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

• Early Appropriate Therapy for Invasive Aspergillosis

Treatment of documented (definite or probable) invasive aspergillosis

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Lessons from the Global Aspergillosis Study

– –

One drug or two (or three) ?

Does cost matter ?

• •

Empirical Therapy Prophylaxis

•

Therapy for Invasive

Polyenes

Aspergillosis

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Lipid Formulations of Amphotericin B

• •

Extended spectrum azoles

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Voriconazole – 1 st line*

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Posaconazole

•

Echinocandins

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Caspofungin, Micafungin, Anidulafungin

IDSA Practice Guidelines for

Aspergillus Update Pending * Steinbach and Stevens. CID 2003; 37(Suppl 3): S157-87.

100 90 80 70 60 50 40 30 20 10 0

Polyene Therapy for Invasive Aspergillosis

Lipid Formulation of AmB DAMB ABLC 42% Hx Control 23% L-AMB 52% DAMB 29% ABCD 18% DAMB 23% Hiemenz Salvage Leenders Includes Suspected IA Bowden Primary Tx Hiemenz JW, et al. Blood 1995;86(suppl 1):849a; Leenders ACAP et al. Br J Haem 1998;103:205; Bowden RA et al. Clin Infect Dis 2002;35:359-66.

Acute Renal Failure and Dose of Amphotericin B

60 40 20 0 <0.5

Bates et al. CID 2000;32:689 0.5-0.9

1.0-1.4

Total AmB Dose (gm) 1.5-1.9

2.0 or More

Clinical Significance of Nephrotoxicity

• •

239 pts receiving AmB; mean duration 20 d

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Cr >2.5 mg/dL: 29%

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Dialysis: Mortality: 14% 60% Risk of dialysis:

– – –

Allo BMT (HR 6.34) Auto BMT (HR 5.06) Cr >2.5 (HR 42.02)



Increased mortality:

• • •

Dialysis (HR 3.05) AmB duration (HR 1.03/d) Nephrotoxic agents (HR 1.96) Wingard et al. CID 1999;29:1402

Voriconazole

N N N F HO Me N F N N N N F HO N N N F Voriconazole F Fluconazole

60 50 40 30 20 10

Global Comparative Aspergillosis Study DRC-Assessed Success at Week 12 (MITT)

Voriconazole +/- OLAT* Amphotericin B +/- OLAT* 76/144 53% 42/133 32% 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 0 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 2002;347:408-15

Global Comparative Aspergillosis Study

1.0

0.8

0.6

0.4

0.2

0.0

0 Hazard ratio = 0.60

95% CI (0.40, 0.89)

Survival

Vori +/- OLAT Ampho B +/- OLAT

• •

Survival at Week 12 Vori ± OLAT 71% AmB ± OLAT 58% 14 28 42 56 Number of days of Therapy 70 Herbrecht R et al. NEJM 2002;347:408-15.

84

•

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

Vori vs Ampho Trial in Invasive Aspergillosis: Success According to Drug After Switch to OLAT

Initial Therapy Voriconazole N = 144 Amphotericin B N = 133 No Switch (improved or died) 51/92 (55.4) 1/26(3.9) Switch - All Regimens 25/52 (48.1) 41/107 (38.3) Lipid Amphotericin B Preparations Itraconazole Decreased Dose Amphotericin B Caspofungin Combination 5/13 (38.5) 11/17 (64.7) 9/20 (45.0) 0 0/2 14/47 (29.8) 18/36 (50.0) 9/14 (64.3) 0/1 0/9 Herbrecht R et al. NEJM 2002;347:408-15; Boucher HW et al ICAAC 2003

What About Lipid Formulations of Amphotericin B (LFAB) for Primary Therapy?

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35% of Amphotericin B patients received LFAB for intolerance or disease progression

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Received a median 13 days LFAB therapy

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Success in 13 of 46 patients (28%) at week 12 Herbrecht R et al. NEJM 2002;347:408-15; Boucher HW et al, ICAAC 2003

Limited Efficacy of Antifungal Therapy for Invasive Aspergillosis in Allogeneic BMT: Need for Better Therapy?

• • •

Allo BMT outcomes at 12 weeks Vori AMB (n=37)(n=30) Response 32% 13% Survival 70% 40%

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AMB: unacceptable response

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Vori: week 12 responses better than AMB (but less than optimal)

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However, improved survival shows benefit of early therapy even in high- risk patients!

1.0

0.8

0.6

0.4

0.2

0.0

0

307 Voriconazole → OLAT 307 Amphotericin B → OLAT 602 Voriconazole → OLAT 602 Amphotericin B → OLAT

14 28 42

Time (days)

56 70 84

Voriconazole in Invasive Aspergillosis: Important Considerations

• • • •

Oral therapy if possible Hepatic dysfunction

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Reduce dose

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Consider increased drug levels Drug interactions

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Monitor immunosuppressive therapy Metabolism

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Increased levels in patients likely to metabolize

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drug poorly May be associated with increased adverse events

•

? Emergence of zygomycetes

H 2 N HO H 2 N HO HO O HO

Echinocandin Antifungal Therapy

O H N N H N N H NH H N O HN H O H N OH O H N O OH CH 3 OH H O OH Caspofungin 2 HOA C MK0991 H 3 C HO H H 3 C O HO HO HO OH O O NH NH N O NH O NH HN N O CH 3 H OH HO O OH OH Anidulafungin Micafungin O NaO S O H 3 C HO O H HO H H 2 N HO O H H H O HO H NH H N O HN OH NH O NH H N H O NH O H CH 3 H OH OH OH O H H N O O(CH 2 ) 4 CH 3 FK463 O HO VER-002 OC 5 H 11

Caspofungin in Salvage Therapy of Invasive Aspergillosis

100 Proven/Probable IA • Well-documented disease 80 60 40 20 47 17 • Efficacy – High-risk patients (72% heme malignancy/SCT) – Progressive infection (86%) 0 Caspofungin (n=83) Historical Controls (n=206) • Minimal toxicity • Clinical questions – Use as primary therapy?

Maertens et al. Clin Infect Dis. 2004; 39: 1563-71.

– Multiple prior antifungals – Role in combinations?

– Optimal dose?

Itraconazole and Posaconazole

N N N CH 3 O O H 3 C N O N N N O N H Cl Cl Itraconazole H 3 C H 3 C O O N N N HO N N N N N O H F F Posaconazole

Open-Label Posaconazole (SCH56592) Salvage Therapy of Invasive Aspergillosis

Posaconazole Historical N = 107 Control N = 86 Underlying Disease: 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); 45 th ASH Abstract 682.

Cost of Voriconazole and Amphotericin B for Primary Therapy of Invasive Aspergillosis • •

Drug acquisition costs determined from the Global Aspergillosis Trial (Herbrecht, 2002)

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“Real-world” drug acquisition costs from our University Hospital Total drug costs (including OLAT): Cost per Patient Cost per Success

•

AmB arm Vori arm $6,210 $5,438 $19,409 $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

Cost of Selected Antifungals University Hospital in Boston Aug 2004

Drug Fluconazole Fluconazole Caspofungin L-AMB L-AMB ABLC Voriconazole Voriconazole Dose 400mg iv 400mg po 50mg iv 3 mg/kg/d (70kg) 5 mg/kg/d (70 kg) 5 mg/kg/d (70 kg) 4 mg/kg Q 12 (70 kg) 200mg po BID Cost/Day $36.32

$1.00

$301.80* $608.80

$1065.40

$427.92

$255.60** $ 51.05

Caspo 70mg load = $262.22; **vori 6mg/kg x 2 load = $370.44

www.doctorfungus.org/thedrugs/cost1.htm

Early Appropriate Treatment Empirical Therapy and Systemic Prophylaxis •

Increased risk of fungal infection with persistent fever and neutropenia

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Candida spp. early (neutropenia > one week)

•

Prophylaxis effective

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Aspergillus spp. later (neutropenia >2-3 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. 1992;326:845; 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.

Efficacy of Empirical Antifungal Therapy in Neutropenic Patients

20 15 10 5 2/16* 5/16 1/18 Other Fungal 0

Abx D/C (n=16) Abx Cont (n=16) Abx + AmB (n=18) *No. Fungal Infections/Total Treated

Pizzo et al. Am J Med 1982;72:101

EORTC Empirical Antifungal Therapy in Febrile Neutropenia

100 80 60 40 20 0 69 % AmB (n=68) 53 % None (n=64)

• •

Overall response



Not different

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Decreased fungal mortality (0 vs 4 pts) Improved responses

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No prophylaxis

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Severely neutropenic

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Clinical infection

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Older patients (>15 yrs)

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Utility in HIGH RISK patients EORTC Am J Med 1989;86:668-72

Efficacy of Empirical L-AmB vs Amphotericin B Deoxycholate in Neutropenic Patients*

L-AmB (343) AmB Deoxycholate (344) Composite Success 50% Breakthrough Infections: 17 (5.0%) 49% 30 (8.7%) Etiological Agents

Aspergillus Candida Fusarium

Zygomycetes Other 12 3 1 1 0 15 12 1 0 2 *Proven or probable breakthrough fungal infection Walsh TJ et al, New Eng J Med, 1999;340:764-71

Efficacy of Empirical Antifungal Therapy in Neutropenic Patients – Study MSG-42

L-AmB (n=422) Vori (n=415) 0 13

Aspergillus

Other

8 4 4 8/415 (1.9%) 5 10 15 20 Fungal Infections (#) 21/422 (5%) Walsh TJ et al, NEJM; 2002;346:225-34 25

• • • •

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%)

Empirical Therapy Study (MSG42) Breakthrough Infections by Risk/Prophylaxis

High Risk Voriconazole L-AMB Moderate Risk Voriconazole L-AMB Total Voriconazole L-AMB Prior Antifungal Prophylaxis n/N (%) 1/83 (1.2) 9/99 (9.1) 1/139 (0.7) 4/151 (2.6) 2/222 (0.9) 13/250 (5.2) No Prophylaxis n/N (%) 1/60 (3.3) 4/42 (9.5) 5/133 (3.8) 4/130 (3.1) 6/193 (3.1) 8/172 (4.7) Total n/N (%) 2/143 (1.4) 13/141 (9.2) 6/272 (2.2) 8/281 (2.8) 8/415 (1.9) 21/422 (5.0)

Empirical Therapy Study (MSG42) Toxicity • • • • •

Vori (415) Severe infusion reactions Nephrotoxicity (Cr >1.5X) Hepatatoxicity (ALT >5X) Visual changes Hallucinations 6.3% 10.4% 7.0% 21.9% 4.3% L-AmB (422) 37.2% 19.0% 8.1% 0.7% 0.5% Walsh TJ, et al. New Engl J Med 2002;346:225-34.

100 80 60 40 20 0

Itraconazole vs. Amphotericin B as Empirical Antifungal Therapy in Febrile Neutropenia

47 % Itra (n=179) 38 % AmB (n=181)

• • • •  

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 > 250ng/ml

–

IV and PO Boogaerts M, et al. Annals of Internal Medicine 2001; 135(6): 412-422

100 80 60 40 20 0

Amphotericin B vs. Liposomal Amphotericin B for Pyrexia of Unknown Origin in Neutropenic Patients

49 % AmB (n=100) 58 % L-AMB 1 (n=117) 64 % L-AMB 3 (n=118)

• • •   

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 Prentice HG, et al. British Journal of Haematology 1997; 98: 711-718

Efficacy of Empirical Caspofungin vs. L-AmB in Neutropenic Patients

Caspo (556) L-AmB (539) Composite Success 33.9% Breakthrough Infections: Etiological Agents

Aspergillus Candida Fusarium

Zygomycetes Trichosporon spp.

Other 29 (5.2%) 10* 16 1 2 1 0 33.7% 24 (4.5%) 9 15 0 0 0 1 Walsh TJ et al, New Eng J Med, 2004;351:1391-1402 * one mixed aspergillosis and C.glabrata infection

Efficacy of Empirical Caspofungin vs. L-AmB in Neutropenic Patients

Caspo (556) L-AmB (539) Composite Success 33.9% Successful tx of Baseline Infections 14/27 (51.9%) Etiological Agents

Aspergillus Candida Fusarium

Zygomycetes

Dipodascus capitatus

Other mould, not id’d 5/12 (41.7) 8/12 (66.7) 0 0/1 0/1 1/1 33.7% n/N (%) 7/27 (25.9%) 1/12 (8.3) 5/12 (41.7) 1/2 0 0 0/1 Walsh TJ et al, New Eng J Med, 2004;351:1391-1402

Empirical Therapy: Historical Breakthrough Fungal Infections

Drug Voriconazole L-AMB Amphotericin B Itraconazole Caspofungin No treatment Caspo vs L-AMB 5 603/ MSG 42 22 (4.1) MSG 32 1 Boogaerts et al 2 EORTC Number (%) of Breakthrough IFIs 8 (1.9) 21 (5.0) 17 (5.0) 3 28 (5.0) 30 (8.7) 5 (2.8) 5 (2.8) 1 (1.5) 6 (9.4) Pizzo et al 4 1 (5.5) 5 (31.3) 1 Walsh et al. N Engl J Med. 1999;340:764-771; 2 Boogaerts et al. Ann Intern Med. 2001;135:412-422; 3 EORTC. Am J Med. 1989;86:668-672; 4 Pizzo et al. Am J Med. 1982;72:101-111; 5 Walsh TJ et al, New Eng J Med, 2004;351:1391-1402

Empirical Therapy What 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

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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/PDF/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

Micafungin vs Fluconazole Prophylaxis/MSG-46 Analysis of Primary Endpoint (MITT)

Number of Patients Success Micafungin 425 340 (80.0%) Fluconazole 457 336 (73.5%) Difference between arms Secondary Endpoint: Empirical Antifungal Use + 6.5% (0.9%, 12%) 64 (15.1%) 98 (21.4%) VanBurik et al, CID 2004; 39: 1407-16

Micafungin vs Fluconazole Prophylaxis/MSG-46 Documented Breakthrough Fungal Infections

Organism and Site Micafungin (N = 425) Fluconazole (N=457)

Aspergillus

1 7 Proven Probable 0 1 4 3

Candida

4 2 1 Fusarium Zygomycetes Total 1 7 (1.6%) 2 0 11 (2.4%)

• Prophylaxis vs Invasive Fungal Infections Ongoing 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 1 transformation/2º AML st relapse, or MDS in

–

Dur tx = period of neutropenia/max 12 wks (84 days)

–

Endpoint = incidence of IFI in both arms from rando to EOT + 7 days

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

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