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Primary antifungal prophylaxis in patients with hematologic neoplasms

Date of document October 2023
This is the current valid version of the document

1Summary

Immunosuppressed patients are at high risk for invasive fungal infections, especially after intensive chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and after allogeneic stem cell transplantation. Despite advances in the treatment of invasive fungal infections in recent decades, they are still associated with substantial morbidity and mortality. Thus, for certain patient populations and clinical situations, there is a proven benefit of antifungal prophylaxis through clinical trials. More recent data lead to periodic changes in previous recommendations.

The guideline 'Antifungal primary prophylaxis in patients with hematologic neoplasms' was prepared by the Working Group on Infections of the DGHO (AGIHO) for the diagnosis and therapy of these patients [1]. It is based on a systematic literature search, a uniform assessment of the strength of evidence [2] and a consensus-building process. This is the summary of these recommendations.

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6Therapy

6.1Therapy structure

The recommendations for antifungal prophylaxis in relation to the underlying disease and treatment are summarized in Figure 1.

Figure 1: Antifungal prophylaxis in patients with hematologic neoplasms. 

1 alternative antifungal agents with lower strength of evidence see Table 1,
2 acute myeloid leukemia,
3 myelodysplastic syndrome,
4 severe aplastic anemia

6.1.1Prolonged neutropenia (<500 neutrophils/µl for ≥ 7 days) after therapy of hematologic neoplasms

Prolonged neutropenia was defined as <500 neutrophils/µl for ≥7 days. Data and recommendations are summarized in Table 1. Patients after allogeneic stem cell transplantation were excluded [2].

Table 1: Recommendations for primary antifungal prophylaxis in patients with hematologic neoplasms with neutropenia ≥ 7 days.1 

Drug

Recommendation and evidence1 [2]

Posaconazole

A-I2

B-III3

Amphotericin B, liposomal, inhalation

B-II

Amphotericin B, liposomal, iv

C-I

Caspofungin

C-I

Fluconazole

C-I

Itraconazole, p.o. + iv

C-I

SUBA itraconazole

C-IIt,h

Isavuconazole

B-IIt

Micafungin

B-IIu, t

Voriconazole

B-IIu

Amphotericin B, deoxycholate

D-I

:
1 Recommendations are not applicable to patients with ALL.
2 strong recommendation for induction therapy of patients with AML/MDS.
3 vSAA, non-intensive therapy of MDS.
Table 2: Dosages of antifungal primary prophylaxis 

Drug

Dosages

Drug monitoring

(target mirror)

Recommendation and evidence [2]

Amphotericin B liposomal, inhalation

  1. mg 2 times/week

Amphotericin B liposomal, infusion solution

Recommended dose is not defined

Anidulafungin

100 mg q24h i.v. (200 mg on day 1).

Caspofungin, iv

50 mg q24h i.v. (70 mg on day 1, 70 mg also from day 2 if > 80 kg).

Fluconazole, capsules

400 mg q24h p.o.

Isavuconazole, iv

200 mg q24h (on day 1-2 q8h)

Itraconazole, capsules

200 mg q24h p.o.

Itraconazole, oral suspension

  1. - 7.5 mg/kg or 200 mg q24h

Itraconazole, iv

200 mg q24h i.v.

SUBA - Itraconazole

200 mg q24h p.o.

Micafungin, iv

50 mg q24h i.v.

Posaconazole, oral suspension

200 mg q8h p.o.

(2 times/day on day 1)

> 700 ng/ml

B-IIt,u

Posaconazole, tablets

300 mg q24h p.o.

(2 times/day on day 1)

> 500 ng/ml

B-IIt,u

Posaconazole, iv

300 mg q24h i.v.

(2 times/day on day 1)

> 500 ng/ml

B-IIt,u

Voriconazole

4 mg/kg q12h i.v./p.o.

B-IIt,u

Table 3: Recommendations for therapeutic drug monitoring 

Substance

Rationale

Destination

SoR

QoE

Comment

All triazoles:

In the event of a possible breakthrough IFI

description of therapeutic options

variable

A

III

Oral itraconazole

Monitoring for efficacy and toxicity

>0.5 mg/L

B

IIt

Isavuconazole

Monitoring in case of toxicity

2 - 5 mg/L

C

IIt

Higher concentrations are associated with increased toxicity

Posaconazole

Oral suspension

Optimization of efficacy (even in case of reduced absorption)

>0.7 mg/L (prophylaxis)

>1 mg/L (therapy)

B

IIt

Reduced plasma levels in GI-GvHD, diarrhea, PPI simultaneous.

Posaconazole p.o./i.v.

Optimization of efficacy

B

III

Voriconazole

Optimization of efficacy

>1 mg/L

B

IIt

Voriconazole

To avoid toxicity

<4.5 mg/L

A

II

Recommended in case of suspected toxicity

Table 4: Oral tumor therapy for AML/MDS and potential interactions with antifungals. 

Therapy

Intention

Intervention

SoR

QoE

Venetoclax

Prophylaxis of invasive mycoses

Triazoles

A

IIu,t

Reduction of interactions / toxicity

Dose reduction of venetoclax by at least 75% in combination with posaconazole or voriconazole and by 50% in combination with fluconazole or isavuconazole.

A

IIu,t

Gilteritinib

Prophylaxis of invasive mycoses

Triazoles, no dose adjustment necessary

A

IIu

Midostaurin

Prophylaxis of invasive mycoses

Triazoles, no dose adjustment necessary

A

IIu,a

Quizartinib

Prophylaxis of invasive mycoses

Triazoles, no dose adjustment necessary

A

IIu,t

Reduction of interactions / toxicity

Dose reduction of quizartinib (60 to 30 mg or 30 mg to 20 mg) in combination with posaconazole or voriconazole.

B

III

Ivosidenib

Prophylaxis of invasive mycoses

Triazoles, no dose adjustment necessary

A

III

Reduction of interactions / toxicity

Dose reduction ivosidenib to 250 mg/d in combination with posaconazole or voriconazole.

B

III

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9References

  1. Stemler, J, Mellinghoff, SC, Khodamoradi Y et al: Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). J Antimicrob Chemother. 2023 Aug 2;78(8):1813-1826. DOI:10.1093/jac/dkad143

  2. Ullmann AJ, Schmidt-Hieber M, Bertz H et al: Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016. Ann Hematol 95:1435-1455, 2016. DOI:10.1007/s00277-016-2711-1

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15Authors' Affiliations

Dr. med. Christoph Buhl
Klinikum Leverkusen
Medizinische Klinik 3
Am Gesundheitspark 11
51375 Leverkusen
Dr. med. Annika-Yanina Classen
Universitätsklinikum Köln
Klinik I für Innere Medizin
Klinische Infektiologie
Kerpener Str. 62
50937 Köln
Prof. Dr. med. Oliver A. Cornely
Uniklinik Köln, Klinik I für Innere Med.
Zentrum für Klinische Studien
Infektiologie-Hämatologie-Onkologie
Kerpener Str. 62
50937 Köln
Prof. Dr. med. Werner Heinz
Caritas-Krankenhaus Bad Mergentheim
Med. Klinik 2
Uhlandstr. 7
97980 Bad Mergentheim
Ass.-Prof. Dr. med. univ. Martin Hoenigl
University of California
Division of Infetctious Diseases
UCSD
200 W. Arbor Drive #8208
San Diego, CA 92103
Prof. Dr. med. Meinolf Karthaus
MVZ Perlach
Schmidbauerstr. 44
81737 München
Dr. med. Yascha Khodamoradi
Dr. med. Michael Klein
Klinikum Vest, Knappschaftskrankenhaus Recklinghausen
Akademisches Lehrkrankenhaus der
Ruhr-Universität Bochum
Medizinische Klinik III
Dorstener Str. 151
45657 Recklinghausen
PD Dr. med. Philipp Köhler
Universitätsklinikum Köln
Klinik I für Innere Medizin
Kerpener Str. 62
50937 Köln
Prof. Dr. med. Dipl.-Biol. Michael Koldehoff
MVZ ZotzKlimas Düsseldorf
Immermannstr. 65D
40210 Düsseldorf
Univ. Prof. Dr. med. Robert Krause
Klinische Abteilung für Infektiologie
Universitätsklinik für Innere Medizin (UKIM)
Medizinische Universität Graz
Auenbruggerplatz 15
A-8036 Graz
Univ.-Prof. Dr. Cornelia Lass-Flörl
Medizinische Universität Innsbruck
Institut für Hygiene und
Med. Mikrobiologie
Schöpfstr. 41
A-6020 Innsbruck
Dr. med. Blasius Liss
HELIOS Universitätsklinikum Wuppertal
Med. Klinik 1 für Hämatologie,
Onkologie und Palliativmedizin,
Nephrologie, Rheumatologie
Heusnerstr. 40
42283 Wuppertal
Prof. Dr. med. Georg Maschmeyer
Deutsche Gesellschaft für Hämatologie
und Medizinische Onkologie (DGHO)
Onkopedia-Koordinator
Bauhofstr. 12
10117 Berlin
PD Dr. med. Sibylle Mellinghoff
Universitätsklinikum Köln
Klinik I für Innere Medizin
Kerpener Str. 62
50937 Köln
Prof. Dr. med. Olaf Penack
Charité - Universitätsmedizin Berlin
CVK: Campus Virchow-Klinikum
CC 14: Tumormedizin
Augustenburger Platz 1
13353 Berlin
Prof. Dr. med. Markus Ruhnke
Helios Klinikum Aue
Klinik für Hämatologie/Onkologie
und Palliativmedizin
Gartenstr. 6
08280 Aue
PD Dr. med. habil. Enrico Schalk
Universitätsklinikum Magdeburg
Klinik für Hämatologie, Onkologie und Zelltherapie
Leipziger Str. 44
39120 Magdeburg
Prof. Dr. med. Martin Schmidt-Hieber
Medizinische Universität Lausitz - Carl Thiem
2. Med. Klinik
Klinik für Hämatologie und Onkologie
Thiemstr. 111
03048 Cottbus
Rosanne Sprute
Uniklinik Köln
Klinik I für Innere Medizin
Klinische Infektiologie
50931 Köln
Dr. Jannik Stemler
Universitätsklinikum Köln
Klinik I für Innere Medizin
CECAD Institut für Translationale Forschung
Kerpener Str. 62
50937 Köln
PD Dr. med. habil. Daniel Teschner
Universitätsklinikum Würzburg
Medizinische Klinik II
Oberdürrbacher Str. 6
97080 Würzburg
Dr. med. Sonja Zapke
Helios Universitätsklinikum Wuppertal
Medizinische Klinik I
Heusnerstr. 40
42283 Wuppertal

16Disclosure of Potential Conflicts of Interest

according to the rules of the responsible Medical Societies.

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