The Importance of Early Appropriate Therapy of Invasive Aspergillosis

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The Importance of Early Appropriate Therapy of
Invasive Aspergillosis

• Helen Whamond Boucher, MD
• Division of Infectious Diseases
• Tufts University-New England Medical Center
• Boston, Massachusetts

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Early Appropriate Therapy for Invasive
Aspergillosis

• Treatment of documented (definite or probable)
  invasive aspergillosis
• Lessons from the Global Aspergillosis Study
• One drug or two (or three) ?
• Does cost matter ?
• Empirical Therapy
• Prophylaxis

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Therapy for Invasive Aspergillosis

• Polyenes
• Lipid Formulations of Amphotericin B
• Extended spectrum azoles
• Voriconazole 1st line
• Posaconazole
• Echinocandins
• Caspofungin, Micafungin, Anidulafungin
• IDSA Practice Guidelines for
• Aspergillus Update Pending

Steinbach and Stevens. CID 2003 37(Suppl 3)
S157-87.
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Polyene Therapy for Invasive Aspergillosis
L-AMB 52
ABLC 42
Response
DAMB 29
Hx Control 23
DAMB 23
ABCD 18
Hiemenz JW, et al. Blood 199586(suppl 1)849a
Leenders ACAP et al. Br J Haem 1998103205
Bowden RA et al. Clin Infect Dis 200235359-66.
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Acute Renal Failure and Dose of Amphotericin B
Bates et al. CID 200032689
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Clinical Significance of Nephrotoxicity

• 239 pts receiving AmB mean duration 20 d
• Cr gt2.5 mg/dL 29
• Dialysis 14
• Mortality 60
• Risk of dialysis
• Allo BMT (HR 6.34)
• Auto BMT (HR 5.06)
• Cr gt2.5 (HR 42.02)

• Increased mortality
• Dialysis (HR 3.05)
• AmB duration (HR 1.03/d)
• Nephrotoxic agents (HR 1.96)

Wingard et al. CID 1999291402
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Voriconazole
Fluconazole
Voriconazole
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Global Comparative Aspergillosis
StudyDRC-Assessed Success at Week 12 (MITT)

• Satisfactory (CR/PR) responses at week 12
• Difference 21.2
• (95 CI 9.9, 32.6)
• Responses at end of initial randomized therapy
• Vori 54
• AmB 22
• Median duration of IRT
• Vori 77 days
• AmB 11 days

76/144
53
42/133
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Difference (raw) 21.2, 95 CI (9.9,
32.6) Difference (adjusted) 21.8, 95 CI
(10.5, 33.0)
OLAT Other licensed antifungal therapy
Herbrecht R et al NEJM 2002347408-15
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Global Comparative Aspergillosis StudySurvival

• Survival at Week 12
• Vori OLAT 71
• AmB OLAT 58
• Discontinuations due to AE/lab abnormality
• Vori 20 / AmB 56
• Poor efficacy of AmB prior gold standard
• Vori recommended for primary therapy
• Questions?
• Role of OLAT
• Lipid for primary therapy
• Efficacy in high risk (HSCT)
• Combinations

Probability of Survival
Hazard ratio 0.60 95 CI (0.40, 0.89)
Number of days of Therapy
Herbrecht R et al. NEJM 2002347408-15.
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Vori vs Ampho Trial in Invasive Aspergillosis
Success According to Drug After Switch to OLAT
Herbrecht R et al. NEJM 2002347408-15 Boucher
HW et al ICAAC 2003
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What About Lipid Formulations of Amphotericin B
(LFAB) for Primary Therapy?

• 35 of Amphotericin B patients received LFAB for
  intolerance or disease progression
• Received a median 13 days LFAB therapy
• Success in 13 of 46 patients (28) at week 12

Herbrecht R et al. NEJM 2002347408-15 Boucher
HW et al, ICAAC 2003
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Limited Efficacy of Antifungal Therapy for
Invasive Aspergillosis in Allogeneic BMT Need
for Better Therapy?

• Allo BMT outcomes at 12 weeks
• Vori AMB
• (n37)(n30)
• Response 32 13
• Survival 70 40
• AMB unacceptable response
• Vori week 12 responses better than AMB (but
  less than optimal)
• However, improved survival shows benefit of early
  therapy even in high- risk patients!

1.0
0.8
0.6
Probability of Survival
0.4
307 Voriconazole ? OLAT
307 Amphotericin B ? OLAT
0.2
602 Voriconazole ? OLAT
602 Amphotericin B ? OLAT
0.0
0
14
28
42
56
70
84
Time (days)
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Voriconazole in Invasive Aspergillosis
Important Considerations

• Oral therapy if possible
• Hepatic dysfunction
• Reduce dose
• Consider increased drug levels
• Drug interactions
• Monitor immunosuppressive therapy
• Metabolism
• Increased levels in patients likely to metabolize
  drug poorly
• May be associated with increased adverse events
• ? Emergence of zygomycetes

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Echinocandin Antifungal Therapy
H
H2N
N
OH
HO
OH
O
O
O
HO
O
HO
OC5H11
H
N
NH
N
H3C
NH
N
H2N
H
O
N
N
HN
OH
O
O
CH3
HN
O
HO
H
H
H
H
O
CH3
NH
HO
O
NH
OH
H
N
H3C
H
O
N
2 HOAC
O
N
NH
HO
HO
OH
H
O
O
OH
OH
OH
Anidulafungin
VER-002
Caspofungin
MK0991
HO
HO
Micafungin
OH
HO
O
O
H
H
O
H
HO
N
O(CH2)4CH3
NH
H3C
NH
H
O
N
CH3
HO
O
HN
O
H
H
O
NH
OH
H
H
O
H2N
N
HO
NH
H
OH
O
H
H
H
H
OH
O
O
NaO
S
FK463
O
HO
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Caspofungin in Salvage Therapy ofInvasive
Aspergillosis

• Well-documented disease
• Efficacy
• High-risk patients (72 heme malignancy/SCT)
• Progressive infection (86)
• Multiple prior antifungals
• Minimal toxicity
• Clinical questions
• Use as primary therapy?
• Role in combinations?
• Optimal dose?

Proven/Probable IA
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CR/PR,
17
Maertens et al. Clin Infect Dis. 2004 39
1563-71.
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Itraconazole and Posaconazole
N
N
N
CH3
O
O
H3C
N
O
N
O
N
N
N
Cl
H
Cl
Itraconazole
N
N
H3C
N
O
O
H3C
N
N
N
N
O
N
HO
F
F
H
Posaconazole
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Open-Label Posaconazole (SCH56592)Salvage
Therapy of Invasive Aspergillosis
Posaconazole N 107 Historical Control N 86
Underlying Disease n () n ()
Heme Malignancy 79 (74) 70 (81)
HSCT 55 (51) 38 (44)
Results
Overall success Data Review Committee 45 (42) 22 (26)
Walsh et al. Blood 2003 102(11) 45th ASH
Abstract 682.
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Cost of Voriconazole and Amphotericin B for
Primary Therapy of Invasive Aspergillosis

• Drug acquisition costs determined from the Global
  Aspergillosis Trial (Herbrecht, 2002)
• Real-world drug acquisition costs from our
  University Hospital
• Total drug costs (including OLAT)
• Cost per Patient Cost per Success
• AmB arm 6,210 19,409
• Vori arm 5,438 10,262
• Primary therapy with voriconazole was 722 less
  per patient than initial AmB

Lewis JS, Boucher HW, Luboski TJ, et al.
Pharmacotherapy 2005 25(6) 839-46
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Cost of Selected AntifungalsUniversity Hospital
in Boston Aug 2004
Drug Dose Cost/Day
Fluconazole 400mg iv 36.32
Fluconazole 400mg po 1.00
Caspofungin 50mg iv 301.80
L-AMB 3 mg/kg/d (70kg) 608.80
L-AMB 5 mg/kg/d (70 kg) 1065.40
ABLC 5 mg/kg/d (70 kg) 427.92
Voriconazole 4 mg/kg Q 12 (70 kg) 255.60
Voriconazole 200mg po BID 51.05
Caspo 70mg load 262.22 vori 6mg/kg x 2 load
370.44 www.doctorfungus.org/thedrugs/cost1.htm

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Early Appropriate Treatment Empirical Therapy
and Systemic Prophylaxis

• Increased risk of fungal infection with
  persistent fever and neutropenia
• Candida spp. early (neutropenia gt one week)
• Prophylaxis effective
• Aspergillus spp. later (neutropenia gt2-3 weeks)
• Prophylaxis under study

• Winston et al, Ann Int Med 99 131(10) 729-37,
  Hadley et al, MSG 44, IDSA 2003
• Winston et al, Transplantation 2002 74(5)
  688-95 Goodman. N Engl J Med. 1992326845
  Winston et al. Annals of Internal Medicine 2003
  138(9) 705-13. Marr et al, Blood 2004 103(4)
  1527-33 VanBurik et al, CID 2004 39 1407-16.

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Efficacy of Empirical Antifungal Therapy in
Neutropenic Patients
2/16
5/16
1/18
No. Fungal Infections/Total Treated
Pizzo et al. Am J Med 198272101
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EORTC Empirical Antifungal Therapy in Febrile
Neutropenia

• Overall response
• Not different
• Decreased fungal mortality (0 vs 4 pts)
• Improved responses
• No prophylaxis
• Severely neutropenic
• Clinical infection
• Older patients (gt15 yrs)
• Utility in HIGH RISK patients

EORTC Am J Med 198986668-72
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Efficacy of Empirical L-AmB vs Amphotericin B
Deoxycholate in Neutropenic Patients

• L-AmB (343) AmB Deoxycholate (344)
• Composite Success 50 49
• Breakthrough Infections 17 (5.0) 30 (8.7)
• Etiological Agents
• Aspergillus 12 15
• Candida 3 12
• Fusarium 1 1
• Zygomycetes 1 0
• Other 0 2

Proven or probable breakthrough fungal infection
Walsh TJ et al, New Eng J Med, 1999340764-71
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Efficacy of Empirical Antifungal Therapy in
Neutropenic Patients Study MSG-42

• Vori vs L-AmB
• Composite success 26 vs 31
• High risk pts 18 Allo BMT
• Similar survival, fever resolution, toxicity/lack
  of efficacy
• Fewer breakthrough infections
• Efficacy in high risk
• Breakthrough infections 2/143 (2) vs 13/143 (9)

21/422 (5)
13
8
8/415 (1.9)
4
4
Walsh TJ et al, NEJM 2002346225-34
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Empirical Therapy Study (MSG42) Breakthrough
Infections by Risk/Prophylaxis
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Empirical Therapy Study (MSG42) Toxicity

• Vori (415) L-AmB (422)
• Severe infusion reactions 6.3 37.2
• Nephrotoxicity (Cr gt1.5X) 10.4 19.0
• Hepatatoxicity (ALT gt5X) 7.0 8.1
• Visual changes 21.9 0.7
• Hallucinations 4.3 0.5

Walsh TJ, et al. New Engl J Med 2002346225-34.
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Itraconazole vs. Amphotericin B asEmpirical
Antifungal Therapy in Febrile Neutropenia

• Overall response
• Not different
• Few BT IFIs (5, 2.8 each arm)
• Success defervescence/RFN
• Failure
• BT IFI
• Death
• No defervescence by day 28
• Additional antifungal tx
• Discont. due to intolerance
• No BMT patients included
• Mean daily AmB dose 0.7 mg/kg
• Itra levels gt 250ng/ml
• IV and PO

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Boogaerts M, et al. Annals of Internal Medicine
2001 135(6) 412-422
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Amphotericin B vs. Liposomal Amphotericin B
forPyrexia of Unknown Origin in Neutropenic
Patients

• Safety study
• Children and adults (adults allowed to switch to
  L-AmB for toxicity)
• Overall response
• L-AMB safer than AmB
• L-AMB as effective as AmB
• L-AMB 3mg/kg/d more effective than AmB (ITT and
  PP)
• Success defervescence x 3d/RFN
• Failure
• IFI
• No defervescence
• Additional antifungal tx
• Mean daily AmB dose 0.76 mg/kg

64
58
49
Prentice HG, et al. British Journal of
Haematology 1997 98 711-718
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Efficacy of Empirical Caspofungin vs. L-AmB in
Neutropenic Patients

• Caspo (556) L-AmB (539)
• Composite Success 33.9 33.7
• Breakthrough Infections 29 (5.2) 24 (4.5)
• Etiological Agents
• Aspergillus 10 9
• Candida 16 15
• Fusarium 1 0
• Zygomycetes 2 0
• Trichosporon spp. 1 0
• Other 0 1

Walsh TJ et al, New Eng J Med, 20043511391-1402
one mixed aspergillosis and C.glabrata infection
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Efficacy of Empirical Caspofungin vs. L-AmB in
Neutropenic Patients

• Caspo (556) L-AmB (539)
• Composite Success 33.9 33.7
• Successful tx of Baseline Infections n/N ()
  
• 14/27 (51.9) 7/27 (25.9)
• Etiological Agents
• Aspergillus 5/12 (41.7) 1/12
  (8.3)
• Candida 8/12 (66.7) 5/12
  (41.7)
• Fusarium 0 1/2
• Zygomycetes 0/1 0
• Dipodascus capitatus 0/1 0
• Other mould, not idd 1/1 0/1

Walsh TJ et al, New Eng J Med, 20043511391-1402
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Empirical Therapy Historical Breakthrough
Fungal Infections
Caspo vs L-AMB5 603/MSG 42 MSG 321 Boogaerts et al2 Boogaerts et al2 Boogaerts et al2 EORTC3 EORTC3 Pizzo et al4
Drug Number () of Breakthrough IFIs Number () of Breakthrough IFIs Number () of Breakthrough IFIs Number () of Breakthrough IFIs Number () of Breakthrough IFIs Number () of Breakthrough IFIs Number () of Breakthrough IFIs Number () of Breakthrough IFIs Number () of Breakthrough IFIs
Voriconazole 8 (1.9)
L-AMB 22 (4.1) 21 (5.0) 17 (5.0) 17 (5.0)
Amphotericin B 30 (8.7) 30 (8.7) 5 (2.8) 1 (1.5) 1 (1.5) 1 (5.5) 1 (5.5)
Itraconazole 5 (2.8)
Caspofungin 28 (5.0)
No treatment 6 (9.4) 6 (9.4) 5 (31.3) 5 (31.3)
1Walsh et al. N Engl J Med. 1999340764-771
2Boogaerts et al. Ann Intern Med.
2001135412-422 3EORTC. Am J Med.
198986668-672 4Pizzo et al. Am J Med.
198272101-111 5Walsh TJ et al, New Eng J Med,
20043511391-1402
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Empirical TherapyWhat is Best in 2005?

• Options for persistent fever and neutropenia
  following 3-5 days Abx therapy and aggressive
  work-up - consider
• Infectious Diseases/Medical Microbiology
  Consultation
• CT Scan of Chest
• G-CSF/GM-CSF
• BAL
• Goal early diagnosis and identify patients at
  high risk of mould infection
• Add mould-active antifungal
• Lipid Formulation of AmB 5mg/kg/day iv
• Voriconazole 3mg/kg q 12 h iv or po (preferred)
  if no prior azole prophylaxis
• Caspofungin for
• Documented intolerance of Lipid Formulation
• Prior voriconazole prophylaxis
• Consider no empirical therapy for patients with
  negative work-up?

National Comprehensive Cancer Network 2004
http//www.nccn.org/prosessionals/physician_gls/P
DF/fever.pdf Hughes WT, et al. CID 2002 34
730-51 MMWR 2000 Vol 49, No. RR-10. Available
from www.CDC.gov Wingard, ICAAC 2004
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Micafungin vs Fluconazole Prophylaxis/MSG-46Analy
sis of Primary Endpoint (MITT)
VanBurik et al, CID 2004 39 1407-16
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Micafungin vs Fluconazole Prophylaxis/MSG-46Docum
ented Breakthrough Fungal Infections
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Prophylaxis vs Invasive Fungal InfectionsOngoing
Studies

• NHLBI Study of Voriconazole vs. Fluconazole for
  prophylaxis of IFI in BMT
• Prophylaxis day 0-180
• Addition of LFAB for empirical therapy
• Prospective use of galactomannan as guide to
  intervention
• Posaconazole (200mg TID) vs. Itra (susp 200 BID)
  or Flu (susp 400 qd) in High Risk Neutropenic
  Patients
• High risk New AML, AML in 1st relapse, or MDS
  in transformation/2º AML
• Dur tx period of neutropenia/max 12 wks (84
  days)
• Endpoint incidence of IFI in both arms from
  rando to EOT 7 days

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Early Appropriate Therapy for Invasive
Aspergillosis

• Therapy of documented infection
• Poor responses
• Role of new azoles
• Primary therapy of aspergillosis voriconazole
• Improved responses with early initiation of
  therapy
• Combination therapy
• Randomized trial needed for primary therapy
• Empirical therapy
• Voriconazole reduction of breakthrough
  infections (including Aspergillus) in high-risk
  patients
• Caspofungin
• LFAB
• Prophylaxis
• Epidemiologic assessment of risk
• Patients at increased risk of Aspergillus/moulds
• Changing etiological agents, timing of infections

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Early Appropriate Therapy for Invasive
Aspergillosis

• Future directions
• Strategies that focus on patients at highest risk
• Prophylaxis vs. Candida in short duration
  neutropenia
• Prophylaxis vs. Aspergillus and other moulds in
  longer duration neutropenia (higher risk)
• Focus on early, prompt diagnosis
• Galactomannan, PCR, other noninvasive diagnostics
• Early imaging with CT, bronchoscopy
• Pre-emptive vs. empirical therapy