乌鸦传媒

Better management of infectious complications in acute myeloid leukemia (AML) has improved care over the past 50 years. But despite advances in antimicrobial therapies and prophylaxis, AML patients with disease- and treatment-related immunosuppression remain at risk for life-threatening infection with resistant organisms, antimicrobial-related adverse events, and higher treatment costs.

Prophylactic targeting of potentially life-threatening viral, bacterial, and fungal pathogens is therefore a significant aspect of preventing infection in AML patients -- especially since some of the potent new targeted agents such as the BCL2 inhibitor venetoclax (Venclexta), alone or in combination with other cytotoxics, can exacerbate myelosuppression.

There is no one-size-fits-all approach to prophylaxis, however, according to Matthew McCarthy, MD, and Thomas Walsh, MD, both of Weill Cornell Medical Center in New York City, writing in a of prophylaxis during AML induction therapy. "Every patient undergoing induction therapy should be evaluated individually and within the context of local microbiologic epidemiology and host risk factors," the authors said.

乌鸦传媒 spoke with AML specialists on the front lines at two southwestern cancer centers, who confirmed the need for a customized approach in the evolving landscape of infection mitigation in AML.

Leukemia patients in general, whether newly diagnosed or relapsed, already have bone marrow failure and abnormal white blood cell counts, so even before myelosuppressive treatment they have neutropenia with reduced numbers of neutrophils, the first line of defense against pathogens, noted Tapan Kadia, MD, of MD Anderson Cancer Center in Houston.

Febrile neutropenia occurs in of acute leukemia patients undergoing chemotherapy, and their weak immune status increases both the frequency and severity of infections, he explained. "In addition to being susceptible to all the same infections as healthy people, [these patients are] also vulnerable to opportunistic infections."

Intensive cytotoxic induction therapy sometimes causes protracted neutropenia, generally defined as an absolute neutrophil count of fewer than 1,500 cells/µL (life-threatening profound neutropenia starts at counts below 100 cells/µL).

Three-pronged prophylaxis against infections -- antibacterial, antiviral, and antifungal -- is therefore the norm for all AML patients undergoing treatment at MD Anderson, said Kadia. "Of the three, the biggest bugaboo is fungal infection. It's not the most common but it's the most virulent and most difficult to eradicate."

Antibacterials

He noted that MD Anderson has pioneered the routine administration of oral broad-spectrum antibiotics, usually fluoroquinolones such as levofloxacin or ciprofloxacin in this patient group. Another option is moxifloxacin.

"If a patient is allergic to or intolerant of fluoroquinolones, we switch to other broad-spectrum agents such as cephalosporins -- particularly the fourth-generation agent cefpodoxime," Kadia said.

Added Gustavo Rivero, MD, of Baylor College of Medicine in Houston: "When neutropenia is severe, the patient might develop fever with or without bloodstream infection, usually from translocation of bacteria from the GI tract, so then delivery is switched from oral to intravenous."

Key Considerations

In assessing the risk of infection, a very comprehensive approach to prioritizing the safety of the patient is required, Rivero emphasized. "Its very important to consider the age of the patient and what type of treatment the person is going to receive -- intense or non-intense, initial induction, re-induction after relapse, or preparation for stem cell transplantation, and also whether they've had steroids and what chemotherapy agents will be used."

Top of mind, Kadia said, should be a patient's comorbidities, and the effect of various drugs: "In addition to allergies, if an older person has heart disease, the fluoroquinolones can lead to prolonged QT interval on EKG and cardiac arrhythmias."

And in younger people, levofloxacin and ciprofloxacin can cause tendinopathies such as tendinitis and even ruptures, which may result in chronic pain and movement restriction, Kadia explained. "So we turn to alternatives like cephalosporins and penicillins."

Rivero added that some of the cytotoxic drugs can also prolong QT interval. "So by prophylacting with levofloxacin and ciprofloxacin you get an added layer of QT prolongation," he said.

Antivirals

The most commonly used antiviral in AML patients is valacyclovir, which targets viruses in the herpes family causing mouth sores (herpes simplex virus 1) and chicken pox/shingles (varicella zoster virus).

"There's also a new arrival called letermovir [Prevymis] for use against cytomegalovirus [CMV]," Kadia noted. "We don't see CMV upfront frequently but in patients who are stem-cell transplanted or have multiple relapsed disease, we can see reactivation of CMV."

Antifungals

Use of antifungals is increasingly becoming more the standard of care, with treatment moving away from lower-cost and lower-toxicity first-generation azoles such as fluconazole, Kadia continued. "Formerly, some people with neutropenia used to die from hepatosplenic candidiasis, and invasive Aspergillus was another killer, but now we protect against these with newer mold-active triazole antifungals such as voriconazole and, preferably, posaconazole."

Posaconazole, the preferred agent for primary fungal prophylaxis, is active against Candida and Aspergillus as well as other invasive molds including Fusarium and Mucorales. A newer extended-release formulation has

Also on the market is the new antifungal isavuconazonium (Cresemba), used to treat adults with invasive aspergillosis and mucormycosis. "While not the optimal choice, this drug does have activity and has fewer drug interactions than the triazoles," Kadia said.

In terms of comorbidities, patients with liver dysfunction should avoid the triazoles as these are metabolized in the liver. Newer agents such as the echinocandin micafungin for example, can be substituted for other antimycotics. "But drugs in this class are bulky and have to be given IV," Kadia cautioned.

In general, antifungal agents are given orally, "but occasionally we may switch to IV prophylaxis for echinocandins if a patient cannot tolerate or afford the oral formulation," he said.

Rivero recommends a baseline CT lung scan as part of the approach to prophylaxis. "If a patient develops fever after treatment, we can retest to see if any new pulmonary nodules have developed and change the antifungal treatment if necessary," he said.

The important thing, Kadia stressed, is to start patients on all three types of prophylaxis and in the case of antifungals, use the newer mold-active ones.

Generally, drug interactions associated with prophylactic agents are mild and well tolerated. But some of the new antineoplastic drugs do interact with antifungals, and antifungals can be strong inhibitors of liver enzymes, he explained. "So if liver impairment is present in a patient, we reduce the dose of the cancer drug to prevent the toxicity that can develop."

One problem with prophylaxis of any type is the ever-present phenomenon of antimicrobial resistance. "So we hope companies will continue to come out with more new drugs," Kadia said.

The management of infection risk has evolved steadily over time, with no sudden monumental shift, he continued. "Some centers in the U.S. and other countries have been slow to adopt routine prophylaxis and may use it only intermittently. But at MD Anderson we see such a high volume of leukemia patients with so many complications and we see so much improvement in outcomes with prophylaxis that we've adopted it universally."

And with the new generation of AML drugs exacerbating neutropenia, "a lot of cancer facilities around the world are thinking maybe we should do the same," Kadia said. "But the approach has to be nuanced."

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