Although evidence is often mixed, the expanding realm of biologics is becoming a resource that’s increasingly tapped to treat pediatric disease, physician experts said at the 2022 Triological Society Combined Sections Meeting. They discussed biologic therapy options for chronic rhinosinusitis with polyps, neurofibromatosis type 2, and recurrent respiratory papillomatosis.
Chronic Rhinosinusitis
There are no biologic therapies approved yet for chronic rhinosinusitis (CRS) in children, but they are on the way, said Amber Luong, MD, PhD, a professor of otorhinolaryngology at the University of Texas at Austin.
Three biologic agents—dupilumab, omalizumab, and mepolizumab are all approved for chronic rhinosinusitis with polyps in adults, but they’re also approved for treating children for other conditions, such as asthma. Two others—reslizumab and benralizumab—have either completed a clinical study or are near completion in adults and could be approved for use in pediatric patients within the next year, Dr. Luong said.
In adults, polyp scores tend to fall after treatment with a biologic begins but rise again when treatment is suspended. This poses a question that will probably face the pediatric population as well once biologics become more widely available in pediatrics: How long should patients be treated with biologics? “They’re not curative, so the question of how long to keep a patient on biologics isn’t known,” Dr. Luong said.
There’s only a very small group of patients that had early onset chronic rhinosinusitis and then consistently had persistent sinus inflammations, even into adulthood. So, it’s a very small group of patients who may be at risk of recurrent disease and needing something like a biologic. —Amber Luong, MD, PhD
In a longitudinal birth cohort study involving 1,246 kids with a 40-year follow-up, researchers found that the prevalence of physician-diagnosed sinusitis was 10.8% (83 of 772) at age 6. By age 32, most patients had never developed sinusitis or experienced transient sinusitis with the prevalence of adult chronic sinusitis, at 14.6% (J Allergy Clin Immunol. 2018;141:1291-1297).
“There’s only a very small group of patients—about 3.4%—that had early onset chronic rhinosinusitis and then consistently had persistent sinus inflammations, even into adulthood,” said Dr. Luong. “So, it’s a very small group of patients that we’re talking about who may be at risk of recurrent disease and needing something like a biologic.”
Allergic Fungal Rhinosinusitis
Allergic fungal rhinosinusitis tends to require revision surgery more frequently than other CRS types, so the only pediatric clinical trial (currently ongoing) for a biologic—dupilumab—targets the condition, Dr. Luong said.
Richard Gurgel, MD, MSCI, an associate professor of otolaryngology at the University of Utah in Salt Lake City, said that biologics are an option for pediatric patients with neurofibromatosis type 2 (NF2) when other options are scant. NF2 is an autosomal dominant disease in which tumors grow in the central nervous system, with the hallmark of bilateral vestibular schwannomas. “This is a really aggressive disease, and these patients can get tumors anywhere in their central nervous system,” Dr. Gurgel said. By their 30s and 40s, many people with severe forms of the disease are deaf or blind and have paralysis.
Although patients tend to be diagnosed in their mid 20s, the disease typically begins many years before. “It just highlights the fact that NF2 is actually a pediatric illness. We don’t typically think of it that way because we see and care for patients later on in life,” he said. “But if you look at when these patients initially present with their symptoms, almost all are within their teenage years, some even younger than that.”
Because the goal is to maximize function and minimize morbidity, a difficult situation arises when patients have diffuse disease, said Dr. Gurgel.
That’s when treatment with a biologic therapy or targeted molecular therapy becomes a reasonable option. Treatment with bevacizumab, a vascular endothelial growth factor inhibitor, for example, has shown positive, although mixed, results in NF2. While patients often show a positive response with tumor regression, there can also be a plateau during treatment (Childs Nerv Syst. 2020;36:2471-2480). “That’s generally been our experience and what the literature demonstrates for these patients,” Dr. Gurgel said. Patients are treated with 5 to 10 mg/kg every two to three weeks, but hypertension, renal function, bleeding, fatigue, and headache must be monitored.
Other biologics, including tyrosine–kinase inhibitors and mTOR inhibitors, are being investigated with the hope that researchers will find the “magic bullet” to help eliminate these tumors, said Dr. Gurgel. “They’re very difficult tumors to treat.”
Recurrent Respiratory Papillomatosis
Biologics are also part of the toolbox for the treatment of recurrent respiratory papillomatosis (RRP), said Alessandro de Alarcon, MD, MPH, a professor of pediatrics at the University of Cincinnati in Ohio. In this pediatric population, bevacizumab can double the time between surgeries. About a fifth of patients have a complete response, about a fifth have no response, and more than half have a partial response, Dr. de Alarcon said.
In some patients, the results can be dramatic, he said, sharing the experience of one of his patients on systemic bevacizumab. “I’ve actually not operated on them in over a year, and this is a patient that we were taking to the operating room basically every three to six weeks,” he said. “It can really change an outcome for a patient when you’re not having to do work on them anymore.”
Long-term results with the drug aren’t known, however and, as with NF2, the therapy isn’t a cure. About 50% of practices have tried the antiviral cidofovir for RRP, but in more than 20 uncontrolled trials and case series, the treatment has shown mixed results, Dr. de Alarcon said. One randomized controlled trial showed no difference using cidofovir compared to a placebo. Cidofovir also has the potential to cause scarring, as well as a possible risk of dysplasia and cancer, he said (Ann Otol Rhinol Laryngol. 2008;117:477-483).
Non-human papillomavirus (HPV) vaccines are thought to cause a local inflammatory response not specific to HPV and could help with RRP and periods between RRP procedures, added Dr. de Alarcon.
DNA vaccines are another promising option on the horizon for driving antigen expression and boosting the host immune response, he said. Open-label trials in adults are ongoing, and there have been reports of two RRP patients treated with a DNA vaccine who had their interval between surgeries increase from six months to more than 500 days, Dr. de Alarcon said (Vaccines (Basel). 2020;8:56).
“There are lots of promising groups, including our own at Cincinnati Children’s, that are doing more basic science and biology [to improve] understanding of RRP with the goal of really trying to identify other algorithms for treatment, whether it’s other biologics or medications to treat these patients.”
Thomas R. Collins is a freelance medical writer based in Florida.