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An overview of EHA guidelines for the use of antifungal prophylactic agents in acute myeloid leukemia

Aug 9, 2021
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With increasing diversity of advances in the treatment of acute myeloid leukemia (AML), the need for prophylaxis against infection has also evolved. Triazoles currently serve as the cornerstone antifungal agent during remission reduction chemotherapy treatment of AML. However, there is always a possibility of the development of complications due to drug-drug interaction caused by CYP3A4 inhibition.

In 2019, a joint initiative was taken by European Hematology Association (EHA) Scientific Working Group (EHA SWG) Infections, EHA SWG AML, and Cochrane Hematology Group to propose a guideline on antifungal prophylaxis (AFP) for patients with AML treated with novel agents. An updated outline of this guideline was provided by Jannik Stemler in his presentation during the EHA2021 Virtual Congress.1

Methods adapted for guideline preparation

The following methods were used for the guideline preparation:

  • The committee included experts from Europe and Israel.
  • In the selection of novel available AFP agents, consideration was given to the available drugs that are licensed or are under clinical trial investigation as monotherapy or combination treatment.
  • A systematic review of the literature, followed by evidence and consensus-based recommendations (using the GRADE approach), was used to provide the first guidance on AFP in this setting.
  • Strong recommendations were given dependent on the availability of strong clinical data. Where the evidence is limited, weak/conditional recommendations were made.

Recommendations

The use of existing guidelines was recommended when using antifungal prophylactic agents. Where the evidence is limited, consideration should be given to individual patient factors and the clinical setting to decide on the appropriate antifungal agents. The risk of potential toxicity and drug-drug interaction in the specific patient population and whether a strong inhibitor is present should also be considered. A list of selective AFP agents, along with the recommendations by EHA, is given in Table 1.

Table 1. Selective AFP agents and usage recommendations*

Agent

Recommendation

Comments

HMA

W against

Broadly available.
W due to lack of prospective studies against AFP prophylaxis when used as monotherapy.
Small retrospective studies have shown the risk of incidence of fungal infection (2–14%).
Can be used for AFP in high-risk setting (e.g., local incidence, heavily pre-treated patient, prolonged neutropenia)

Venetoclax + HMA

C for

Widely available.
Can be used with HMA after dose optimization.
Venetoclax up to 70 mg is recommended when used with posaconazole.

Gemtuzumab-ozogamicin

Monotherapy: W against
Combination therapy: S for

Mostly used as a combination drug during intensive chemotherapy.
No evidence for potential toxicity due to DDI.

Glasdegib

W against (especially triazoles)

Used in palliative settings.
Strong impact of potential toxicity, specifically QTc prolongation
Up to 50% dose reduction is recommended if strong CYP3A4 inhibitors are used.

Ivosidenib

Monotherapy: W against
Combination therapy: S for

Still under investigation in a clinical trial.
Not licenced in many European countries.
If azole is co-administered, adverse event monitoring is recommended, specifically QTc prolongation.

Midostaurin

Monotherapy: W against
Combination therapy: S for

Frontline agent during intensive chemotherapy.
More evidence needed for dose reduction or therapeutic drug monitoring.

Sorafenib

Monotherapy: W against
Combination therapy: S for

Used for intensive chemotherapy in elderly patients.
Significant deaths due to infection have been reported.
Coadministration with other drugs is recommended.
When used with azoles, QTc prolongation and elevated levels in blood were observed.

Lestaurtinib

C for

Dose reduction from 80 to 40/60 mg is recommended if a strong CYP3A4 inhibitor is administered for AFP.

Crenolanib

W against

If strong CYP3A4 inhibitors are used, weak recommendations are made.
More data are needed.

Gilteritinib

Monotherapy: C for

Monitoring of adverse events is advised if co-administrated with azole.
More data are needed

Idasanutlin

W for

Avoid strong CYP3A4 inhibitors.
If co-administrated, there are strong recommendations for dose adaptation.

Dasatinib

S for

 NA

AFP, antifungal prophylaxis; C, conditional; CYP3A4, cytochrome P450 family 3 subfamily A member 4; DDI, drug-drug interaction; HMA, hypomethylating agent; NA, not available; QTc, corrected QT interval; S, strong; W, weak.
*Adapted from Stemler, et al.1
The QT interval is an electrocardiogram representation of ventricular depolarization and repolarization.

Conclusion

EHA guidelines for the use of antifungal prophylactic agents suggest that selection of an agent should be based on finding the right balance between the risk of fungal infection, toxicity, and drug-drug interaction. For many of the antifungal agents listed, the evidence is scarce and only weak recommendations can be made. Nevertheless, this represents the first guidance on AFP management in the context of patients with AML receiving novel agents, which could assist healthcare professionals and oncologists in their treatment decisions.

  1. Stemler J, Skoetz N, de Jonge N, et al. Antifungal prophylaxis in acute myeloid leukemia treated with novel agents. Oral abstract #S281. European Hematology Association 2021 Virtual Congress; Jun 11; Virtual.

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