antifungal prophylaxis in 2015: target populations and agents 2... · - cost x 3 months (subsequent...

Carlos Vallejo HSCT Program, head

University Hospital of Donostia (San Sebastián)

Porto, 2nd March 2.015

Antifungal prophylaxis in 2015: target populations and agents



Saudações de Donostia/San Sebastián



EMPIRICAL THERAPY

DIAGNOSTIC-DRIVEN THERAPY

TARGETED THERAPY

PROPHYLAXIS

Picture of Roser Capdevila

IFI: total therapy

Rapidly evolving

IFI: PROPHYLAXIS

Why?

Fungi are everywhere

Sy

mp

tom

s a

nd

sig

ns

Immunocompromised

Time

Immunocompetent

Invasive Fungal Infection

Immunocompromised

Immunocompetent

Time Mic

rob

iolo

gic

al

(fu

ngal)

load

IFI: Rapidly evolving disease

Histopathological appearances of early IPA (x 400)

Conidia within pulmonary alveolar macrophages

Hoper WW, et al. The Initial 96 Hours of Invasive Pulmonary Aspergillosis: Histopathology, Comparative Kinetics of

Galactomannan and (133)--D-Glucan, and Consequences of Delayed Antifungal Therapy. Antimicrobial Agents and

Chemotherapy 2010, 54 (11): 4879–86.

IFI: Rapidly evolving disease

Histopathological appearances of early IPA (x 400)

Progressive hyphal invasion into contiguous lung / inflammatory infiltrate

Hoper WW, et al. The Initial 96 Hours of Invasive Pulmonary Aspergillosis: Histopathology, Comparative Kinetics of

Galactomannan and (133)--D-Glucan, and Consequences of Delayed Antifungal Therapy. Antimicrobial Agents and

Chemotherapy 2010, 54 (11): 4879–86.

Rapidly evolving

Impact on survival

IFi: PROPHYLAXIS

Why?

Wald A, et al. The Journal of Infectious Diseases 1997; 175: 1459-66.

Ifi: IMPACT ON SURVIVAL

Even C, et al. Impact of invasive fungal disease on the chemotherapy schedule and event-free

survival in acute leukemia patients who survived fungal disease: a case-control study.

Haematologica 2011, 96 (2): 337-41.


Case-control study


survival in acute leukemia patients who survived fungal disease:

a case-control study. Haematologica 2011, 96 (2): 337-41.

EFS OS


IFD during the course of acute leukemia therapy,

despite initial survival, impacts on the chemotherapy

regimen which have a negative impact on the overall

prognosis (OS and EFS)

To decrease the IFD in AL pts is very important:

- direct mortality of IFD

- Maintain unchanged the chemotherapy regimen

indirect mortality


survival in acute leukemia patients who survived fungal disease:

a case-control study. Haematologica 2011, 96 (2): 337-41.


MDA CC Hospital (1989-2003):

- 1017 autopsies IFI: 31%

- Diagnosed post-mortem: 75%

Chamilos et al. Hematologica 2006; 91: 986-9 (B)


Rapidly evolving

Impact on survival

Impact on costs

IFi: PROPHYLAXIS

Why?

Methods:

- Retrospective / Unicentric

- IFI in Allo- HSCTP or CT for AL

- Compared to matched controls w/o IFI

- Modern costing techniques (micro-costing)

Results:

- 17 pts with IFI (male 75%, age 47y; 14 IC and 5 IA) vs 171 control

- Cost of admission: IFI $ 215,248 vs 29,193

- Cost x 3 months (subsequent admissions): $ 302,563 vs 64,911

Conclusions:

- cost of IFIs in HM pts: $ 237,652 per patient

- Pharmacy costs being major cost driver

Ananda-Rajah MR, et al. Attributable hospital cost and antifungal treatment of IFD in

high-risk hematology pts: an economic modeling approach.

Antimicrob Agents Chemother 2011; 55:1953–60.

Ifi: IMPACT on costs

Rapidly evolving

Impact on survival

Impact on costs

Recommended

( guidelines)

IFi: PROPHYLAXIS

Why?

ECIL-3

IFI: PROPHYLAXIS

Target populations?

IFI: PROPHYLAXIS

• Neutropenia (profound, prolonged)

• Baseline disease (AML, ALL, MDS, AA, MM)

• Lymphopenia (particularly T)

• Monocytopenia

• Advanced-phase disease (diagnosis, refractoriness, relapse)

• Advanced age

• Iron overload

• Persistent hyperglycemia

• Acidosis

• Malnutrition

• Poor general condition

• Renal dysfunction

• Liver dysfunction

• Underlying lung disease

• History of IFI

• History of repeated blood components transfusion

• Certain patient polymorphisms (toll-like receptors,…)

Vallejo C, Ruiz I. Enferm Infecc Microbiol Clin. 2012; 30(9):572-579.

1. The host as a risk factor for IFI

• Treatment phase (induction, re-induction, rescue)

• Steroids (high doses, prolonged)

• Purine analogs (Fludarabine, Cladribine)

• MoAb (Alemtuzumab, infliximab)

• Citarabine (intermediate-high doses)

• Radiotherapy (high doses)


2. The treatment as a risk factor for IFI

• Fludarabine: T cell depletion

Takada K, et al. Rheum Dis 2003 Nov;62(11):1112-5.


• Alemtuzumab: T cell depletion


Parexel, 2002

• Alemtuzumab: infections


Eter T, et al. Annals of Hematology 2009, 88 (2): 121-132.

ALZ

• Umbilical cord blood

• Mismatched

• Acute GVHD (II-IV / III-IV)

• Extensive chronic GVHD

• CD34 selection / T depletion

• CMV serology (patient, donor)

• CMV disease

• Respiratory viruses infection (RSV, influenza, parainfluenza)

• Certain donor polymorphisms (toll-like receptors,…)


3. The transplant as a risk factor for IFI

• Proximity to areas of construction or remodeling

• Staying in rooms without HEPA filters

• Summer (?)

• Geographic differences (?)

• Staying in rooms without laminar flow (???)


4. The enviroment as a risk factor for IFI

Vallejo C, et al. Rev Esp Quimioter 2013;26 (4): 378-86.

IFD: risk patients

IFI RISK IFI RISK

Agents

IFI: PROPHYLAXIS

Fluconazole Candins

Amphotericin B

Posaconazole

Itraconazole

Voriconazole

Non-absorbable antifungal drugs

IFI: PROPHYLAXIS

Agents: news

IFI: PROPHYLAXIS

Fluconazole Candins

Amphotericin B

Posaconazole

Itraconazole

Voriconazole


Prophylaxis of IFI in hematological patients

• Importance of exposure:

– Effectiveness

• Salvage treatment of IA1

1 Walsh TJ, et al. CID 2007, 44:2–12.


• Importance of exposure:

– Effectiveness

• Salvage treatment of IA1

• Prophylactic setting

– Unproved

– Steady-state average concentration (Cavg) in:

» Neutropenic pts with AML/MDS: 582 ng/ml2

» HSCT pts with GVHD: 922 ng/ml3

– Area for improvement

– Toxicity • Unknown*

1 Walsh TJ, et al. CID 2007, 44:2–12. 2 Cornely OA, et al. NEJM 2007, 356:348–359. 3 Ullman AJ, et al. NEJM 2007, 356:335–347.

* No dose-limiting safety events have been identified


• Healthy volunteers1:

– Improved exposure

– Low variability

– Not affected by food

1 Krishna G, et al. AAC 2012, 56:4196–4201.

Mean (SD) posaconazole (100 mg) plasma concentrations

versus time under fed and fasted conditions for tablet

Posaconazole tablets exposure



– Low variability


– Not affected by medications altering gastric pH & motility

1 Kraft WK, et al. AAC 2014, 58(7):4020-5.




– Low variability


– Not affected by medications altering gastric pH & motility

• Pts with AML/MDS undergoing chemotherapy2:

– Desired exposure targets

• Mean steady-state (Cavg ):

– > 500 ng/ml in > 90% pts*

– < 2500 ng/ml in > 90% pts**

– PK results

1 Krishna G, et al. AAC 2012, 56:4196–4201.

2 Duarte RF, et al. AAC 2014, 58(10):5758–65.

* PCZ MIC for 90% isolates (MIC90) for Aspergillus isolated from clinical infections

** No dose-limiting safety events have been identified


• PK results

– Day 2 [just after 2 doses of 300 mg/day]:

• Mean through [ ] (Cmin): > 500 ng/ml

• 90% pts: Cmin > 491 ng/ml

Duarte RF, et al. AAC 2014, 58(10):5758–

65.


• PK results




– Steady state:

• Attained generally between days 6 and 8

• 100% pts reached steady-state Cavg exp >500 ng/ml

• 97% pts: >500 ng/ml / 3% pts: > 2,500 ng/ml (2,680 ng/ml)

• Day 8 mean: 1,460 ng/ml


Duarte RF, et al. AAC 2014, 58(10):5758–65.

• PK results




– Steady state:

• Attained generally between days 6 and 8

• 100% pts reached steady-state Cavg exp >500 ng/ml

• 97% pts: >500 ng/ml / 3% pts: > 2,500 ng/ml (2,680 ng/ml)

• Day 8 mean: 1,460 ng/ml

– Average Tmax: 4 h after daily dosing

– Day 28: trend for increasing mean serum levels



McKeage K. Posaconazole: A Review of the Gastro-Resistant Tablet and Intravenous Solution in IFI.

Drugs 2015 (prepublished on line: DOI 10.1007/s40265-015-0348-3)

Posaconazole tablets for prevention of IFI in high risk patients

Fluconazole Candins

Amphotericin B

Posaconazole

Itraconazole

Voriconazole



Advantages

Oral & intravenous

Biodisponibility

Safety

Clinical experience

Voriconazole for IFI prophylaxis in the hematological patients

Paper

Gergis (BMT 2009) Vori / Fluco / Itra Primary Px Allo-HSCT

Torres (Eur J Haematol 2009) Vori Primary Px Allo-HSCT/AML

Wingard (Blood 2010) Vori vs Fluco Primary Px Allo-HSCT

Marks (Br J Haematol 2011) Vori vs Itra Primary Px Allo-HSCT

Molina (BMT 2011) Vori Primary Px Allo-HSCT

Döring (Eur J Clin Microbiol Infect Dis 2014) Vori / Fluco / Posa Primary Px Allo-HSCT

Takagi (Int J Hematol 2014) Vori Primary Px Allo-HSCT

Mandhaniya (J Pediatr Hematol Oncol 2011) Vori vs AmB Primary Px AML/ALL

Barreto (Am J Haematol 2013) Vori Primary Px AML/MDS

Gomes (AAC 2014) Vori / Posa / EC Primary Px AML


Voriconazole prophylaxis for IFI in pts receiving glucocorticoid therapy for GVHD

Gergis U, et al. BMT 2009; 1-6.


First 100 days with steroids Vori (n=97) Fluco (n=36)/Itra (n=36) p

IFI 2 (2%) 7 (10%) 0.03

IA 0 (0%) 5 (7%) * 0.008

* Resulted in death in all of them

Blood and Marrow Transplant Clinical Trials Network (NCI)

Phase 3, randomized, double blind, multicentric

Cx intensivo, no risk selection

600 pts (305 vori / 295 fluco)

Px until day +100/+180 *

Wingard JR, et al. Blood 2010; 116 (24): 5111-8.

VCZ vs FCZ for primary prophylaxis of IFI in Allo-HSCT pts


6 months Fluconazole Voriconazole p

Empirical Rx 30.2 % 24.1 % Ns

IA 17 9 Ns

IFI 11.2 % 7.3 % Ns

IFI-free SRV 75 % 78 % Ns

Wingard JR, et al. Blood 2010; 116 (24): 5111-8.


VCZ vs FCZ for primary prophylaxis of IFI in Allo-HSCT pts

Marks DI, et al. Br J Haematol 2011; 155(3):318-27.

Prospective, phase 3, multicenter, randomized, open label

(stratified by Cx regimen intensity and donor relatedness)

March’06 to February’09 in 47 transplant centres / 12 countries

Compared efficacy and safety of voriconazole vs itraconazole in

alloHCT recipients

ESTUDIO IMPROVIT Design



ESTUDIO IMPROVIT Design


Flow Chart

465

(N = 224) (N = 241)

(one day)

[* If mucositis or gut GvHD: pts could be given the study drug iv (VCZ: 4 mg/kg/12 h; ITZ: 200 mg/24 h]

Px was scheduled to start on day 0 of HCT

(tablets or oral suspension)

(two days)

(oral solution)

(if risk factors persisted)

Randomization


VOR ITR P

Success of px (day +100) 54.9 % 39.8 % < 0.01

VOR ITR p

Success of px (day +180) 48.7 % 33.2 % < 0.01

VOR ITR

Days of px (median) 97 68

VOR ITR p

Tolerance of px for 100 d 53. 6 % 39.0 % < 0.01

Efficacy


Voriconazol: non-inferiority and superiority

48,7 %

33,2 % 16.4 %

(95 % CI, 7.7-25.1;

p = 0.0002)

Success of antifungal prophylaxis at day +180 (primary endpoint)

Efficacy


VOR ITR

During the study period 1.3 % 2.1 %

Onset (average) D + 118 D + 74

While receiving Rx (or < 7 d post-D/C) * 0 pts 2 pts

* Treatment-emergent IFIs

Development of proven or probable IFI (breakthrough IFI)


VOR ITR

Cases 1 5

Fatal cases 0 1

Documented Aspergillus infection

No cases of zygomycosis reported in either study arm


Survival day +180 VOR ITR

Day + 180 81.9 % 80.9 %

Day + 365 75.5 % 67.0 %

Voriconazol

Itraconazol

Survival

P = ns


VOR ITR p

29.9 % 49.9 % < 0.01

Other systemic antifungals


Most common Rx-related AE VOR ITR P

Vomiting 3.6 % 16.6 % < 0.01

Nausea 7.1 % 15.8 % < 0.01

Diarrohea 4.0 % 10.4 % < 0.01

LFT abnormality 12.9 % 5.0 % < 0.01

Visual impairment 5.4 % 0 % < 0.01

Toxicity


Voriconazole proved to be a

safe and effective option to prevent

IA/IFI after allo-HSCT

ESTUDIO IMPROVIT


Improvit: subanalysis

Bow EJ, et al. 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2012


Improvit subanalysis: Medical Resource Utilization (MRU) for the first 100 days

Gao X, et al. J Med Econ 2013; 16(8):1061-70.


Vori Itra p

Study drug DC: all causes 50% 63% 0.01

Study drug DC: intolerance 7% 22% 0.0001

Study drug: exposure 96 68 0.0001

Use of other antifungals -- 2-times more likely 0.01

Gao X, et al. J Med Econ 2013; 16(8):1061-70.


• Pts who D/C prophylaxis

- 10 more hospital days (p < 0.0001)

- 17 more other antifungal days (p < 0.0001)

• Pts' ability to tolerate/continue AF px

- < MRU (other AF, hospital days)

- Economic impact of the tolerability of AF px

Improvit subanalysis: Medical Resource Utilization (MRU) for the first 100 days

Mandhaniya, S, et al. J Pediatr Hematol Oncol 2011;33(8):e333–e341.

• 100 AML/ALL children receiving induction chemotherapy

• IFI px: oral VCZ vs low dose iv AmB* (randomized)


VCZ AmB p

Px failure 14/50 17/50 0.66

11 EAT

1 mucor

1 possible IFI

1 hepatotoxicity

13 EAT

3 possible IFI

1 difficult venous access

Drug-related SAE 6% 30% < 0.01

Gomes, et al. Antimicrobial Agents & Chemotherapy 2014; 58(2):865-73.

• 152 AML pts receiving remission induction chemotherapy (RIC)

• IFI px: VCZ, PCZ or echinocandin


VCZ / PCZ Echinocandin p

IFI at 42 days * 2.4 8.6 0.03

IFI at 120 days * 1.1 7.1 < 0.0001

* Cases/1,000 px days

Ifi/ia: PROPHYLAXIS

Alarcón C, Martínez C, Fernandez R, González, Palomo P, González A, Jonte F, Rayón C, Vallejo C.

Mould-active antifungal prophylaxis with voriconazole in high-risk allo-HSCT recepients.

BMT 2013; 48 (Suppl 2): P970 (S326).

http://www.google.com.tr/url?sa=i&rct=j&q=london&source=images&cd=&cad=rja&docid=gN5dJODSekRGbM&tbnid=3mex0EPy-mfXIM:&ved=0CAUQjRw&url=http://www.123rf.com/photo_6503920_tower-bridge-london-england-uk-europe-illuminated-at-dusk.html&ei=XtxfUeT3Eq720gXg3IG4Bg&bvm=bv.44770516,d.ZG4&psig=AFQjCNFCo7_rTE6tEEyGgtsTHTGVf8vyoA&ust=1365323218961034

Primary prophylaxis of IFI with Voriconazol

Ifi/ia: PROPHYLAXIS



BMT 2013; 48 (Suppl 2): P970 (S326).

Ifi/ia: PROPHYLAXIS




BMT 2013; 48 (Suppl 2): P970 (S326).

Ifi/ia: PROPHYLAXIS

• Six patients (15.7 %) received additional systemic antifungal

therapy during the study period.

• Conclusions: the use of MAP with oral voriconazole showed

to be a feasible and effective approach for the prevention of IFI

in high risk allo-HSCT recipients.

• Cost of 51 days (median): 3138.55 euros




BMT 2013; 48 (Suppl 2): P970 (S326).

Ifi/ia: PROPHYLAXIS


Vallejo C, et al. (in process)

Ifi/ia: PROPHYLAXIS



Cost of 61 days (median): 4352.35 € (po)

Ifi/ia: PROPHYLAXIS



Prophylaxis with voriconazole:

effective and economically

reasonable approach for allo-HSCT

recipients at high-risk for IFI

antifungal prophylaxis in 2015: target populations and agents 2... · - cost x 3 months (subsequent...

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