First line therapy for IA ECIL II 2007IDSA 2008BSH 2008 VoriconazoleA I (oral CIII)A I (1°...

First line therapy for IA ECIL II 2007 IDSA 2008 BSH 2008

Voriconazole A I (oral CIII) A I (1° line) Recommended

L-AMB B I A I (1° line for some pts) Recommended

ABLC B II - -

ABCD D I - -

D-AMB D I - Not recommended - A I

Caspofungin C III Alternative Recommended

Micafungin Alternative -

Posaconazole Alternative -

Itraconazole C III Alternative -

Combination D III Not recommended – B II Discouraged – A I

Surgery (selected pts)

C III B III B III

Salvage therapy

ECIL II 2007 IDSA 2008 BSH 2008LF-AMB B III A II No recommendation

The design of these trials is so heterogeneous that it is not possible to make a recommendation on

the basis of their evidence.

ABLC B III

Posaconazole B II B II

Vorico B II

Itraconazole C III B II

Caspofungin B II B II

Micafungin B II

Combination therapy

C II

(Caspo + L-AMB or Caspo + Vori)

B II

Pivotal factors associated with evaluation of outcome in IA

• Reaching the right blood levels with voriconazole

• Disease certainty– Micro-confirmed vs non micro-confirmed

• Underlying condition – Status of underlying disease– Transplant vs non transplant– Type of transplant– Neutropenia

• Outcome definition

Pharmacokinetics of Voriconazole Influence of CYP2C19 genotype

FDA - Briefing document for Voriconazole - Pfizer, October 2001courtesy of Dr. N. Wood, Pfizer Central Research

Pascual A et al. CID 2008; 46:201-Pascual A et al. CID 2008; 46:201-211211

Voriconazole: variability of blood concentrations

Voriconazole trough blood levels and Voriconazole trough blood levels and clinical response to antifungal therapyclinical response to antifungal therapy

Pascual A et al. CID 2008; 46:201-211Pascual A et al. CID 2008; 46:201-211

Voriconazole trough blood levels and safety of Voriconazole trough blood levels and safety of antifungal therapyantifungal therapy

Pascual A et al. CID 2008; 46:201-211Pascual A et al. CID 2008; 46:201-211

Fungal infection: level of certaintyFungal infection: level of certainty

• Proven

• Probable

• Possible

Host factors

One micro

criterion

One major or 2 minor clinical criteria

++ ++

ProbableProbable invasive fungal infectioninvasive fungal infection

Host factors

One micro criterion

Clinical criteria (halo

sign)++ ++

Modified EORTC_MSG criteria used in many Modified EORTC_MSG criteria used in many clinical trialsclinical trials

CID 2007

HR (95% CI) P

Proven IA 2.2 (1.5-3.2) <.0001

CID 2008

Reference category HR (95% CI) P

Degree of certainty of IA diagnosis

Possible vs.Proven or probable 0.5 (0.3-0.9) .010

Drug performance in patients with “true” probable/proven IA

• Denning, vorico phase II– Response overall 54%– Response in proven/probable 38%

• Herbrecht, vorico phase III– Response overall 53%– Response proven/probable 46%

• Ambiload, 3 mg/Kg arm– Response overall 50%– Response proven/probable 39%

• Caspofungin– Only proven/probable (both AL and HSCT) 35%

EXTRAPOLATED FROM AVAILABLE PUBLICATIONSEXTRAPOLATED FROM AVAILABLE PUBLICATIONS

Upton et alCID 2007

Nivoix et al, CID 2008

Difference in proportions (%) and 95% CI

Vori Ampho B 53 32

55 34 43 13

32 13 63 38 50 32

51 32 54 32

45 20 60 37

50 28

Overall (MITT)

Pulmonary onlyExtra pulmonary

Allogeneic HSCTOther hemat. dis.

Other

Non-neutropenic

Definite IA

Neutropenic

Probable IA

Overall (ITT)

-20 0 20 40 60

Week 12 successful response rate (%)Favors voriFavors AmB

Cornely O et al, CID 2007 39

BMT 2009

In our study, a relapsing underlying disease was strongly associated with the risk of developinginvasive aspergillosis and was also associated with therisk of dying from aspergillosis (OR=3.8)

Multicenter, open, phase II study to Multicenter, open, phase II study to estimate the activity and safety of estimate the activity and safety of caspofungin as first-line therapy of caspofungin as first-line therapy of probable and proven invasive probable and proven invasive aspergillosis in:aspergillosis in:

-patients with hematological -patients with hematological malignances or recipients of autologous malignances or recipients of autologous HSCTHSCT

-recipients of allogeneic HSCT-recipients of allogeneic HSCT Viscoli C, Herbrecht R, Akan H, Baila L, Doyen C, Gallamini A, Giagounidis Viscoli C, Herbrecht R, Akan H, Baila L, Doyen C, Gallamini A, Giagounidis A, Marchetti O, Martino R, Meert L, Paesmans M, Shivaprakash M, Ullmann A, Marchetti O, Martino R, Meert L, Paesmans M, Shivaprakash M, Ullmann

AJ and Maertens J for the Infectious Disease Group of the EORTCAJ and Maertens J for the Infectious Disease Group of the EORTC

8

The EORTC studies of caspofungin The EORTC studies of caspofungin in IAin IA

Open label, phase II, non comparative Open label, phase II, non comparative studies in:studies in:

– Hematological patients undergoing Hematological patients undergoing standard chemotherapy or autologous standard chemotherapy or autologous HSCTHSCT

– Hematological patients undergoing Hematological patients undergoing allogeneic HSCTallogeneic HSCT

Main methodological Main methodological characteristicscharacteristics

Only patients with proven/probable IA (i.e. only Only patients with proven/probable IA (i.e. only cases supported or proven by positive microbiology cases supported or proven by positive microbiology or GM antigen detection test).or GM antigen detection test).

Sample size calculation based on results of the only Sample size calculation based on results of the only available study, at that time, although designed available study, at that time, although designed differently, i.e. the voriconazole vs. AmB deaxy differently, i.e. the voriconazole vs. AmB deaxy study (52% for standard chemo, 32% for allaHSCT)study (52% for standard chemo, 32% for allaHSCT)

Very sick patients not excluded a prioriVery sick patients not excluded a priori Evaluation End of Treatment (EOT)Evaluation End of Treatment (EOT) Patients with less than 50% reduction in the sum of Patients with less than 50% reduction in the sum of

the areas at CT scan considered as stable disease the areas at CT scan considered as stable disease (i.e. failure) at EOT(i.e. failure) at EOT

Schema of the studySchema of the study

HM or auto/allo HSCTHM or auto/allo HSCT

Signs, symptoms and/or Signs, symptoms and/or laboratory/radiological data laboratory/radiological data

suggestive of suggestive of probable/proven/possible IAprobable/proven/possible IA

Proven/Proven/probableprobable

PossiblePossible

Registration/start study treatmentRegistration/start study treatment

YesYesContinue Continue study study

treatmenttreatment

End of study treatmentEnd of study treatment(min 14 days – max 84 days)(min 14 days – max 84 days)

SUCCESSSUCCESS FAILUREFAILURE

Shifting to oral drugs Shifting to oral drugs allowed for allowed for

maintenance or maintenance or secondary prophylaxissecondary prophylaxis

Further treatment at Further treatment at the discretion of the the discretion of the

investigatorinvestigator

NoNo

Upgraded to probable/proven IA within 7 days from Upgraded to probable/proven IA within 7 days from registration, based on tests performed prior to or registration, based on tests performed prior to or

within 48 hrs after registrationwithin 48 hrs after registration

Stop study Stop study treatment treatment

(evaluable for (evaluable for safety)safety)

1212

Efficacy Response at EOT by Specific Outcome – MITT Analysis

Hemato(N=61)

Allo-HSCT(N=24)

Complete Response 1 (2%) 0 (0%)

Partial Response 19 (31%) 10 (42%)

Stable Disease 9 (15%) 1 (4%)

Progression of Disease 31 (51%) 11 (46%)

Not Done or Unknown 1 (2%) 2 (8%)

Survival at Day 84 - MITT Analysis

HematoHemato(N=61)(N=61)

Allo-HSCTAllo-HSCT(N=24)(N=24)

AliveAlive 32 (54%)32 (54%) 11 (46%)11 (46%)

DeathDeath

Main Cause of Death (according to DRC)Main Cause of Death (according to DRC)

IAIA

Haemorrhage with IAHaemorrhage with IA

Underlying Disease with AspergillosisUnderlying Disease with Aspergillosis

IA + Concomitant InfectionIA + Concomitant Infection

OtherOther

28 (44%)28 (44%)

1818

22

44

11

33

12 (50%)12 (50%)

55

11

33

00

33

Unknown (Lost to Follow Up)Unknown (Lost to Follow Up) 1 (2%)1 (2%) 1 (4%)1 (4%)

Baseline Characteristics -MITT Analysis

CharacteristicCharacteristic HematoHemato

(N=61)(N=61)

Allo-HSCTAllo-HSCT

(N=24)(N=24)

GenderGender MaleMale FemaleFemale

43 (70%)43 (70%)

18 (30%)18 (30%)

8 (33%)8 (33%)

16 (67%)16 (67%)

AgeAge

Median (range)Median (range) 64 (19-86)64 (19-86) 50 (19-65)50 (19-65) Uncontrolled CancerUncontrolled Cancer

(not in remission)(not in remission)46 (75%)46 (75%) 4 (20%)4 (20%)

Underlying ConditionUnderlying Condition ALLALL AMLAML Chronic leukemiasChronic leukemias Lymphoma Lymphoma

(NHL/HD)(NHL/HD) OtherOther

4 (7%)4 (7%)

34 (56%)34 (56%)

9 (15%)9 (15%)

11 (18%)11 (18%)

3 (5%)3 (5%)

2 (8%)2 (8%)

9 (38%)9 (38%)

4 (17%)4 (17%)

6 (25%)6 (25%)

3 (13%)3 (13%)

Baseline Characteristics - MITT Analysis (cont.)

HematoHemato

(N=61)(N=61)

Allo-HSCTAllo-HSCT

(N=24)(N=24) Diagnosis of IADiagnosis of IA

Proven Proven ProbableProbable Possible at Baseline, Possible at Baseline,

upgraded to Probable upgraded to Probable within 7 dayswithin 7 days

1 (2%)1 (2%)

36 (59%)36 (59%)

24 (39%)24 (39%)

--

11 (46%)11 (46%)

13 (54%)13 (54%)

Site of InfectionSite of Infection Lower Respiratory TractLower Respiratory Tract Sinonasal InfectionSinonasal Infection

60 (98%)60 (98%)1 (2%)1 (2%)

24 (100%)24 (100%)--

Neutropenia (<500/mmNeutropenia (<500/mm33)) at at start of study treatmentstart of study treatment

51 (85%)51 (85%) 12 (50%)12 (50%)

Factor associated with survival at multivariate analysis (57/61 pts)

OR pvalue

Karnofsky score

Underlying disease not in remission

Neutropenia at EOT

1.07

37.52

0.04

0.012

<0.01

<0.01

32

Only hematological patients

Survival at 12 weeks in the caspofungin, voriconazole and liposomal-AmB trials

Vorico D-AmB L-AmB3 L-AmB10 Caspo

Overall

In pts with non progressingCancer

In pts with progressingcancer

71 58 72 59 54

? ? 54 40

? ? 81 93

Numbers are percentages

Difference in proportions (%) and 95% CI

Vori Ampho B 53 32

55 34 43 13

32 13 63 38 50 32

51 32 54 32

45 20 60 37

50 28

Overall (MITT)

Pulmonary onlyExtra pulmonary

Allogeneic HSCTOther hemat. dis.

Other

Non-neutropenic

Definite IA

Neutropenic

Probable IA

Overall (ITT)

-20 0 20 40 60

Week 12 successful response rate (%)Favors voriFavors AmB

Cornely O et al, CID 2007 39

OUTCOMES BY NEUTROPENIA IN HSCT AND ACUTE LEUKEMIA

0

10

20

30

40

50

60

70

RESPONSE EOT SURVIVAL

%

NEUTROPENIA AT ONSET YES

NEUTROPENIA AT ONSET NO

HISTORY OF NEUTROPENIA YES

HISTORY OF NEUTROPENIA NO

All differences are not statistically significant

Caspo study EORTC

CID 2008

Outcome DefinitionsOutcome Definitions (Standard Response Criteria)(Standard Response Criteria)

Complete ResponseComplete Response Resolution of all attributable clinical signs and symptomsResolution of all attributable clinical signs and symptoms No new clinical signs or radiological abnormalities compatible with IA No new clinical signs or radiological abnormalities compatible with IA Disappearance of all radiological lesions attributable to aspergillosis.Disappearance of all radiological lesions attributable to aspergillosis.

Partial ResponsePartial Response Major improvement of fever and attributable clinical signs and Major improvement of fever and attributable clinical signs and

symptomssymptoms No new clinical signs or radiological abnormalities compatible with IANo new clinical signs or radiological abnormalities compatible with IA At least 50% decrease in the sum of the area of the attributable At least 50% decrease in the sum of the area of the attributable

measurable lesions;measurable lesions;

ProgressionProgression Worsening of clinical signs and symptomsWorsening of clinical signs and symptoms New clinical signs or radiological abnormalities compatible with IA New clinical signs or radiological abnormalities compatible with IA Increase in the sum of the area of the attributable measurable Increase in the sum of the area of the attributable measurable

lesionslesions

Stable DiseaseStable Disease Criteria for complete or partial remission or progression are not metCriteria for complete or partial remission or progression are not met

Correlation between EOT response and change in size of the radiological lesions (available in 45/61 pts)

Response Median change in size

(95% CI)

Partial

Stable

Progression

- 73% (60-81)

- 36%

103% (69-421)

29

Only hematological patients

CR/PR(N = 20)

SD(N = 9)

PD(N = 31)Difference in size of the

lesions

N 19 8 30Median (95% CI*) Reduction of

75% (65%-82%)Reduction of

36% Increase of

103% (69% - 421%) Fever

Improvement 55% (11/20) 78% (7/9) 32% (10/31)Stabilization 40% (8/20) 22% (2/9) 61% (19/31)

Deteroriation 5% (1/20) - - 6% (2/31)Galactomannan

Improvement 64% (9/14) 100% (6/6) 42% (11/26)Stabilization 36% (5/14) - - 50% (13/26)

Deteroriation - - - - 8% (2/26)Sputum production


Deteroriation 5% (1/20) - - 10% (3/31)Cough


Deteroriation 10% (2/20) 11% (1/9) 20% (6/30)Dyspnea


Deteroriation 5% (1/20) 22% (2/9) 58% (18/31)Chest Pain


Deteroriation - - - - - -

There was no clinical difference between patients with partial remission and stable disease. The only difference was in the degree of reduction in the size of the lesion

ConclusionConclusion

Voriconazole blood levels should probably be monitored

Results of therapy of IA may vary substantially based upon: Disease certainty Severity of underlying conditions HSCT vs non HSCT (???)

Role of neutropenia not clearA stable disease might be considered as

success in very sick patients

Infections in Infections in compromised patients compromised patients are unique because we are unique because we treat an infection in a treat an infection in a patient with another patient with another disease. The backgroud disease. The backgroud noise of the other noise of the other disease is crucial in disease is crucial in evaluating the results evaluating the results of the antinfective of the antinfective therapy therapy

Thank you for your Thank you for your attentionattention

HR (95% CI) P

Proven IA 2.7 (2.0-3.7) <.0001

Nivoix et al, CID 2008Nivoix et al, CID 2008

Including possible

HR (95% CI) P

Degree of certainty of IA diagnosis

Possible vs Proven or probable 0.5 (0.3-0.8) .001

Nivoix et al, CID 2008Nivoix et al, CID 2008

Upton et al

CID 2007

Response to treatment with Response to treatment with stable disease as failure or stable disease as failure or success with vorico, L.Amb, success with vorico, L.Amb,

caspocaspo(Numbers are percentages)(Numbers are percentages)

• Vorico (NEJM 2002) 52vs58

• L-AmB 3 (CID 2007) 50vs57

• Caspo (TIMM 2007, ICAAC 2008)

35vs47

Just an exercise. I know that different studies cannot be compared

RESPONSE EOT SURVIVALHSCT AL ALL HSCT AL ALL

n (%)

NEUTROPENIA AT ONSETYES 5/12 (42) 15/51 (29) 20/63 (32) 6/12 (50) 27/51 (53) 36/63 (57)NO 5/12 (42) 5/9 (56) 10/21 (48) 5/11 (45) 5/8 (63) 10/19 (53)

HISTORY OF NEUTROPENIAYES 6/13 (46) 11/44 (25) 17/57 (30) 4/12 (33) 23/44 (52) 27/56 (48)NO 4/11 (36) 9/17 (53) 13/28 (46) 7/11 (64) 9/16 (56) 16/27 (59)

Outcomes by neutropenia

P value for response EOT by history of neutropenia= 0.04All other p values are not statistically significant

First line therapy for IA ECIL II 2007IDSA 2008BSH 2008 VoriconazoleA I (oral CIII)A I (1°...

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