109 (36)
P†
95% CI
138 (46)
.009
–18.3% to – 2.6%
7 (2)
25 (8)
<.001
–9.7% to – 2.5%
Use of systemic antifungal for 4
consecutive days for
suspected/probable/proven invasive
fungal infection
68 (22)
101 (34)
.002
–18.7% to – 4.3%
Related adverse event leading to study
drug discontinuation
25 (8)
25 (8)
0.94
—
Use of IV study drug for 4 consecutive
or 10 total days
6 (2)
12 (4)
0.14
—
Withdrawal from study for any reason
and loss to follow-up
8 (3)
1 (<1)
.02
Clinical Response, n (%)
Proven or probable invasive fungal
infection
0% to 4.2%
*Patients might have been classified as experiencing clinical failure for more than 1 reason. Clinical failure
included patients randomly assigned but not treated (posaconazole, 7 [2%]; standard azoles, 6 [2%]).
†Chi-square test.
Overall Mortality – Time to Death
Probability of Survival
1.00
0.75
log rank, P = .035
0.50
0.25
Posaconazole
FLU/ITZ
0.00
0
20
40
60
Days after Randomization
80
100
Censoring time is last contact or day 100.
Numbers Needed to Treat
Primary and Secondary Endpoints in the Neutropenia Trial
All diagnostic procedures applied – IFI still under diagnosed.
Cornely OA, Ullmann AJ. Clin Inf Dis 2008.
Posaconazole
3x 200 mg
Fluconazole
1x 400 mg
Ullmann AJ et al. NEJM 2007.
Incidence of Proven/Probable IFIs
Posaconazole
30
Number of IFIs
25
Fluconazole
P = .074
27
P = .004
22
20
P = .006
P = .001
17
15
21
16
10
5
7
7
3
0
All IFIs
Invasive
Aspergillosis
While on treatment
All IFIs
Invasive
Aspergillosis
Primary time period
112 days after randomization
Ullmann AJ et al. NEJM 2007.
Posaconazole Prophylaxis in Real Life
The Cologne Institutional Experience
2003-2005
No changes in diagnostic and therapeutic strategy
2006-2008
Posaconazole Prophylaxis
→ Two time periods for a historic comparison of AML/MDS
patients undergoing 1st induction chemotherapy
Current Approach to Febrile Neutropenia
Neutropenia >10 Days
Posaconazole Prophylaxis
Fever >72h or Galactomannan positive
Rüping MJGT et al. Drugs. 2008.
Current Approach to Febrile Neutropenia
Neutropenia >10 Days
Posaconazole Prophylaxis
Fever >72h or Galactomannan positive
CT
BAL
Empiric
Treatment
Targeted
Treatment
Rüping MJGT et al. Drugs. 2008.
Characteristics
Age (Years)
Topical polyene
Posaconazole
(N= 82)
(N= 77)
52  14.1
54  13.5
Median
54
55
Range
18 – 76
19 – 75
32 (39.0%)
42 (54.5%)
31.2  12.99
32.8  11.54
Median
28
32
Range
5 – 89
10 – 66
43 (52.4%)
27 (35.1%)
Mean
Female – no. (%)
Neutropenic Days
G-CSF‡ (no. [%])
Mean
*P-test for independent samples (two-sided) †Fisher’s exact test (two-sided)
‡Granulocyte colony stimulating factor
P
NS*
NS†
NS*
0.037†
Endpoints
100
19.5% – 3.9%
= 6.4
Other Clinical Endpoints
Pharmacokinetic Aspects
PK of Posaconazole – AML Induction
Patient Characteristic
*t-test.
†White vs nonwhite.
P Value*
Age
.4637
Sex
.3242
Race
.0028†
Baseline body weight
.1716
Baseline BSA
.1157
GGT
.0184
Liver enzymes
.4077
Mucositis
.6409
Neutropenia
.4575
Diarrhea
<.0001
Vomiting
.5561
H2 receptor antagonist use
.5887
PPI use
.0010
Cornely et al. ICAAC 2006.
Posaconazole Plasma Levels Were
Similar in Patients With and Without IFIs
Krishna G, et al. Pharmacotherapy. 2008;28:1223-1232.
Posaconazole Plasma Concentrations in AML/MDS
Cologne Cohort
Posaconazole Distribution into Pulmonary Components:
Steady State Levels in Healthy Volunteers
Alveolar cells
Pulmonary epithelial
lining fluid
Plasma
MIC90 Aspergillus spp
Posaconazole Concentration,
μg/mL
10000
1000
100
10
1
0.1
0.01
0
2
4
6
8
10
12
14
16
18
20
22
24
Hours Following Last Dose
Conte JE et al. Antimicrob Agents Chemother. 2009;53:703-707.
Posaconazole Concentrations in
Peripheral Blood Compartments
*
PSC concentration
[mg/mL]
100000
10000
***
1000
***
100
10
1
PBMC
PMN
RBC
Plasma
PBMC (n=23), PMN (n=20), RBC (n=22), plasma (n=23); *p=.01, unpaired t-test; ***p<.001
Farowski F et al. TIMM-4, Athens, 2009.
Posaconazole Prophylaxis – Undefined Areas
• Patient groups outside the RCTs
– Remission consolidation chemotherapy
– Neutropenic allogeneic SCT
– Other neutropenic, e.g. aplastic anemia, CLL,
pallative AML or MDS
• Pharmacokinetics
– Is there a cut-off plasma concentration?
– Bridging with IV during periods of e.g. nausea
• Antifungal strategy
– Persistent fever
– Possible breakthrough IFI