A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network; Food Allergy Research and Education, and the Wallace Research Foundation. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network; Food Allergy Research and Education, and the Wallace Research Foundation. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network; Food Allergy Research and Education, and the Wallace Research Foundation. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A previously healthy infant who survived sudden cardiac arrest at home was later found to have a de novo likely pathogenic genetic mutation in the SOS1 gene, which might be an unrecognized cause of sudden infant death, report clinicians from Missouri.

SOS1 gene variants are associated with Noonan syndrome, a genetic disorder that affects the RAS/MAPK signaling pathway. However, on presentation, the infant had none of the usual structural cardiac findings typical of Noonan syndrome, such as valvular disease or hypertrophic cardiomyopathy.

“To date, this is the first case reported of a ventricular fibrillation arrest in a patient with a RASopathy-related variant prior to development of the typically associated structural cardiac phenotype and may represent a previously unrecognized etiology of sudden death during infancy,” write Christopher W. Follansbee, MD, and Lindsey Malloy-Walton, DO, from the Ward Family Heart Center, Children’s Mercy Kansas City, and the University of Missouri School of Medicine.

“Genetic testing in cases of unexplained aborted or sudden cardiac deaths, even in previously healthy children, can be valuable in establishing a diagnosis, determining the prognosis, and assessing risk to family members,” they add in a news release.

Dr. Follansbee and Dr. Malloy-Walton describe the case in a report published in the August issue of HeartRhythm Case Reports.
 

Case details

The case involved a 2-month-old girl who did not wake up as usual for her morning feeding. Her mother found her limp, pale, and having difficulty breathing.

When emergency medical services arrived, the infant had no pulse. Cardiopulmonary resuscitation was initiated and an external defibrillator revealed coarse ventricular fibrillation. An initial shock of 10 J was given with conversion to an atrial rhythm with aberrant ventricular conduction.

The infant developed increasing frequency of ectopy before degenerating to ventricular fibrillation. A second shock with 20 J was unsuccessful, but a third shock of 20 J successfully converted the rhythm to sinus with aberrant ventricular conduction and atrial ectopy with return of spontaneous circulation.

In the ICU, the infant displayed incessant, nonsustained ectopic atrial tachycardia, with rapid episodes of ectopic atrial tachycardia with ventricular rates up to 300 beats per minute in the setting of seizure activity, they report. 

With intravenous lorazepam, seizure activity resolved and treatment with amiodarone boluses led to transient establishment of sinus rhythm.

The QTc was noted to be above 500 ms and Brugada positioning of leads was unrevealing, the authors note.

Transthoracic echocardiogram showed a structurally normal heart with normal valve morphology and a patent foramen ovale with left-to-right flow. The initial ejection fraction was 49%. There was no evidence of ventricular hypertrophy, dilation, or noncompaction.

The infant was started on an esmolol infusion titrated to 225 μg/kg per min with frequent, nonsustained breakthrough of ectopic atrial tachycardia. Over the next 24 hours, the QTc interval normalized with normal T-wave morphology.

A procainamide challenge was negative. Cardiac MRI revealed normalization of ventricular function.

The genetics team was called in and a standard three-generation family history was obtained. An older sibling, 2 years of age, had no known medical conditions. The child’s paternal grandfather had died of a presumed myocardial infarction in his 50s, but no autopsy had been performed.

There was no family history of congenital heart disease, arrhythmia, sudden death, cardiomyopathy, recurrent syncope, congenital deafness, seizure, miscarriage, or developmental delay. Electrocardiograms obtained on the parents were normal.

Genetic testing using a comprehensive arrhythmia and cardiomyopathy next-generation sequencing panel revealed a de novo likely pathogenetic variant of the SOS1 gene associated with Noonan syndrome.

Given the aborted sudden cardiac death, the patient underwent dual-chamber epicardial implantable cardioverter-defibrillator implantation prior to discharge.

Dr. Follansbee and Dr. Malloy-Walton say a limitation to the case report is the lack of definitive association of the SOS1 variant with the presentation.

However, knowing the infant has the SOS1 variant and a history of aborted sudden death will allow for “monitoring and early intervention on typical manifestations of Noonan syndrome as the patient grows,” they say.

This research had no specific funding. Dr. Follansbee and Dr. Malloy-Walton have disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

A previously healthy infant who survived sudden cardiac arrest at home was later found to have a de novo likely pathogenic genetic mutation in the SOS1 gene, which might be an unrecognized cause of sudden infant death, report clinicians from Missouri.

SOS1 gene variants are associated with Noonan syndrome, a genetic disorder that affects the RAS/MAPK signaling pathway. However, on presentation, the infant had none of the usual structural cardiac findings typical of Noonan syndrome, such as valvular disease or hypertrophic cardiomyopathy.

“To date, this is the first case reported of a ventricular fibrillation arrest in a patient with a RASopathy-related variant prior to development of the typically associated structural cardiac phenotype and may represent a previously unrecognized etiology of sudden death during infancy,” write Christopher W. Follansbee, MD, and Lindsey Malloy-Walton, DO, from the Ward Family Heart Center, Children’s Mercy Kansas City, and the University of Missouri School of Medicine.

“Genetic testing in cases of unexplained aborted or sudden cardiac deaths, even in previously healthy children, can be valuable in establishing a diagnosis, determining the prognosis, and assessing risk to family members,” they add in a news release.

Dr. Follansbee and Dr. Malloy-Walton describe the case in a report published in the August issue of HeartRhythm Case Reports.
 

Case details

The case involved a 2-month-old girl who did not wake up as usual for her morning feeding. Her mother found her limp, pale, and having difficulty breathing.

When emergency medical services arrived, the infant had no pulse. Cardiopulmonary resuscitation was initiated and an external defibrillator revealed coarse ventricular fibrillation. An initial shock of 10 J was given with conversion to an atrial rhythm with aberrant ventricular conduction.

The infant developed increasing frequency of ectopy before degenerating to ventricular fibrillation. A second shock with 20 J was unsuccessful, but a third shock of 20 J successfully converted the rhythm to sinus with aberrant ventricular conduction and atrial ectopy with return of spontaneous circulation.

In the ICU, the infant displayed incessant, nonsustained ectopic atrial tachycardia, with rapid episodes of ectopic atrial tachycardia with ventricular rates up to 300 beats per minute in the setting of seizure activity, they report. 

With intravenous lorazepam, seizure activity resolved and treatment with amiodarone boluses led to transient establishment of sinus rhythm.

The QTc was noted to be above 500 ms and Brugada positioning of leads was unrevealing, the authors note.

Transthoracic echocardiogram showed a structurally normal heart with normal valve morphology and a patent foramen ovale with left-to-right flow. The initial ejection fraction was 49%. There was no evidence of ventricular hypertrophy, dilation, or noncompaction.

The infant was started on an esmolol infusion titrated to 225 μg/kg per min with frequent, nonsustained breakthrough of ectopic atrial tachycardia. Over the next 24 hours, the QTc interval normalized with normal T-wave morphology.

A procainamide challenge was negative. Cardiac MRI revealed normalization of ventricular function.

The genetics team was called in and a standard three-generation family history was obtained. An older sibling, 2 years of age, had no known medical conditions. The child’s paternal grandfather had died of a presumed myocardial infarction in his 50s, but no autopsy had been performed.

There was no family history of congenital heart disease, arrhythmia, sudden death, cardiomyopathy, recurrent syncope, congenital deafness, seizure, miscarriage, or developmental delay. Electrocardiograms obtained on the parents were normal.

Genetic testing using a comprehensive arrhythmia and cardiomyopathy next-generation sequencing panel revealed a de novo likely pathogenetic variant of the SOS1 gene associated with Noonan syndrome.

Given the aborted sudden cardiac death, the patient underwent dual-chamber epicardial implantable cardioverter-defibrillator implantation prior to discharge.

Dr. Follansbee and Dr. Malloy-Walton say a limitation to the case report is the lack of definitive association of the SOS1 variant with the presentation.

However, knowing the infant has the SOS1 variant and a history of aborted sudden death will allow for “monitoring and early intervention on typical manifestations of Noonan syndrome as the patient grows,” they say.

This research had no specific funding. Dr. Follansbee and Dr. Malloy-Walton have disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

A previously healthy infant who survived sudden cardiac arrest at home was later found to have a de novo likely pathogenic genetic mutation in the SOS1 gene, which might be an unrecognized cause of sudden infant death, report clinicians from Missouri.

SOS1 gene variants are associated with Noonan syndrome, a genetic disorder that affects the RAS/MAPK signaling pathway. However, on presentation, the infant had none of the usual structural cardiac findings typical of Noonan syndrome, such as valvular disease or hypertrophic cardiomyopathy.

“To date, this is the first case reported of a ventricular fibrillation arrest in a patient with a RASopathy-related variant prior to development of the typically associated structural cardiac phenotype and may represent a previously unrecognized etiology of sudden death during infancy,” write Christopher W. Follansbee, MD, and Lindsey Malloy-Walton, DO, from the Ward Family Heart Center, Children’s Mercy Kansas City, and the University of Missouri School of Medicine.

“Genetic testing in cases of unexplained aborted or sudden cardiac deaths, even in previously healthy children, can be valuable in establishing a diagnosis, determining the prognosis, and assessing risk to family members,” they add in a news release.

Dr. Follansbee and Dr. Malloy-Walton describe the case in a report published in the August issue of HeartRhythm Case Reports.
 

Case details

The case involved a 2-month-old girl who did not wake up as usual for her morning feeding. Her mother found her limp, pale, and having difficulty breathing.

When emergency medical services arrived, the infant had no pulse. Cardiopulmonary resuscitation was initiated and an external defibrillator revealed coarse ventricular fibrillation. An initial shock of 10 J was given with conversion to an atrial rhythm with aberrant ventricular conduction.

The infant developed increasing frequency of ectopy before degenerating to ventricular fibrillation. A second shock with 20 J was unsuccessful, but a third shock of 20 J successfully converted the rhythm to sinus with aberrant ventricular conduction and atrial ectopy with return of spontaneous circulation.

In the ICU, the infant displayed incessant, nonsustained ectopic atrial tachycardia, with rapid episodes of ectopic atrial tachycardia with ventricular rates up to 300 beats per minute in the setting of seizure activity, they report. 

With intravenous lorazepam, seizure activity resolved and treatment with amiodarone boluses led to transient establishment of sinus rhythm.

The QTc was noted to be above 500 ms and Brugada positioning of leads was unrevealing, the authors note.

Transthoracic echocardiogram showed a structurally normal heart with normal valve morphology and a patent foramen ovale with left-to-right flow. The initial ejection fraction was 49%. There was no evidence of ventricular hypertrophy, dilation, or noncompaction.

The infant was started on an esmolol infusion titrated to 225 μg/kg per min with frequent, nonsustained breakthrough of ectopic atrial tachycardia. Over the next 24 hours, the QTc interval normalized with normal T-wave morphology.

A procainamide challenge was negative. Cardiac MRI revealed normalization of ventricular function.

The genetics team was called in and a standard three-generation family history was obtained. An older sibling, 2 years of age, had no known medical conditions. The child’s paternal grandfather had died of a presumed myocardial infarction in his 50s, but no autopsy had been performed.

There was no family history of congenital heart disease, arrhythmia, sudden death, cardiomyopathy, recurrent syncope, congenital deafness, seizure, miscarriage, or developmental delay. Electrocardiograms obtained on the parents were normal.

Genetic testing using a comprehensive arrhythmia and cardiomyopathy next-generation sequencing panel revealed a de novo likely pathogenetic variant of the SOS1 gene associated with Noonan syndrome.

Given the aborted sudden cardiac death, the patient underwent dual-chamber epicardial implantable cardioverter-defibrillator implantation prior to discharge.

Dr. Follansbee and Dr. Malloy-Walton say a limitation to the case report is the lack of definitive association of the SOS1 variant with the presentation.

However, knowing the infant has the SOS1 variant and a history of aborted sudden death will allow for “monitoring and early intervention on typical manifestations of Noonan syndrome as the patient grows,” they say.

This research had no specific funding. Dr. Follansbee and Dr. Malloy-Walton have disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

Background: ACE-I and ARB therapy is widely used for hypertension, albuminuric chronic kidney disease, heart failure with reduced ejection fraction, and coronary artery disease. They are known to potentially cause hemodynamic reductions in eGFR, hyperkalemia, and acute kidney injury. We know to temporarily discontinue ACE-I or ARB in patients with eGFR less than 60 mL/min per 1.73 m² who have serious intercurrent illness that increases the risk of acute kidney injury, but existing literature evaluating the risks and benefits of using ACE-I and ARBs in individuals with advanced chronic kidney disease is conflicting.

Although this study is observational it has a large sample size and confounding factors have been accounted for by propensity score matching. The results are clinically relevant in daily practice.

Bottom line: Continuing ACE-I or ARB after an eGFR decrease to below 30 mL/min per m² is associated with lower risk of mortality and MACE without significant increased risk of end-stage kidney disease.

Citation: Qiao Y et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA Intern Med. 2020 Mar 9;180(5):718-26.

Dr. Kumar is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: ACE-I and ARB therapy is widely used for hypertension, albuminuric chronic kidney disease, heart failure with reduced ejection fraction, and coronary artery disease. They are known to potentially cause hemodynamic reductions in eGFR, hyperkalemia, and acute kidney injury. We know to temporarily discontinue ACE-I or ARB in patients with eGFR less than 60 mL/min per 1.73 m² who have serious intercurrent illness that increases the risk of acute kidney injury, but existing literature evaluating the risks and benefits of using ACE-I and ARBs in individuals with advanced chronic kidney disease is conflicting.

Although this study is observational it has a large sample size and confounding factors have been accounted for by propensity score matching. The results are clinically relevant in daily practice.

Bottom line: Continuing ACE-I or ARB after an eGFR decrease to below 30 mL/min per m² is associated with lower risk of mortality and MACE without significant increased risk of end-stage kidney disease.

Citation: Qiao Y et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA Intern Med. 2020 Mar 9;180(5):718-26.

Dr. Kumar is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: ACE-I and ARB therapy is widely used for hypertension, albuminuric chronic kidney disease, heart failure with reduced ejection fraction, and coronary artery disease. They are known to potentially cause hemodynamic reductions in eGFR, hyperkalemia, and acute kidney injury. We know to temporarily discontinue ACE-I or ARB in patients with eGFR less than 60 mL/min per 1.73 m² who have serious intercurrent illness that increases the risk of acute kidney injury, but existing literature evaluating the risks and benefits of using ACE-I and ARBs in individuals with advanced chronic kidney disease is conflicting.

Although this study is observational it has a large sample size and confounding factors have been accounted for by propensity score matching. The results are clinically relevant in daily practice.

Bottom line: Continuing ACE-I or ARB after an eGFR decrease to below 30 mL/min per m² is associated with lower risk of mortality and MACE without significant increased risk of end-stage kidney disease.

Citation: Qiao Y et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA Intern Med. 2020 Mar 9;180(5):718-26.

Dr. Kumar is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Adding or switching biologics is a common practice in the treatment of patients with inflammatory bowel disease (IBD), but there is a dearth of clinical data on whether patients should receive their first or second biologic as monotherapy or combined with immunomodulatory therapies. It’s a clinical conundrum made more difficult by the increasing number of biologics and drugs available to treat IBD, and the fact that some first-line biologics may fail because of immune responses.

The authors of a new review by Roni Aoun, MD, published in the Journal of Clinical Gastroenterology sought to provide some much-needed advice on these issues, surveying the literature that does exist in order to offer evidence-based recommendations for how and when biologics should be used.
 

A confusing array of therapeutic choices

The review arrives at a moment when IBD treatments have hit a therapeutic plateau, producing remission rates of only around 30%-35%, despite new treatments and mechanisms of action. “That’s just not where we want to be [so] there’s a lot of interest in how we can make our therapies better,” said David Rubin, MD, a professor of medicine and the codirector of the Digestive Diseases Center at the University of Chicago, and the chair of the scientific advisory committee for the Crohn’s & Colitis Foundation.

Dr. Rubin, who did not participate in authoring the review, added that the field also faces questions of what patients should receive after their first has either failed to work entirely or the initial response has waned.

“Understanding sequencing is important,” he said. “The best way to assess that right now has been through claims data, which are notoriously missing important information like [disease activity].”

The landmark SONIC and SUCCESS studies concluded that combining antibodies with immunomodulatory drugs was the best approach, but times have changed since these results were published. One recent study showed that the patient’s HLA subtype can be associated with anti–tumor necrosis factor (TNF) immune responses.

“We now know that you can be much more specific and precise about this. You can predict the likelihood someone’s going to have antidrug antibodies against an anti-TNF [agent],” said Dr. Rubin.

Factors that go into the decision of whether or not to prescribe an immunomodulator include the class of biologic, whether it is a first or second biologic, the presence or absence of antidrug antibodies, patient preference, and any comorbid conditions.

Anti-TNF agents often lose efficacy, with one study finding an average 41% loss of response to certolizumab, 33% to infliximab, and 30% to adalimumab. Another problem is posed by the intrinsic risk of immunogenicity with biologics, with rates reported to be as high as 65.3% for infliximab and 38% for adalimumab.

Immunogenicity to one anti-TNF agent often predicts immunogenicity to other anti-TNF biologics. Some data suggest that, in patients who produced antibodies to an initial anti-TNF agent, combination therapy can provide benefit with a second anti-TNF biologic. However, there are some scenarios that call for monotherapy, such as when a patient can’t take immunomodulators or when over-suppression could be risky. According to Dr. Aoun and colleagues, limited data and lessons from clinical practice suggest that monotherapy anti-TNF biologics with proactive therapeutic drug monitoring is a reasonable approach in these cases. Monitoring may also reduce the risk of immunogenicity.
 

What the authors recommended

For those reasons, if the first biologic is an anti-TNF agent, the authors recommend an immunomodulator combined with anti-TNF agents for induction or maintenance treatment of either ulcerative colitis or Crohn’s disease. If immunogenicity is present after a loss of response, they recommend a second anti-TNF agent with an immunomodulator. If there is no immunogenicity and the failure is mechanistic, they recommend switching to vedolizumab monotherapy or ustekinumab monotherapy. Immunomodulators can be prescribed on an individualized basis.

When vedolizumab or ustekinumab are the patient’s first biologic, they should be used as monotherapy. Both have very low rates of immunogenicity, and an immunomodulator is unlikely to confer a meaningful benefit, according to the review authors, who nonetheless called for prospective trials to explore these questions further. If there is a loss of response, they recommend anti-TNF agents combined with an immunomodulator, or monotherapy if the second agent is ustekinumab or vedolizumab.

In severe IBD cases, when combining agents with different mechanisms of action, or in patients who have immunogenicity to more than one class of biologic, the authors don’t provide general recommendations. Instead, they noted that the risks and benefits to individual patients should be weighed for combinations with immunomodulators.

The authors declare that they have nothing to disclose. Dr. Rubin has consulted for Janssen, AbbVie, and Takeda.

Help your patients understand biologics and biosimilars by using AGA resources for providers and patients available at gastro.org/biosimilars.

Adding or switching biologics is a common practice in the treatment of patients with inflammatory bowel disease (IBD), but there is a dearth of clinical data on whether patients should receive their first or second biologic as monotherapy or combined with immunomodulatory therapies. It’s a clinical conundrum made more difficult by the increasing number of biologics and drugs available to treat IBD, and the fact that some first-line biologics may fail because of immune responses.

The authors of a new review by Roni Aoun, MD, published in the Journal of Clinical Gastroenterology sought to provide some much-needed advice on these issues, surveying the literature that does exist in order to offer evidence-based recommendations for how and when biologics should be used.
 

A confusing array of therapeutic choices

The review arrives at a moment when IBD treatments have hit a therapeutic plateau, producing remission rates of only around 30%-35%, despite new treatments and mechanisms of action. “That’s just not where we want to be [so] there’s a lot of interest in how we can make our therapies better,” said David Rubin, MD, a professor of medicine and the codirector of the Digestive Diseases Center at the University of Chicago, and the chair of the scientific advisory committee for the Crohn’s & Colitis Foundation.

Dr. Rubin, who did not participate in authoring the review, added that the field also faces questions of what patients should receive after their first has either failed to work entirely or the initial response has waned.

“Understanding sequencing is important,” he said. “The best way to assess that right now has been through claims data, which are notoriously missing important information like [disease activity].”

The landmark SONIC and SUCCESS studies concluded that combining antibodies with immunomodulatory drugs was the best approach, but times have changed since these results were published. One recent study showed that the patient’s HLA subtype can be associated with anti–tumor necrosis factor (TNF) immune responses.

“We now know that you can be much more specific and precise about this. You can predict the likelihood someone’s going to have antidrug antibodies against an anti-TNF [agent],” said Dr. Rubin.

Factors that go into the decision of whether or not to prescribe an immunomodulator include the class of biologic, whether it is a first or second biologic, the presence or absence of antidrug antibodies, patient preference, and any comorbid conditions.

Anti-TNF agents often lose efficacy, with one study finding an average 41% loss of response to certolizumab, 33% to infliximab, and 30% to adalimumab. Another problem is posed by the intrinsic risk of immunogenicity with biologics, with rates reported to be as high as 65.3% for infliximab and 38% for adalimumab.

Immunogenicity to one anti-TNF agent often predicts immunogenicity to other anti-TNF biologics. Some data suggest that, in patients who produced antibodies to an initial anti-TNF agent, combination therapy can provide benefit with a second anti-TNF biologic. However, there are some scenarios that call for monotherapy, such as when a patient can’t take immunomodulators or when over-suppression could be risky. According to Dr. Aoun and colleagues, limited data and lessons from clinical practice suggest that monotherapy anti-TNF biologics with proactive therapeutic drug monitoring is a reasonable approach in these cases. Monitoring may also reduce the risk of immunogenicity.
 

What the authors recommended

For those reasons, if the first biologic is an anti-TNF agent, the authors recommend an immunomodulator combined with anti-TNF agents for induction or maintenance treatment of either ulcerative colitis or Crohn’s disease. If immunogenicity is present after a loss of response, they recommend a second anti-TNF agent with an immunomodulator. If there is no immunogenicity and the failure is mechanistic, they recommend switching to vedolizumab monotherapy or ustekinumab monotherapy. Immunomodulators can be prescribed on an individualized basis.

When vedolizumab or ustekinumab are the patient’s first biologic, they should be used as monotherapy. Both have very low rates of immunogenicity, and an immunomodulator is unlikely to confer a meaningful benefit, according to the review authors, who nonetheless called for prospective trials to explore these questions further. If there is a loss of response, they recommend anti-TNF agents combined with an immunomodulator, or monotherapy if the second agent is ustekinumab or vedolizumab.

In severe IBD cases, when combining agents with different mechanisms of action, or in patients who have immunogenicity to more than one class of biologic, the authors don’t provide general recommendations. Instead, they noted that the risks and benefits to individual patients should be weighed for combinations with immunomodulators.

The authors declare that they have nothing to disclose. Dr. Rubin has consulted for Janssen, AbbVie, and Takeda.

Help your patients understand biologics and biosimilars by using AGA resources for providers and patients available at gastro.org/biosimilars.

Adding or switching biologics is a common practice in the treatment of patients with inflammatory bowel disease (IBD), but there is a dearth of clinical data on whether patients should receive their first or second biologic as monotherapy or combined with immunomodulatory therapies. It’s a clinical conundrum made more difficult by the increasing number of biologics and drugs available to treat IBD, and the fact that some first-line biologics may fail because of immune responses.

The authors of a new review by Roni Aoun, MD, published in the Journal of Clinical Gastroenterology sought to provide some much-needed advice on these issues, surveying the literature that does exist in order to offer evidence-based recommendations for how and when biologics should be used.
 

A confusing array of therapeutic choices

The review arrives at a moment when IBD treatments have hit a therapeutic plateau, producing remission rates of only around 30%-35%, despite new treatments and mechanisms of action. “That’s just not where we want to be [so] there’s a lot of interest in how we can make our therapies better,” said David Rubin, MD, a professor of medicine and the codirector of the Digestive Diseases Center at the University of Chicago, and the chair of the scientific advisory committee for the Crohn’s & Colitis Foundation.

Dr. Rubin, who did not participate in authoring the review, added that the field also faces questions of what patients should receive after their first has either failed to work entirely or the initial response has waned.

“Understanding sequencing is important,” he said. “The best way to assess that right now has been through claims data, which are notoriously missing important information like [disease activity].”

The landmark SONIC and SUCCESS studies concluded that combining antibodies with immunomodulatory drugs was the best approach, but times have changed since these results were published. One recent study showed that the patient’s HLA subtype can be associated with anti–tumor necrosis factor (TNF) immune responses.

“We now know that you can be much more specific and precise about this. You can predict the likelihood someone’s going to have antidrug antibodies against an anti-TNF [agent],” said Dr. Rubin.

Factors that go into the decision of whether or not to prescribe an immunomodulator include the class of biologic, whether it is a first or second biologic, the presence or absence of antidrug antibodies, patient preference, and any comorbid conditions.

Anti-TNF agents often lose efficacy, with one study finding an average 41% loss of response to certolizumab, 33% to infliximab, and 30% to adalimumab. Another problem is posed by the intrinsic risk of immunogenicity with biologics, with rates reported to be as high as 65.3% for infliximab and 38% for adalimumab.

Immunogenicity to one anti-TNF agent often predicts immunogenicity to other anti-TNF biologics. Some data suggest that, in patients who produced antibodies to an initial anti-TNF agent, combination therapy can provide benefit with a second anti-TNF biologic. However, there are some scenarios that call for monotherapy, such as when a patient can’t take immunomodulators or when over-suppression could be risky. According to Dr. Aoun and colleagues, limited data and lessons from clinical practice suggest that monotherapy anti-TNF biologics with proactive therapeutic drug monitoring is a reasonable approach in these cases. Monitoring may also reduce the risk of immunogenicity.
 

What the authors recommended

For those reasons, if the first biologic is an anti-TNF agent, the authors recommend an immunomodulator combined with anti-TNF agents for induction or maintenance treatment of either ulcerative colitis or Crohn’s disease. If immunogenicity is present after a loss of response, they recommend a second anti-TNF agent with an immunomodulator. If there is no immunogenicity and the failure is mechanistic, they recommend switching to vedolizumab monotherapy or ustekinumab monotherapy. Immunomodulators can be prescribed on an individualized basis.

When vedolizumab or ustekinumab are the patient’s first biologic, they should be used as monotherapy. Both have very low rates of immunogenicity, and an immunomodulator is unlikely to confer a meaningful benefit, according to the review authors, who nonetheless called for prospective trials to explore these questions further. If there is a loss of response, they recommend anti-TNF agents combined with an immunomodulator, or monotherapy if the second agent is ustekinumab or vedolizumab.

In severe IBD cases, when combining agents with different mechanisms of action, or in patients who have immunogenicity to more than one class of biologic, the authors don’t provide general recommendations. Instead, they noted that the risks and benefits to individual patients should be weighed for combinations with immunomodulators.

The authors declare that they have nothing to disclose. Dr. Rubin has consulted for Janssen, AbbVie, and Takeda.

Help your patients understand biologics and biosimilars by using AGA resources for providers and patients available at gastro.org/biosimilars.

The use of novel, chemotherapy-free regimens in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is poised to become the new standard of care, according to a review assessment by Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

Since the introduction of highly potent BCR-ABL–mutation tyrosine kinase inhibitors (TKIs), Ph+ ALL in adults has been transformed from an historically poor prognosis disease to a relatively favorable–risk acute leukemia, according to their report published online in Clinical Lymphoma, Myeloma and Leukemia.

Dr. Short and colleagues reviewed the state of the art in Ph+ ALL care, comparing historically intensive with the more modern nonintensive treatments as part of the SOHO (Society of Hematologic Oncology) State of the Art Updates & Next Questions.
 

Treatment comparisons

Ph+ ALL outcomes have dramatically improved in the past 20 years, first with the addition of BCR-ABL TKIs to chemotherapy backbones and, more recently, with the development of more potent later-generation TKIs and the use of chemotherapy-free regimens.

Since the introduction of TKIs, most studies have evaluated them in combination with intensive chemotherapy such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine) or similar regimens, according to Dr. Short and colleagues. However, the role of intensive chemotherapy in treating patients with Ph+ ALL has been increasingly questioned with the development of more active, broader spectrum TKIs such as ponatinib and effective novel monoclonal antibody constructs such as blinatumomab.

In particular, encouraging early results have been observed with blinatumomab-based, chemotherapy-free regimens, challenging previous notions that all patients with Ph+ ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, according to Dr. Short and colleagues. These regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib.

“Given the multiple recent advances in the management of Ph+ ALL, we can reasonably envision a future in which what was once one of the most aggressive forms of leukemia is now considered nearly universally curable without either need for either chemotherapy or HSCT,” the authors concluded.

Disclosures for the authors were not reported in the review article.

[email protected]

The use of novel, chemotherapy-free regimens in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is poised to become the new standard of care, according to a review assessment by Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

Since the introduction of highly potent BCR-ABL–mutation tyrosine kinase inhibitors (TKIs), Ph+ ALL in adults has been transformed from an historically poor prognosis disease to a relatively favorable–risk acute leukemia, according to their report published online in Clinical Lymphoma, Myeloma and Leukemia.

Dr. Short and colleagues reviewed the state of the art in Ph+ ALL care, comparing historically intensive with the more modern nonintensive treatments as part of the SOHO (Society of Hematologic Oncology) State of the Art Updates & Next Questions.
 

Treatment comparisons

Ph+ ALL outcomes have dramatically improved in the past 20 years, first with the addition of BCR-ABL TKIs to chemotherapy backbones and, more recently, with the development of more potent later-generation TKIs and the use of chemotherapy-free regimens.

Since the introduction of TKIs, most studies have evaluated them in combination with intensive chemotherapy such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine) or similar regimens, according to Dr. Short and colleagues. However, the role of intensive chemotherapy in treating patients with Ph+ ALL has been increasingly questioned with the development of more active, broader spectrum TKIs such as ponatinib and effective novel monoclonal antibody constructs such as blinatumomab.

In particular, encouraging early results have been observed with blinatumomab-based, chemotherapy-free regimens, challenging previous notions that all patients with Ph+ ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, according to Dr. Short and colleagues. These regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib.

“Given the multiple recent advances in the management of Ph+ ALL, we can reasonably envision a future in which what was once one of the most aggressive forms of leukemia is now considered nearly universally curable without either need for either chemotherapy or HSCT,” the authors concluded.

Disclosures for the authors were not reported in the review article.

[email protected]

The use of novel, chemotherapy-free regimens in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is poised to become the new standard of care, according to a review assessment by Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

Since the introduction of highly potent BCR-ABL–mutation tyrosine kinase inhibitors (TKIs), Ph+ ALL in adults has been transformed from an historically poor prognosis disease to a relatively favorable–risk acute leukemia, according to their report published online in Clinical Lymphoma, Myeloma and Leukemia.

Dr. Short and colleagues reviewed the state of the art in Ph+ ALL care, comparing historically intensive with the more modern nonintensive treatments as part of the SOHO (Society of Hematologic Oncology) State of the Art Updates & Next Questions.
 

Treatment comparisons

Ph+ ALL outcomes have dramatically improved in the past 20 years, first with the addition of BCR-ABL TKIs to chemotherapy backbones and, more recently, with the development of more potent later-generation TKIs and the use of chemotherapy-free regimens.

Since the introduction of TKIs, most studies have evaluated them in combination with intensive chemotherapy such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine) or similar regimens, according to Dr. Short and colleagues. However, the role of intensive chemotherapy in treating patients with Ph+ ALL has been increasingly questioned with the development of more active, broader spectrum TKIs such as ponatinib and effective novel monoclonal antibody constructs such as blinatumomab.

In particular, encouraging early results have been observed with blinatumomab-based, chemotherapy-free regimens, challenging previous notions that all patients with Ph+ ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, according to Dr. Short and colleagues. These regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib.

“Given the multiple recent advances in the management of Ph+ ALL, we can reasonably envision a future in which what was once one of the most aggressive forms of leukemia is now considered nearly universally curable without either need for either chemotherapy or HSCT,” the authors concluded.

Disclosures for the authors were not reported in the review article.

[email protected]

About one-third of the U.S. population had been infected with SARS-CoV-2 by the end of 2020, according to a modeling study published Aug. 26 online in Nature.

Jeffrey Shaman, PhD, professor in the department of environmental health sciences and director of the climate and health program at the Columbia University Mailman School of Public Health, New York City, and colleagues developed a model to simulate how SARS-CoV-2 was transmitted within and between all 3,142 counties in the United States.

In their model, the researchers considered migration data between counties, the observed case numbers, and estimates of infections based on the number of people who test positive for SARS-CoV-2 antibodies.

The United States had the highest number of confirmed COVID-19 cases and deaths in the world during 2020. More than 19.6 million cases were reported by the end of the year.

But the authors point out that “69% of the population remained susceptible to viral infection.”

The researchers also studied the ascertainment rate, or the ratio of detected cases to the number of confirmed cases. Nationally, that value increased from 11.3% in March 2020 to 24.5% in December 2020.

That’s one of the biggest pandemic lessons from the data, Dr. Shaman said: “It is vitally important when there is an outbreak and you’re counting cases that there are many more people infected in your community who are contagious than reported cases. Each individual is infectious for multiple days, and there are many more unreported cases.”

That applies now with the Delta variant, he said.

“Vaccinated people who get infected with the Delta variant are part of the transmission chain,” he said.
 

Fatality rates dropped

Some of the data were very positive, Dr. Shaman told this news organization. The infection fatality rate fell from 0.77% in April to 0.31% in December. The authors suggest that that may be because of improvements in diagnosis and treatment, patient care, and reduced disease severity.

However, the fatality rate was still nearly four times as high as the estimated fatality rate for seasonal influenza (0.08%) and the 2009 influenza pandemic (0.0076%), the authors point out.

Joe K. Gerald, MD, PhD, associate professor and program director of public health policy and management at the University of Arizona, Tucson, told this news organization that this article helps confirm that COVID is much deadlier than the flu and that the intensity of the response has been appropriate.

“We should be willing to invest a lot more in mitigating COVID-19 than seasonal influenza because it has much greater consequences,” he said.

The numbers emphasize that testing must improve.

“We didn’t have enough tests available, and they weren’t easily accessible. For much of the year we were flying in the dark,” Dr. Gerald said.

The number of tests has increased this year, he acknowledged, but testing still lags. “We just can’t miss this many infections or diagnoses and hope to gain control,” he said.

The study also points out the huge variation by state and by county in infections and deaths, and that variation continues. Gerald noted that the varied numbers make it difficult for some regions to accept broader mandates, because the threat from COVID-19 appears very different where they are.

“We have to think about regions, how many people are susceptible, and what the testing capacity is,” he said. “States and even counties should have some leeway to make some important public health decisions, because local conditions are going to differ at different points in time.”
 

‘We have not turned the corner’

Jill Foster, MD, a pediatric infectious disease physician at the University of Minnesota Medical School, Minneapolis, said in an interview that the study adds evidence: “We have not turned the corner on COVID-19 and are nowhere near herd immunity – if it exists for SARS-CoV-2.”

She said the numbers presented are particularly concerning in regard to how many people were susceptible and were actively able to infect others: “Much higher than most people imagined and very much higher than their comparison, influenza.

“There are still more people susceptible than we had believed,” Dr. Foster added. “If the pattern continues where the Delta variant infects a significant portion of those vaccinated, the number of people susceptible rises even higher than was predicted.”

She said that it is reassuring that the analysis shows a decrease in case fatality and said the finding supports the common opinion that medicine is better able to fight the disease.

“However,” she said, “the optimism is tempered by acknowledging that in order to benefit from these advances, we must not overwhelm the facilities where patients are cared for so that optimal care can be delivered.”

Dr. Foster said these numbers represent a warning that COVID should be treated as a continuing threat.

“We need to acknowledge that there is COVID-19 infection simmering and periodically erupting throughout the country,” she said. “It is not monolithic and varies by geography and seasons in ways that are difficult to predict other than at any given time there is likely more infection present than we are identifying and more people susceptible to infection than we have calculated.”

The authors and Dr. Gerald have disclosed no relevant financial relationships. Dr. Foster has received clinical trials funding from Moderna.

A version of this article first appeared on Medscape.com.

About one-third of the U.S. population had been infected with SARS-CoV-2 by the end of 2020, according to a modeling study published Aug. 26 online in Nature.

Jeffrey Shaman, PhD, professor in the department of environmental health sciences and director of the climate and health program at the Columbia University Mailman School of Public Health, New York City, and colleagues developed a model to simulate how SARS-CoV-2 was transmitted within and between all 3,142 counties in the United States.

In their model, the researchers considered migration data between counties, the observed case numbers, and estimates of infections based on the number of people who test positive for SARS-CoV-2 antibodies.

The United States had the highest number of confirmed COVID-19 cases and deaths in the world during 2020. More than 19.6 million cases were reported by the end of the year.

But the authors point out that “69% of the population remained susceptible to viral infection.”

The researchers also studied the ascertainment rate, or the ratio of detected cases to the number of confirmed cases. Nationally, that value increased from 11.3% in March 2020 to 24.5% in December 2020.

That’s one of the biggest pandemic lessons from the data, Dr. Shaman said: “It is vitally important when there is an outbreak and you’re counting cases that there are many more people infected in your community who are contagious than reported cases. Each individual is infectious for multiple days, and there are many more unreported cases.”

That applies now with the Delta variant, he said.

“Vaccinated people who get infected with the Delta variant are part of the transmission chain,” he said.
 

Fatality rates dropped

Some of the data were very positive, Dr. Shaman told this news organization. The infection fatality rate fell from 0.77% in April to 0.31% in December. The authors suggest that that may be because of improvements in diagnosis and treatment, patient care, and reduced disease severity.

However, the fatality rate was still nearly four times as high as the estimated fatality rate for seasonal influenza (0.08%) and the 2009 influenza pandemic (0.0076%), the authors point out.

Joe K. Gerald, MD, PhD, associate professor and program director of public health policy and management at the University of Arizona, Tucson, told this news organization that this article helps confirm that COVID is much deadlier than the flu and that the intensity of the response has been appropriate.

“We should be willing to invest a lot more in mitigating COVID-19 than seasonal influenza because it has much greater consequences,” he said.

The numbers emphasize that testing must improve.

“We didn’t have enough tests available, and they weren’t easily accessible. For much of the year we were flying in the dark,” Dr. Gerald said.

The number of tests has increased this year, he acknowledged, but testing still lags. “We just can’t miss this many infections or diagnoses and hope to gain control,” he said.

The study also points out the huge variation by state and by county in infections and deaths, and that variation continues. Gerald noted that the varied numbers make it difficult for some regions to accept broader mandates, because the threat from COVID-19 appears very different where they are.

“We have to think about regions, how many people are susceptible, and what the testing capacity is,” he said. “States and even counties should have some leeway to make some important public health decisions, because local conditions are going to differ at different points in time.”
 

‘We have not turned the corner’

Jill Foster, MD, a pediatric infectious disease physician at the University of Minnesota Medical School, Minneapolis, said in an interview that the study adds evidence: “We have not turned the corner on COVID-19 and are nowhere near herd immunity – if it exists for SARS-CoV-2.”

She said the numbers presented are particularly concerning in regard to how many people were susceptible and were actively able to infect others: “Much higher than most people imagined and very much higher than their comparison, influenza.

“There are still more people susceptible than we had believed,” Dr. Foster added. “If the pattern continues where the Delta variant infects a significant portion of those vaccinated, the number of people susceptible rises even higher than was predicted.”

She said that it is reassuring that the analysis shows a decrease in case fatality and said the finding supports the common opinion that medicine is better able to fight the disease.

“However,” she said, “the optimism is tempered by acknowledging that in order to benefit from these advances, we must not overwhelm the facilities where patients are cared for so that optimal care can be delivered.”

Dr. Foster said these numbers represent a warning that COVID should be treated as a continuing threat.

“We need to acknowledge that there is COVID-19 infection simmering and periodically erupting throughout the country,” she said. “It is not monolithic and varies by geography and seasons in ways that are difficult to predict other than at any given time there is likely more infection present than we are identifying and more people susceptible to infection than we have calculated.”

The authors and Dr. Gerald have disclosed no relevant financial relationships. Dr. Foster has received clinical trials funding from Moderna.

A version of this article first appeared on Medscape.com.

About one-third of the U.S. population had been infected with SARS-CoV-2 by the end of 2020, according to a modeling study published Aug. 26 online in Nature.

Jeffrey Shaman, PhD, professor in the department of environmental health sciences and director of the climate and health program at the Columbia University Mailman School of Public Health, New York City, and colleagues developed a model to simulate how SARS-CoV-2 was transmitted within and between all 3,142 counties in the United States.

In their model, the researchers considered migration data between counties, the observed case numbers, and estimates of infections based on the number of people who test positive for SARS-CoV-2 antibodies.

The United States had the highest number of confirmed COVID-19 cases and deaths in the world during 2020. More than 19.6 million cases were reported by the end of the year.

But the authors point out that “69% of the population remained susceptible to viral infection.”

The researchers also studied the ascertainment rate, or the ratio of detected cases to the number of confirmed cases. Nationally, that value increased from 11.3% in March 2020 to 24.5% in December 2020.

That’s one of the biggest pandemic lessons from the data, Dr. Shaman said: “It is vitally important when there is an outbreak and you’re counting cases that there are many more people infected in your community who are contagious than reported cases. Each individual is infectious for multiple days, and there are many more unreported cases.”

That applies now with the Delta variant, he said.

“Vaccinated people who get infected with the Delta variant are part of the transmission chain,” he said.
 

Fatality rates dropped

Some of the data were very positive, Dr. Shaman told this news organization. The infection fatality rate fell from 0.77% in April to 0.31% in December. The authors suggest that that may be because of improvements in diagnosis and treatment, patient care, and reduced disease severity.

However, the fatality rate was still nearly four times as high as the estimated fatality rate for seasonal influenza (0.08%) and the 2009 influenza pandemic (0.0076%), the authors point out.

Joe K. Gerald, MD, PhD, associate professor and program director of public health policy and management at the University of Arizona, Tucson, told this news organization that this article helps confirm that COVID is much deadlier than the flu and that the intensity of the response has been appropriate.

“We should be willing to invest a lot more in mitigating COVID-19 than seasonal influenza because it has much greater consequences,” he said.

The numbers emphasize that testing must improve.

“We didn’t have enough tests available, and they weren’t easily accessible. For much of the year we were flying in the dark,” Dr. Gerald said.

The number of tests has increased this year, he acknowledged, but testing still lags. “We just can’t miss this many infections or diagnoses and hope to gain control,” he said.

The study also points out the huge variation by state and by county in infections and deaths, and that variation continues. Gerald noted that the varied numbers make it difficult for some regions to accept broader mandates, because the threat from COVID-19 appears very different where they are.

“We have to think about regions, how many people are susceptible, and what the testing capacity is,” he said. “States and even counties should have some leeway to make some important public health decisions, because local conditions are going to differ at different points in time.”
 

‘We have not turned the corner’

Jill Foster, MD, a pediatric infectious disease physician at the University of Minnesota Medical School, Minneapolis, said in an interview that the study adds evidence: “We have not turned the corner on COVID-19 and are nowhere near herd immunity – if it exists for SARS-CoV-2.”

She said the numbers presented are particularly concerning in regard to how many people were susceptible and were actively able to infect others: “Much higher than most people imagined and very much higher than their comparison, influenza.

“There are still more people susceptible than we had believed,” Dr. Foster added. “If the pattern continues where the Delta variant infects a significant portion of those vaccinated, the number of people susceptible rises even higher than was predicted.”

She said that it is reassuring that the analysis shows a decrease in case fatality and said the finding supports the common opinion that medicine is better able to fight the disease.

“However,” she said, “the optimism is tempered by acknowledging that in order to benefit from these advances, we must not overwhelm the facilities where patients are cared for so that optimal care can be delivered.”

Dr. Foster said these numbers represent a warning that COVID should be treated as a continuing threat.

“We need to acknowledge that there is COVID-19 infection simmering and periodically erupting throughout the country,” she said. “It is not monolithic and varies by geography and seasons in ways that are difficult to predict other than at any given time there is likely more infection present than we are identifying and more people susceptible to infection than we have calculated.”

The authors and Dr. Gerald have disclosed no relevant financial relationships. Dr. Foster has received clinical trials funding from Moderna.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) led to complete and long-lasting responses in 2 of 16 patients with metastatic non-small cell lung cancer (NSCLC) who fully underwent the therapy in a phase 1 study.

The results are “very impressive, with two complete responses that are ongoing 1.5 years later, so it’s durable, and that’s encouraging,” Fred Hirsch, MD, PhD, director of the Center of Excellence for Thoracic Oncology at Mount Sinai’s Tisch Cancer Institute, New York, told this news organization.

Dr. Hirsch, who wasn’t involved in the research, also noted that this study is in immunotherapy-resistant metastatic lung cancer – “a situation where we actually don’t know exactly how best to treat it today.”

The study was published online in Nature Medicine.

A form of immunotherapy, TILs have been studied extensively in melanoma, as reported by this news organization, but this is the first test of the TIL therapy in metastatic NSCLC.

The single-arm, open-label phase 1 trial involved 20 patients who had TILs collected, including 16 who eventually received TILs. Median age was 54 years; all patients had metastatic NSCLC and disease progression after nivolumab monotherapy.

TILs cultured from an individual patient’s tumor were expanded ex vivo from minced tumors cultured with interleukin-2 (IL-2). Via this method, “billions of activated T cells can be produced and infused back into a patient,” explain the authors.

The full treatment regimen comprised cyclophosphamide and fludarabine lymphodepletion, TIL infusion and IL-2, followed by maintenance nivolumab.

“We found that infusion of TILs in combination with lymphodepletion and IL-2 had manageable toxicity and mediated tumor regressions in several patients, including complete responses,” report Benjamin Creelan, MD, of the Moffitt Cancer Center & Research Institute, Tampa, and colleagues.

The endpoint of safety was met according to the prespecified criteria of a rate of severe toxicity of 17% or less.

Among 13 evaluable patients, three had confirmed responses and 11 had reduction in tumor burden. Two patients achieved complete responses that were ongoing 1.5 years following TIL treatment.

One durable complete response occurred in a PD-L1-negative never-smoker, who had a low tumor mutation burden and who was refractory to nivolumab.

“This may be particularly encouraging for the large subset of never-smoker patients, for whom immune-checkpoint inhibitors have historically had limited efficacy,” the investigators say.

This complete responder had “features where you wouldn’t expect to see a response for immunotherapy,” Dr. Hirsch told this news organization.

“Low tumor mutation burden, negative PDL-1, and never-smoker are three factors which indicate some kind of resistance to immunotherapy, and despite that, there was a complete response with this specific therapy. That is fascinating,” he said.

In exploratory analyses, T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in patients who responded to treatment. 

The researchers say these early data indicate that TILs can mediate effective responses in tumor subtypes that are not sensitive to traditional immune-checkpoint-targeted therapy.

“Therefore, therapy with TILs may extend the scope and impact of immunotherapy into wider populations,” they write.
 

‘Yeoman’s effort’ paving the way forward

Also weighing in on the study, Philip Greenberg, MD, professor and head of immunology, Fred Hutchinson Cancer Center, Seattle, said, “In some respects, it’s quite promising and in other respects, actually more limited than you would hope for.”

“I think it’s a great demonstration that there is activity here, and there’s a world of things that can be done to improve the activity and no doubt that will be done. After this trial, I’m sure we will see next-generation trials,” said Dr. Greenberg.

He said key issues going forward are how cells are selected and manufactured: “That’s going to be a critical piece for making it better.”

“There is now a world of data that says T cells that recognize mutations in cancers can be effective in solid tumors,” Dr. Greenberg said.

“Sustaining that response is still a huge obstacle for achieving the kinds of therapeutic benefits we’d like to be achieved. And having that response be broad enough, particularly in the setting where most of the mutations are just passenger mutations, not driver oncogenes, is going to require a way of generating a large polyspecific population of cells that can persist for a long time,” he further commented.

All in all, this study was a “yeoman’s effort” and the researchers “deserve a lot of credit for pushing it forward,” Dr. Greenberg said.

The study was supported in part by grants from Stand Up to Cancer Foundation, the Barbara Bauer Prelude to a Cure Foundation, Iovance Biotherapeutics, and a Young Investigator award from Adaptive Biotechnologies. Nivolumab was supplied by Bristol-Myers Squibb. Aldesleukin (IL-2) was supplied by Clinigen Group.  A complete list of author disclosures is available with the original article. Dr. Hirsch and Dr. Greenberg have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) led to complete and long-lasting responses in 2 of 16 patients with metastatic non-small cell lung cancer (NSCLC) who fully underwent the therapy in a phase 1 study.

The results are “very impressive, with two complete responses that are ongoing 1.5 years later, so it’s durable, and that’s encouraging,” Fred Hirsch, MD, PhD, director of the Center of Excellence for Thoracic Oncology at Mount Sinai’s Tisch Cancer Institute, New York, told this news organization.

Dr. Hirsch, who wasn’t involved in the research, also noted that this study is in immunotherapy-resistant metastatic lung cancer – “a situation where we actually don’t know exactly how best to treat it today.”

The study was published online in Nature Medicine.

A form of immunotherapy, TILs have been studied extensively in melanoma, as reported by this news organization, but this is the first test of the TIL therapy in metastatic NSCLC.

The single-arm, open-label phase 1 trial involved 20 patients who had TILs collected, including 16 who eventually received TILs. Median age was 54 years; all patients had metastatic NSCLC and disease progression after nivolumab monotherapy.

TILs cultured from an individual patient’s tumor were expanded ex vivo from minced tumors cultured with interleukin-2 (IL-2). Via this method, “billions of activated T cells can be produced and infused back into a patient,” explain the authors.

The full treatment regimen comprised cyclophosphamide and fludarabine lymphodepletion, TIL infusion and IL-2, followed by maintenance nivolumab.

“We found that infusion of TILs in combination with lymphodepletion and IL-2 had manageable toxicity and mediated tumor regressions in several patients, including complete responses,” report Benjamin Creelan, MD, of the Moffitt Cancer Center & Research Institute, Tampa, and colleagues.

The endpoint of safety was met according to the prespecified criteria of a rate of severe toxicity of 17% or less.

Among 13 evaluable patients, three had confirmed responses and 11 had reduction in tumor burden. Two patients achieved complete responses that were ongoing 1.5 years following TIL treatment.

One durable complete response occurred in a PD-L1-negative never-smoker, who had a low tumor mutation burden and who was refractory to nivolumab.

“This may be particularly encouraging for the large subset of never-smoker patients, for whom immune-checkpoint inhibitors have historically had limited efficacy,” the investigators say.

This complete responder had “features where you wouldn’t expect to see a response for immunotherapy,” Dr. Hirsch told this news organization.

“Low tumor mutation burden, negative PDL-1, and never-smoker are three factors which indicate some kind of resistance to immunotherapy, and despite that, there was a complete response with this specific therapy. That is fascinating,” he said.

In exploratory analyses, T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in patients who responded to treatment. 

The researchers say these early data indicate that TILs can mediate effective responses in tumor subtypes that are not sensitive to traditional immune-checkpoint-targeted therapy.

“Therefore, therapy with TILs may extend the scope and impact of immunotherapy into wider populations,” they write.
 

‘Yeoman’s effort’ paving the way forward

Also weighing in on the study, Philip Greenberg, MD, professor and head of immunology, Fred Hutchinson Cancer Center, Seattle, said, “In some respects, it’s quite promising and in other respects, actually more limited than you would hope for.”

“I think it’s a great demonstration that there is activity here, and there’s a world of things that can be done to improve the activity and no doubt that will be done. After this trial, I’m sure we will see next-generation trials,” said Dr. Greenberg.

He said key issues going forward are how cells are selected and manufactured: “That’s going to be a critical piece for making it better.”

“There is now a world of data that says T cells that recognize mutations in cancers can be effective in solid tumors,” Dr. Greenberg said.

“Sustaining that response is still a huge obstacle for achieving the kinds of therapeutic benefits we’d like to be achieved. And having that response be broad enough, particularly in the setting where most of the mutations are just passenger mutations, not driver oncogenes, is going to require a way of generating a large polyspecific population of cells that can persist for a long time,” he further commented.

All in all, this study was a “yeoman’s effort” and the researchers “deserve a lot of credit for pushing it forward,” Dr. Greenberg said.

The study was supported in part by grants from Stand Up to Cancer Foundation, the Barbara Bauer Prelude to a Cure Foundation, Iovance Biotherapeutics, and a Young Investigator award from Adaptive Biotechnologies. Nivolumab was supplied by Bristol-Myers Squibb. Aldesleukin (IL-2) was supplied by Clinigen Group.  A complete list of author disclosures is available with the original article. Dr. Hirsch and Dr. Greenberg have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) led to complete and long-lasting responses in 2 of 16 patients with metastatic non-small cell lung cancer (NSCLC) who fully underwent the therapy in a phase 1 study.

The results are “very impressive, with two complete responses that are ongoing 1.5 years later, so it’s durable, and that’s encouraging,” Fred Hirsch, MD, PhD, director of the Center of Excellence for Thoracic Oncology at Mount Sinai’s Tisch Cancer Institute, New York, told this news organization.

Dr. Hirsch, who wasn’t involved in the research, also noted that this study is in immunotherapy-resistant metastatic lung cancer – “a situation where we actually don’t know exactly how best to treat it today.”

The study was published online in Nature Medicine.

A form of immunotherapy, TILs have been studied extensively in melanoma, as reported by this news organization, but this is the first test of the TIL therapy in metastatic NSCLC.

The single-arm, open-label phase 1 trial involved 20 patients who had TILs collected, including 16 who eventually received TILs. Median age was 54 years; all patients had metastatic NSCLC and disease progression after nivolumab monotherapy.

TILs cultured from an individual patient’s tumor were expanded ex vivo from minced tumors cultured with interleukin-2 (IL-2). Via this method, “billions of activated T cells can be produced and infused back into a patient,” explain the authors.

The full treatment regimen comprised cyclophosphamide and fludarabine lymphodepletion, TIL infusion and IL-2, followed by maintenance nivolumab.

“We found that infusion of TILs in combination with lymphodepletion and IL-2 had manageable toxicity and mediated tumor regressions in several patients, including complete responses,” report Benjamin Creelan, MD, of the Moffitt Cancer Center & Research Institute, Tampa, and colleagues.

The endpoint of safety was met according to the prespecified criteria of a rate of severe toxicity of 17% or less.

Among 13 evaluable patients, three had confirmed responses and 11 had reduction in tumor burden. Two patients achieved complete responses that were ongoing 1.5 years following TIL treatment.

One durable complete response occurred in a PD-L1-negative never-smoker, who had a low tumor mutation burden and who was refractory to nivolumab.

“This may be particularly encouraging for the large subset of never-smoker patients, for whom immune-checkpoint inhibitors have historically had limited efficacy,” the investigators say.

This complete responder had “features where you wouldn’t expect to see a response for immunotherapy,” Dr. Hirsch told this news organization.

“Low tumor mutation burden, negative PDL-1, and never-smoker are three factors which indicate some kind of resistance to immunotherapy, and despite that, there was a complete response with this specific therapy. That is fascinating,” he said.

In exploratory analyses, T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in patients who responded to treatment. 

The researchers say these early data indicate that TILs can mediate effective responses in tumor subtypes that are not sensitive to traditional immune-checkpoint-targeted therapy.

“Therefore, therapy with TILs may extend the scope and impact of immunotherapy into wider populations,” they write.
 

‘Yeoman’s effort’ paving the way forward

Also weighing in on the study, Philip Greenberg, MD, professor and head of immunology, Fred Hutchinson Cancer Center, Seattle, said, “In some respects, it’s quite promising and in other respects, actually more limited than you would hope for.”

“I think it’s a great demonstration that there is activity here, and there’s a world of things that can be done to improve the activity and no doubt that will be done. After this trial, I’m sure we will see next-generation trials,” said Dr. Greenberg.

He said key issues going forward are how cells are selected and manufactured: “That’s going to be a critical piece for making it better.”

“There is now a world of data that says T cells that recognize mutations in cancers can be effective in solid tumors,” Dr. Greenberg said.

“Sustaining that response is still a huge obstacle for achieving the kinds of therapeutic benefits we’d like to be achieved. And having that response be broad enough, particularly in the setting where most of the mutations are just passenger mutations, not driver oncogenes, is going to require a way of generating a large polyspecific population of cells that can persist for a long time,” he further commented.

All in all, this study was a “yeoman’s effort” and the researchers “deserve a lot of credit for pushing it forward,” Dr. Greenberg said.

The study was supported in part by grants from Stand Up to Cancer Foundation, the Barbara Bauer Prelude to a Cure Foundation, Iovance Biotherapeutics, and a Young Investigator award from Adaptive Biotechnologies. Nivolumab was supplied by Bristol-Myers Squibb. Aldesleukin (IL-2) was supplied by Clinigen Group.  A complete list of author disclosures is available with the original article. Dr. Hirsch and Dr. Greenberg have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Differences in lesion evolution may help neurologists distinguish between multiple sclerosis (MS) and other demyelinating disorders in new findings that may help explain differences in disease course, particularly progressive disability in MS.

Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).

“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.

The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.

The findings were published online July 14 in Neurology.
 

Lesion evolution

MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.

Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.

Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.

They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.

Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.

Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.

An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.

Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.

In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.

Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.

Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
 

Complete resolution

Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).

Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).

Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.

For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.

Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm²) than in those with NMOSD (104 mm²; P = .02) or MS (36 mm²; P < .001).

Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm²) and NMOSD (309 mm²) groups; both experienced greater reductions than the MS group (23 mm²; P < .001).
 

Lesion prevention

Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.

Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.

“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.

He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.

“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
 

Differences in pathology

Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.

“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.

The study’s cross-sectional comparison was its main strength, he noted.

“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”

The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.

Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.

“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”

The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.

Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.

The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.

This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Differences in lesion evolution may help neurologists distinguish between multiple sclerosis (MS) and other demyelinating disorders in new findings that may help explain differences in disease course, particularly progressive disability in MS.

Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).

“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.

The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.

The findings were published online July 14 in Neurology.
 

Lesion evolution

MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.

Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.

Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.

They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.

Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.

Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.

An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.

Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.

In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.

Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.

Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
 

Complete resolution

Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).

Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).

Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.

For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.

Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm²) than in those with NMOSD (104 mm²; P = .02) or MS (36 mm²; P < .001).

Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm²) and NMOSD (309 mm²) groups; both experienced greater reductions than the MS group (23 mm²; P < .001).
 

Lesion prevention

Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.

Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.

“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.

He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.

“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
 

Differences in pathology

Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.

“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.

The study’s cross-sectional comparison was its main strength, he noted.

“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”

The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.

Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.

“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”

The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.

Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.

The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.

This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Differences in lesion evolution may help neurologists distinguish between multiple sclerosis (MS) and other demyelinating disorders in new findings that may help explain differences in disease course, particularly progressive disability in MS.

Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).

“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.

The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.

The findings were published online July 14 in Neurology.
 

Lesion evolution

MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.

Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.

Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.

They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.

Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.

Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.

An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.

Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.

In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.

Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.

Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
 

Complete resolution

Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).

Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).

Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.

For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.

Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm²) than in those with NMOSD (104 mm²; P = .02) or MS (36 mm²; P < .001).

Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm²) and NMOSD (309 mm²) groups; both experienced greater reductions than the MS group (23 mm²; P < .001).
 

Lesion prevention

Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.

Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.

“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.

He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.

“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
 

Differences in pathology

Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.

“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.

The study’s cross-sectional comparison was its main strength, he noted.

“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”

The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.

Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.

“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”

The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.

Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.

The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.

This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In medical school, I remember thinking that telling a patient “you have cancer” would be the most professionally challenging phrase I would ever utter. And don’t get me wrong – it certainly isn’t easy; but, compared with telling someone “you are infertile,” it’s a cakewalk.

Maybe it’s because people “have” cancer and cancer is something you “fight.” Or maybe because, unlike infertility, cancer has become a part of public life (think lapel pins and support groups) and is now easier to accept. On the other hand, someone “is” infertile. The condition is a source of embarrassment for the couple and is often hidden from society.

Here’s another concerning point of contrast: While the overall rate of cancer death has declined since the early 1990s, infertility is increasing. Reports now show that one in six couples have problems conceiving and the use of assisted reproductive technologies is increasing by 5%-10% per year. Many theories exist to explain these trends, chief among them the rise in average maternal age and the increasing incidence of obesity, as well as various other male- and female-specific factors.

But interestingly, recent data suggest that the most male of all male-specific factors – total sperm count – may be specifically to blame.

According to a recent meta-analysis, the average total sperm count in men declined by 59.3% between 1973 and 2011. While these data certainly have limitations – including the exclusion of non-English publications, the reliance on total sperm count and not sperm motility, and the potential bias of those patients willing to give a semen sample – the overall trend nevertheless seems to be clearly downward. What’s more concerning, if you believe the data presented, is that there does not appear to be a leveling off of the downward curve in total sperm count.

Think about that last statement. At the current rate of decline, the average sperm count will be zero in 2045. One of the lead authors on the meta-analysis, Hagai Levine, MD, MPH, goes so far as to state, “We should hope for the best and prepare for the worst.”

As a matter of personal philosophy, I’m not a huge fan of end-of-the-world predictions because they tend not to come true (think Montanism back in the 2nd century; the 2012 Mayan calendar scare; or my personal favorite, the Prophet Hen of Leeds). On the other hand, the overall trend of decreased total sperm count in the English-speaking world seems to be true and it raises the interesting question of why.

According to the Mayo Clinic, causes of decreased sperm count include everything from anatomical factors (like varicoceles and ejaculatory issues) and lifestyle issues (such as recreational drugs, weight gain, and emotional stress) to environmental exposures (heavy metal or radiation). The senior author of the aforementioned meta-analysis, Shanna Swan, PhD, has championed another theory: the widespread exposure to endocrine-disrupting chemicals in everyday plastics.

It turns out that at least two chemicals used in the plastics industry, bisphenol A and phthalates, can mimic the effect of estrogen when ingested into the body. Even low levels of these chemicals in our bodies can lead to health problems.

Consider for a moment the presence of plastics in your life: the plastic wrappings on your food, plastic containers for shampoos and beauty products, and even the coatings of our oral supplements. A study by the Centers for Disease Control and Prevention looked at the urine of people participating in the National Health and Nutrition Examination Survey and found detectable concentrations of both of these chemicals in nearly all participants.

In 2045, I intend to be retired. But in the meantime, I think we all need to be aware of the potential impact that various endocrine-disrupting chemicals could be having on humanity. We need more research. If indeed the connection between endocrine disruptors and decreased sperm count is borne out, changes in our environmental exposure to these chemicals need to be made.

Henry Rosevear, MD, is a private-practice urologist based in Colorado Springs. He comes from a long line of doctors, but before entering medicine he served in the U.S. Navy as an officer aboard the USS Pittsburgh, a fast-attack submarine based out of New London, Conn. During his time in the Navy, he served in two deployments to the Persian Gulf, including combat experience as part of Operation Iraqi Freedom. Dr. Rosevear disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

In medical school, I remember thinking that telling a patient “you have cancer” would be the most professionally challenging phrase I would ever utter. And don’t get me wrong – it certainly isn’t easy; but, compared with telling someone “you are infertile,” it’s a cakewalk.

Maybe it’s because people “have” cancer and cancer is something you “fight.” Or maybe because, unlike infertility, cancer has become a part of public life (think lapel pins and support groups) and is now easier to accept. On the other hand, someone “is” infertile. The condition is a source of embarrassment for the couple and is often hidden from society.

Here’s another concerning point of contrast: While the overall rate of cancer death has declined since the early 1990s, infertility is increasing. Reports now show that one in six couples have problems conceiving and the use of assisted reproductive technologies is increasing by 5%-10% per year. Many theories exist to explain these trends, chief among them the rise in average maternal age and the increasing incidence of obesity, as well as various other male- and female-specific factors.

But interestingly, recent data suggest that the most male of all male-specific factors – total sperm count – may be specifically to blame.

According to a recent meta-analysis, the average total sperm count in men declined by 59.3% between 1973 and 2011. While these data certainly have limitations – including the exclusion of non-English publications, the reliance on total sperm count and not sperm motility, and the potential bias of those patients willing to give a semen sample – the overall trend nevertheless seems to be clearly downward. What’s more concerning, if you believe the data presented, is that there does not appear to be a leveling off of the downward curve in total sperm count.

Think about that last statement. At the current rate of decline, the average sperm count will be zero in 2045. One of the lead authors on the meta-analysis, Hagai Levine, MD, MPH, goes so far as to state, “We should hope for the best and prepare for the worst.”

As a matter of personal philosophy, I’m not a huge fan of end-of-the-world predictions because they tend not to come true (think Montanism back in the 2nd century; the 2012 Mayan calendar scare; or my personal favorite, the Prophet Hen of Leeds). On the other hand, the overall trend of decreased total sperm count in the English-speaking world seems to be true and it raises the interesting question of why.

According to the Mayo Clinic, causes of decreased sperm count include everything from anatomical factors (like varicoceles and ejaculatory issues) and lifestyle issues (such as recreational drugs, weight gain, and emotional stress) to environmental exposures (heavy metal or radiation). The senior author of the aforementioned meta-analysis, Shanna Swan, PhD, has championed another theory: the widespread exposure to endocrine-disrupting chemicals in everyday plastics.

It turns out that at least two chemicals used in the plastics industry, bisphenol A and phthalates, can mimic the effect of estrogen when ingested into the body. Even low levels of these chemicals in our bodies can lead to health problems.

Consider for a moment the presence of plastics in your life: the plastic wrappings on your food, plastic containers for shampoos and beauty products, and even the coatings of our oral supplements. A study by the Centers for Disease Control and Prevention looked at the urine of people participating in the National Health and Nutrition Examination Survey and found detectable concentrations of both of these chemicals in nearly all participants.

In 2045, I intend to be retired. But in the meantime, I think we all need to be aware of the potential impact that various endocrine-disrupting chemicals could be having on humanity. We need more research. If indeed the connection between endocrine disruptors and decreased sperm count is borne out, changes in our environmental exposure to these chemicals need to be made.

Henry Rosevear, MD, is a private-practice urologist based in Colorado Springs. He comes from a long line of doctors, but before entering medicine he served in the U.S. Navy as an officer aboard the USS Pittsburgh, a fast-attack submarine based out of New London, Conn. During his time in the Navy, he served in two deployments to the Persian Gulf, including combat experience as part of Operation Iraqi Freedom. Dr. Rosevear disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

In medical school, I remember thinking that telling a patient “you have cancer” would be the most professionally challenging phrase I would ever utter. And don’t get me wrong – it certainly isn’t easy; but, compared with telling someone “you are infertile,” it’s a cakewalk.

Maybe it’s because people “have” cancer and cancer is something you “fight.” Or maybe because, unlike infertility, cancer has become a part of public life (think lapel pins and support groups) and is now easier to accept. On the other hand, someone “is” infertile. The condition is a source of embarrassment for the couple and is often hidden from society.

Here’s another concerning point of contrast: While the overall rate of cancer death has declined since the early 1990s, infertility is increasing. Reports now show that one in six couples have problems conceiving and the use of assisted reproductive technologies is increasing by 5%-10% per year. Many theories exist to explain these trends, chief among them the rise in average maternal age and the increasing incidence of obesity, as well as various other male- and female-specific factors.

But interestingly, recent data suggest that the most male of all male-specific factors – total sperm count – may be specifically to blame.

According to a recent meta-analysis, the average total sperm count in men declined by 59.3% between 1973 and 2011. While these data certainly have limitations – including the exclusion of non-English publications, the reliance on total sperm count and not sperm motility, and the potential bias of those patients willing to give a semen sample – the overall trend nevertheless seems to be clearly downward. What’s more concerning, if you believe the data presented, is that there does not appear to be a leveling off of the downward curve in total sperm count.

Think about that last statement. At the current rate of decline, the average sperm count will be zero in 2045. One of the lead authors on the meta-analysis, Hagai Levine, MD, MPH, goes so far as to state, “We should hope for the best and prepare for the worst.”

As a matter of personal philosophy, I’m not a huge fan of end-of-the-world predictions because they tend not to come true (think Montanism back in the 2nd century; the 2012 Mayan calendar scare; or my personal favorite, the Prophet Hen of Leeds). On the other hand, the overall trend of decreased total sperm count in the English-speaking world seems to be true and it raises the interesting question of why.

According to the Mayo Clinic, causes of decreased sperm count include everything from anatomical factors (like varicoceles and ejaculatory issues) and lifestyle issues (such as recreational drugs, weight gain, and emotional stress) to environmental exposures (heavy metal or radiation). The senior author of the aforementioned meta-analysis, Shanna Swan, PhD, has championed another theory: the widespread exposure to endocrine-disrupting chemicals in everyday plastics.

It turns out that at least two chemicals used in the plastics industry, bisphenol A and phthalates, can mimic the effect of estrogen when ingested into the body. Even low levels of these chemicals in our bodies can lead to health problems.

Consider for a moment the presence of plastics in your life: the plastic wrappings on your food, plastic containers for shampoos and beauty products, and even the coatings of our oral supplements. A study by the Centers for Disease Control and Prevention looked at the urine of people participating in the National Health and Nutrition Examination Survey and found detectable concentrations of both of these chemicals in nearly all participants.

In 2045, I intend to be retired. But in the meantime, I think we all need to be aware of the potential impact that various endocrine-disrupting chemicals could be having on humanity. We need more research. If indeed the connection between endocrine disruptors and decreased sperm count is borne out, changes in our environmental exposure to these chemicals need to be made.

Henry Rosevear, MD, is a private-practice urologist based in Colorado Springs. He comes from a long line of doctors, but before entering medicine he served in the U.S. Navy as an officer aboard the USS Pittsburgh, a fast-attack submarine based out of New London, Conn. During his time in the Navy, he served in two deployments to the Persian Gulf, including combat experience as part of Operation Iraqi Freedom. Dr. Rosevear disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.