Updated guidelines on antifungal prophylaxis in adult patients with acute myeloid leukemia

Patients diagnosed with acute myeloid leukemia (AML) and receiving intensive chemotherapy treatment are at high risk of invasive fungal disease. Infection is more common in patients who experience longer durations of neutropenia, and those who are in a relapsed or refractory disease state.¹

While antifungal prophylaxis is strongly recommended during remission induction chemotherapy, optimal management of fungal disease in patients receiving novel targeted treatments is uncertain.¹ Of particular concern is the potential for cytochrome-P450-mediated drug–drug interactions with triazole antifungals and targeted agents. Here, we summarize the expert consensus recommendations from the European Hematology Association for antifungal use in adult patients treated with novel targeted agents, providing an update on current prophylaxis guidance.¹

Azacitidine

Azacitidine is a hypomethylating agent (HMA) that inhibits the action of DNA methyltransferase, preventing DNA methylation and cancer cell division and growth. The reported incidence of invasive fungal disease during treatment is between 2.6% and 14.4%. The incidence per treatment cycle is between 0.42% and 1.22%, and it occurs more often in the first four cycles. Studies have reported increased fungal infections in patients previously treated with intensive chemotherapy, who had subsequently developed neutropenia below 500 cells/µl.

Guidance

• There are no known cytochrome P450 interactions, therefore, drug–drug interactions are not expected, and no additional precautions are required when azacitidine is coadministered with antifungal triazole medications.
• The strength of evidence for antifungal prophylaxis is low and is not generally recommended for adult patients receiving azacitidine monotherapy.
• Antifungal prophylaxis may be considered; however, it should be limited to patients with neutropenia at treatment initiation, or those who have received intensive chemotherapy.

Decitabine

Decitabine is another HMA that inhibits DNA methyltransferase and is used in the treatment of de novo or secondary patients with AML. The incidence of fungal infections during treatment is between 7% and 16.2%. In a retrospective study that identified the highest number of patients with invasive fungal disease, possible or confirmed Aspergillus spp. infection was diagnosed in 13 of 19 patients, and only one of those patients received mold-active antifungal prophylaxis. Two further retrospective studies recorded a mortality rate of 1% and 1.2% due to invasive fungal disease.

Guidance

• Mold-active treatment should be the preferred option.
• There is no reported cytochrome P450 metabolism, and no drug–drug interactions are expected, so no precautions are needed when decitabine is coadministered with triazoles.
• Standard prophylaxis is not recommended but may be considered for patients with neutropenia at treatment initiation, or those who have received intensive chemotherapy.

Venetoclax

Venetoclax is a potent selective inhibitor of the antiapoptotic protein BCL-2 and is used in combination with HMAs for newly diagnosed adult patients with AML who are ineligible for intensive chemotherapy. In the VIALE-A trial (NCT02993523), infections overall were reported in 239 (84%) out of the 283 patients participating in the trial. More information on the VIALE-A trial can be found on the AML Hub here. A further retrospective study recorded a fungal invasiveness rate of 13%, and patients who did not record a hematologic response had a higher risk of infection.

Guidance

• Posaconazole and voriconazole are potent inhibitors of CYP3A4 and may cause increases in venetoclax exposures that require dose reduction.
• The manufacturer and product summary recommend an empirical dose reduction of venetoclax by at least 75%.
• There is currently still a debate on whether to administer 70 mg or 100 mg of venetoclax to gain the bioequivalent exposure of posaconazole-boosted venetoclax, compared to venetoclax alone at full dose without a strong CYP3A4 inhibitor.
• Further dose reduction of venetoclax to 50 mg should be explored due to the combination with a 300 mg posaconazole tablet, which results in a higher exposure compared to venetoclax monotherapy.
• Since the drug–drug interactions are manageable, fungal prophylaxis is recommended, preferably with a triazole, for adult patients treated with venetoclax in combination with a HMA who are at high risk of invasive fungal disease.

Midostaurin

Midostaurin is a FLT3 inhibitor used in the treatment of AML with a FLT3 tyrosine kinase domain/internal tandem duplication mutation in combination with intensive chemotherapy. Previous studies have recorded no invasive fungal infections when treating patients with midostaurin together with isavuconazole. A retrospective study showed that the number of breakthrough invasive mold infections did not differ between patients undergoing intensive induction chemotherapy, with or without midostaurin.

Guidance

• While fungal prophylaxis is generally recommended and posaconazole is the preferred drug, there are some concerns with drug–drug interactions due to the strong inhibition of CYP3A4. This results in an increased midostaurin concentration and potential for toxicity. As a precaution, patients should be monitored closely for any adverse effects.
• Adult patients who are at high risk of fungal infection during treatment should receive antifungal prophylaxis, preferably posaconazole; however, for those at a lower risk it is only a conditional recommendation, based on patient factors such as neutropenia, or history of fungal disease.

Gilteritinib

Gilteritinib is a second generation FLT3 inhibitor that inhibits both the FLT3 tyrosine kinase domain and AML cells with internal tandem duplication mutations. It is used to treat patients with relapsed or refractory AML. A recent study recorded a higher incidence of invasive fungal disease in the gilteritinib group than in the salvage chemotherapy group for relapsed or refractory patients. Coadministration of gilteritinib with azoles causes strong inhibition of CYP3A4 and is therefore a concern for drug–drug interactions and increased toxicity. Pharmacokinetic data shows a 2.2-fold increase in total drug exposure when gilteritinib is administered with a strong CYP3A4 inhibitor. In contrast, a retrospective observational study showed no difference in the number of adverse events or mortality rate in patients treated with gilteritinib together with an azole, compared to gilteritinib alone.

Guidance

• When gilteritinib is administered at 120 mg/day as specified by the manufacturer, no precautions or dose adjustments are required; however, close monitoring is still warranted.
• Prophylaxis with triazoles is considered only in patients at high risk of fungal infection, and the treatment should otherwise be decided on the context of the individual patient.

Ivosidenib

Ivosidenib is an inhibitor of isocitrate dehydrogenase and is used as a monotherapy for the following two groups: adults with relapsed or refractory AML and a susceptible isocitrate dehydrogenase 1 mutation; and newly diagnosed patients, over the age of 75 years, or with comorbidities that exclude intensive chemotherapy. Due to being metabolized in the liver by CYP3A4, both moderate and strong CYP3A4 inhibitors may alter the pharmacokinetics of ivosidenib.

Guidance

• When combined with itraconazole, the total drug exposure of ivosidenib is increased by 169%, and, similarly, with fluconazole the exposure increases by 73%. As a result, the prescribing information recommends a dose reduction of ivosidenib from 500 mg to 250 mg daily when strong CYP3A4 inhibitors are used.
• Patients should be monitored frequently via an electrocardiograph due to the potential of QTc interval prolongation.
• If ivosidenib is given as a monotherapy, there is a conditional recommendation against antifungal prophylaxis.
• If administered as part of a combination therapy, there is a strong recommendation for antifungal prophylaxis.
• Monitoring the QTc interval is recommended if strong CYP3A4 inhibitors are coadministered with ivosidenib at the reduced 250 mg/day dosage.

Conclusion

While the risk of invasive fungal infections is not unusually high for most novel targeted therapies, when used in combination with intensive chemotherapy, or in a relapsed or refractory disease state, the risk notably increases. Treatment with a triazole is generally recommended for patients with AML, with posaconazole being the preferred therapeutic. However, the individual medical history of the patient, including previous chemotherapy, duration of neutropenia, and previous history of fungal disease should always be considered prior to prophylaxis.