Newer (ECIL and ESCMID/ECMM) guidelines in the treatment of IFI in leukemic patients ANNA SKIADA, MD

1 ST DEP. OF INTERNAL MEDICINE

UNIVERSITY OF ATHENS, GREECE

Introduction Patients with haematological malignancies have an increased risk for fungal infections

High risk: patients receiving induction chemotherapy for acute myeloid

leukemia patients undergoing haemopoietic stem-cell transplantation Patients with myelodysplastic syndrome in transformation

Most common fungal infections: Candidiasis Aspergillosis Mucormycosis

Guidelines from Europe

The European Conference on Infections in Leukemia (ECIL)

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

The European Confederation of Medical Mycology (ECMM)

2013-Update of the ECIL Guidelines for Antifungal Therapy in Leukemia

and HSCT Patients (ECIL-5)

Raoul Herbrecht, Frederic Tissot, Samir Agrawal, Livio Pagano, Georgios Petrikkos, Claudio Viscoli, Andreas Groll, Anna Skiada, Cornelia Lass-Flörl, Thierry Calandra

ECIL-5 (2013)

Grading scale Strength of Recommendations

Grade ESCMID/ECMM guidelines ECIL-5 guidelines

A ESCMID and ECMM strongly support a recommendation for use

Good evidence to support a recommendation for use

B ESCMID and ECMM moderately support a recommendation for use

Moderate evidence to support a recommendation for use

C ESCMID and ECMM marginally support a recommendation for use

Poor evidence to support a recommendation for use

D ESCMID and ECMM support a recommendation against use

Omitted

Quality of Evidence (ECIL and ESCMID/ECMM)

I Evidence from ≥ 1 properly randomized, controlled trial

II Evidence from ≥ 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytical studies (preferably from >1 center); from multiple time-series; or from dramatic results from uncontrolled experiments

III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Guidelines for antifungal prophylaxis in patients with haematological malignancies (ECIL-5)

Recommended for patients with:

high risk for fungal infection

CML in blastic crisis, ALL receiving the newer chemotherapy treatments, CLL and prolonged neutropenia and aplastic anemia (treating physician)

Posaconazole: sir 200 mg x 3 po, tabl 300 mg x 1 po AI

Itraconazole: sir 2,5 mg/kg x 2 po BI

Voriconazole: 200 mg x 2 po ή 4 mg/kg x 2 iv BII

Liposomal amphotericin B: 3 mg/kg iv CII

Guidelines for antifungal empirical treatment in patients with haematological malignancies (ECIL-3)

Recommended for patients with:

neutropenia which is expected to last for more than 10 days

fever which has not responded to treatment with broad spectrum antibiotics

no identified source of the fever

Liposomal amphotericin B: 3 mg/kg AI Caspofungin: 50 mg/kg AI Voriconazole: 4 mg/kg x 2 iv BI Itraconazole: 200 mg iv BI Micafungin: 100 mg iv BII

If the patient was not receiving any antifungal prophylaxis.

Guidelines for treatment of invasive candidiasis in patients with haematological malignancies (unknown species)

Drug ESCMID/ECMM ECIL-5

Micafungin AII AII

Anidulafungin BII AIII

Caspofungin AII AII

AmBisome AII AII

ABLC, ABCD CII, CIII BII

AmB deoxycholate DII CII

Fluconazole CII CIII

Voriconazole CII BII

Guidelines for treatment of invasive candidiasis in patients with haematological malignancies (ESCMID and ECIL-5)

ESCMID: “..fluconazole should only be considered

as a step- down treatment option in neutropenia when

the Candida species isolates demonstrate

susceptibility to fluconazole”

ECIL-5: Fluconazole is recommended only for

C.parapsilosis

CMI, 2012;8 (Suppl. 7), 53–67

Candidemia: Catheter removal

• Removal of central venous line

– In non-hematological patients A II

– In hematology patients B II

• When catheter cannot be removed, treatment with an echinocandin or a lipid formulation of amphotericin B is preferred B III

ECIL-5 (2013)

Hepatosplenic candidiasis

CMI, 2012;18 (Suppl. 7), 53–67

Guidelines for treatment of invasive aspergillosis : First line (ECIL-5)

Agent Grade Comments

Voriconazole AI 2x6mg/kg D1 then 2x4mg/kg (initiation with oral: CIII)

Ambisome BI Dose 3 mg/kg

ABLC BII Dose 5 mg/kg

Caspofungin CII

Itraconazole CIII

ABCD CI

Combination vori + anidulafungin

CI

Other combinations CIII

AGAINST THE USE

Amphotericin B deoxycholate A I

Guidelines for treatment of invasive aspergillosis : Salvage treatment (ECIL-5)

Agent Grade Comments

Ambisome BII No data in voriconazole failure

ABLC BII No data in voriconazole failure

Caspofungin BII No data in voriconazole failure

Itraconazole CIII Insufficient data

Posaconazole BII No data in voriconazole failure

Voriconazole BII If not used in 1st line

Combination BII Different studies, not randomized

Guidelines for treatment of mucormycosis (ESCMID/ECMM and ECIL-5)

Drug ESCMID/ECMM ECIL-5

Liposomal Ampho AII BII

ABLC AII BII

ABCD CII

AmB deoxycholate DI CII

Posaconazole BII CIII

Combination CIII CIII

Liposomal amphotericin B should be preferred in CNS infection and/or renal failure

First Line treatment

CMI, 2014; 20 (Suppl. 3), 5–26

Recommendation for first line (part 2)

Management includes antifungal therapy, control of underlying conditions and surgery. A II

Control of underlying condition A II 3

Surgery

- rhino-orbito-cerebral A II - soft tissue A II - localized pulmonary lesion B III - disseminated CIII4

Hyperbaric oxygen CIII

3 Control of underlying condition includes control of diabetes, hematopoietic growth factor if neutropenia, discontinuation/tapering of steroids, reduction of immunosuppressive therapy 4 Surgery should be considered on a case by case basis, using a multi-disciplinary approach

ECIL-5 (2013)

Guidelines for treatment of mucormycosis (ESCMID/ECMM and ECIL-5)

Drug ESCMID/ECMM ECIL-5

Posaconazole AII BII

Combination ABLC and caspofungin

CIII BIII

Combination ABLC and posaconazole

BII BIII

AGAINST THE USE Combination with deferasirox AII

Salvage treatment (failure of first line)

Other ESCMID/ECMM guidelines

Question 1 A 43 yo male patient is hospitalized with acute myeloid leukemia. He develops neutropenia after receiving induction chemotherapy. He hasn’t received any antifungal prophylaxis. The patient becomes febrile and a blood culture shows C.albicans. Which of the below should be selected?

1. Fluconazole

2. Voriconazole

3. Caspofungin

4. Liposomal amphotericin B

Question 2 A patient with AML has prolonged neutropenia and fever. He is on prophylaxis with posaconazole. He has been receiving meropenem and vancomycin for 7 days. Galactomannan was sent to the lab. A CT-scan was performed.

Which antifungal would you select? 1. Liposomal amphotericin B 2. Voriconazole 3. Anidulafungin 4. Caspofungin

Molecular diagnosis: Aspergillosis AND mucormycosis!

Thank you!