Managing Breakthrough Fungal Infections in Acute Myeloid Leukemia

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Yoav Golan, MD, MS, FIDSA, attending physician and associate professor of medicine at Tufts University School of Medicine, Boston, MA, comments on two patient scenarios highlighting treatment approaches and management of breakthrough fungal infections in acute myeloid leukemia (AML).

Let’s highlight some of the principles we discussed on prophylaxis, and particularly antifungal prophylaxis within the context of a patient or two who are typical to my practice as an infectious disease doctor caring for immunocompromised patients with AML.

The first case is a 53-year-old woman who was diagnosed with AML. She has good performance status and no severe underlying comorbidities as well. She is scheduled to begin standard chemotherapy with cytarabine and daunorubicin. She is expected, because of this kind of therapy, to have severe neutropenia as therapy targets her neutrophils, and this neutropenia is expected to be prolonged— for sure longer than seven days. And the question is what strategy to recommend in this patient, particularly for antifungal therapy. When I look at such a patient, I stratify this patient into the high-risk group, not because of her background comorbidities, but because of what I expect as she starts to get chemotherapy; severe prolonged neutropenia. As such, she is going to be at high risk for both fungal as well as bacterial and virus pathogens, and will start anti-infective agents to prevent all of those.

Focusing on antifungal pathogens, being a high-risk patient and relying on currently published literature, I would use posaconazole pills in this patient. I would use a dose of 300 mg a day and start as prophylaxis with chemotherapy that’s going to lead to neutropenia. I will continue posaconazole antifungal prophylaxis around each cycle of chemotherapy until the resolution of neutropenia and a week later. I would then stop antifungal prophylaxis and restart it again with the next cycle of chemotherapy, and I would repeat that for each of the cycles of chemotherapy. As I do that, I’ll make sure that the patient does not suffer any side effects and will monitor liver enzymes as well as other labs to make sure that drug toxicity does not develop in this patient.

The second patient, another one who’s common to our practice, is a patient with AML who undergoes bone marrow transplantation to complete treatment for his disease. Let’s discuss a patient who is a 62 year-old man who has AML and achieved complete remission after two cycles of induction chemotherapy. He has an HLA-matched unrelated donor and is planned to undergo myoablative allogeneic transplantation. And the question again here is, in this patient, what kind of antifungal strategy would be preferred? Again, this patient is considered to be a high-risk patient because he is going to have myoablative therapy which means that he’s going to be neutropenic in a severe way for a very long period of time, typically for a period of time around a month if not even longer, depending on the specific characteristics of the bone marrow transplantation. In addition to being neutropenic for a long period of time, he is going to be at risk for some degree of graft versus host disease (GvHD) and may require therapy with agents that further suppress the immune system, such as steroids as well as cyclosporine and other immunosuppressants.

Because of that, the patient is stratified as high-risk and should benefit from antifungal prophylaxis. Like in a patient with AML that undergoes chemotherapy, my choice in my practice would be a posaconazole pill of 300 mg at one pill given daily. I would start this treatment with the high-dose chemotherapy as a preparation for the bone marrow transplant and would continue that until the patient is no longer neutropenic plus a few more days. If the patient requires steroids or develops graft versus host disease, I may decide to continue antifungal prophylaxis, depending on the manifestation of GvHD, depending on the type of therapies that he’s receiving, and depending on the severity of those conditions.

One of the most common challenges in the care of patients with AML is treating an infection that develops while being on an anti-infective prophylaxis. Some of those anti-infectives are our most active agents and obviously, one could not continue to use an agent on which someone developed an infection. Specifically, when looking at antifungal prophylaxis, I’m often asked what you do with a patient who received posaconazole prophylaxis and develops a breakthrough infection. I should start by saying that I see many more breakthrough infections that are Candida or mold infections in patients who received antifungal prophylaxis other than posaconazole. However, posaconazole is associated with a low risk of invasive breakthrough infections. When that happens, it is really important to try and understand what the reason was for the breakthrough infection. In the past, when we used posaconazole solution, one of the possible reasons had been inadequate serum levels or plasma levels of posaconazole, so that the perception was that the patient is receiving the drug but the levels were not adequate enough to be preventative. This is less of an issue nowadays with the pill form that typically produces levels that are required for effective prevention.

One then has to further ask what could be the fungus, what could be the susceptibility of this particularly fungus, and what should be the better approach.

For some of the patients, we do have a diagnosis, we do have positive cultures, and we can adjust the antifungal therapy based on the cultures. For example, if your patient is growing a Candida from the bloodstream which is likely to be associated with an infected vascular line, and if this Candida is Candida glabrata, which is often resistant to azoles, including posaconazole, then my drug of choice as a replacement to posaconazole will most likely be an echinocandin, including caspofungin, micafungin, or anidulafungin. If we do have another patient with a breakthrough mold infection, [say that] mold is mucormycosis, one of the agents we may consider is amphotericin or lipid preparations of amphotericin. Often, people consider combination therapy in those patients who broke through on antifungal prophylaxis, although I must say that there are no clear data from clinical trials showing the effectiveness of combination therapy beyond the effectiveness of monotherapy in those infections.