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‘Urgent Need’ to Examine Anti-Seizure Medication Pricing
LOS ANGELES — results of a new study showed.
These findings highlight an “urgent need” to examine ASM pricing, said study investigator Pradeep Javarayee, MD, MBA, assistant professor, Department of Neurology, Medical College of Wisconsin, Milwaukee.
“The price disparity between generic and brand-name anti-seizure medications is growing,” said Javarayee. “Understanding these trends is essential for clinicians to make cost-conscious prescribing decisions and to advocate for policies that ensure equitable access to treatment for patients with epilepsy.”
The findings were presented at American Epilepsy Society (AES) 78th Annual Meeting 2024.
Concerning Trends
Researchers analyzed prices of ASMs using National Average Drug Acquisition Cost (NADAC) data provided by the Centers for Medicare & Medicaid Services from November 2013 to July 2023.
A publicly available resource, NADAC is widely regarded as the most reliable benchmark for drug reimbursement in the United States, said Javarayee. It is based on the price/unit of Medicaid-covered outpatient drugs collected though monthly surveys of retail community pharmacies across the United States.
The database includes medication names, strengths, formulations, and National Drug Codes.
The study examined 23 US Food and Drug Administration–approved ASMs, encompassing 223 oral formulations, which included 112 brand-name and 111 generic products.
To account for inflation, researchers adjusted ASM prices using the Consumer Price Index for Medicinal Drugs–Seasonally Adjusted. They also explored the effects of the COVID-19 pandemic on drug pricing.
The study uncovered trends that Javarayee found concerning. For example, between 2013 and 2023, the average price of brand-name ASMs increased from $8.71 to $15.43, whereas the average price of generic ASMs decreased from $1.39 to $1.26.
Most generic ASMs remained in the low-cost range ($0-$0.25) during the study period, whereas the proportion of higher-priced brand-name ASMs ($10-$50) increased.
The number of brand-name ASMs with a mean price exceeding $15 rose from two (2013-2016) to six (2017-2019) and then to eight (2020-2023).
Unsustainable Price Increases
The study uncovered examples of what Javarayee called “extreme” price differences. For instance, matched brand-name and generic ASMs with price differences of 1000%-9999% increased from 32.88% in 2013-2016 to 41.43% in 2020-2023.
Among brand-name ASMs, cenobamate (Xcopri), which is approved in the United States for partial-onset seizures, had the highest mean price between 2020 and 2023 ($35.59). For generic ASMs, topiramate had the highest mean price in the same time period ($6.64).
Looking at formulation-based cost differences, the study found generic immediate-release formulations were significantly cheaper than extended-release or delayed-release counterparts, with cost differences reaching as high as 7751.20%.
The study also showed the COVID-19 pandemic led to a 24.4% increase in brand-name ASM prices and a 23.1% decrease in generic ASM prices.
The results underscore the need to raise awareness of drug pricing dynamics and call for targeted policy interventions to alleviate the rising cost burden on patients, said Javarayee.
He emphasized that such price increases are unsustainable. “Addressing these disparities is critical not only for improving patient adherence and outcomes but also for reducing the overall economic strain on the healthcare system.”
‘Tip of the Iceberg’
Reached for a comment, Tim Welty, a pharmacist in Des Moines, Iowa, who specializes in epilepsy drugs, agreed that the issue of medication costs needs to be addressed.
“I absolutely think physicians and others need to advocate for transparency in pricing,” he said. It’s not unusual for physician requests to have newer ASMs covered for their patients to be denied, he added.
Welty also noted Congress is currently considering bills that address the lack of transparency in the way medications are reimbursed.
This new study doesn’t reveal what patients are paying for their medications, he said. “These data tell me the national average of the cost to the pharmacy, but don’t tell me what the patient is actually paying, or what the insurance companies are actually paying for these medications.”
A “hot topic” in the industry is the role of pharmacy benefit managers, who are contracted by health insurance companies to manage medication portfolios, in influencing drug prices.
Drug pricing is a complicated topic. “There’s a lot more behind this; this is just like a tip of the iceberg,” said Welty.
Also commenting, Jacqueline French, MD, professor, NYU Comprehensive Epilepsy Center, New York City, said the much higher ASM prices are “very problematic,” particularly for drugs that don’t have a generic.
“I wonder how much the drugs for orphan indications, which are usually higher priced, influenced the numbers.”
The good news, though, is that many people “can safely take generics if they’re available,” said French.
The investigators and Welty reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — results of a new study showed.
These findings highlight an “urgent need” to examine ASM pricing, said study investigator Pradeep Javarayee, MD, MBA, assistant professor, Department of Neurology, Medical College of Wisconsin, Milwaukee.
“The price disparity between generic and brand-name anti-seizure medications is growing,” said Javarayee. “Understanding these trends is essential for clinicians to make cost-conscious prescribing decisions and to advocate for policies that ensure equitable access to treatment for patients with epilepsy.”
The findings were presented at American Epilepsy Society (AES) 78th Annual Meeting 2024.
Concerning Trends
Researchers analyzed prices of ASMs using National Average Drug Acquisition Cost (NADAC) data provided by the Centers for Medicare & Medicaid Services from November 2013 to July 2023.
A publicly available resource, NADAC is widely regarded as the most reliable benchmark for drug reimbursement in the United States, said Javarayee. It is based on the price/unit of Medicaid-covered outpatient drugs collected though monthly surveys of retail community pharmacies across the United States.
The database includes medication names, strengths, formulations, and National Drug Codes.
The study examined 23 US Food and Drug Administration–approved ASMs, encompassing 223 oral formulations, which included 112 brand-name and 111 generic products.
To account for inflation, researchers adjusted ASM prices using the Consumer Price Index for Medicinal Drugs–Seasonally Adjusted. They also explored the effects of the COVID-19 pandemic on drug pricing.
The study uncovered trends that Javarayee found concerning. For example, between 2013 and 2023, the average price of brand-name ASMs increased from $8.71 to $15.43, whereas the average price of generic ASMs decreased from $1.39 to $1.26.
Most generic ASMs remained in the low-cost range ($0-$0.25) during the study period, whereas the proportion of higher-priced brand-name ASMs ($10-$50) increased.
The number of brand-name ASMs with a mean price exceeding $15 rose from two (2013-2016) to six (2017-2019) and then to eight (2020-2023).
Unsustainable Price Increases
The study uncovered examples of what Javarayee called “extreme” price differences. For instance, matched brand-name and generic ASMs with price differences of 1000%-9999% increased from 32.88% in 2013-2016 to 41.43% in 2020-2023.
Among brand-name ASMs, cenobamate (Xcopri), which is approved in the United States for partial-onset seizures, had the highest mean price between 2020 and 2023 ($35.59). For generic ASMs, topiramate had the highest mean price in the same time period ($6.64).
Looking at formulation-based cost differences, the study found generic immediate-release formulations were significantly cheaper than extended-release or delayed-release counterparts, with cost differences reaching as high as 7751.20%.
The study also showed the COVID-19 pandemic led to a 24.4% increase in brand-name ASM prices and a 23.1% decrease in generic ASM prices.
The results underscore the need to raise awareness of drug pricing dynamics and call for targeted policy interventions to alleviate the rising cost burden on patients, said Javarayee.
He emphasized that such price increases are unsustainable. “Addressing these disparities is critical not only for improving patient adherence and outcomes but also for reducing the overall economic strain on the healthcare system.”
‘Tip of the Iceberg’
Reached for a comment, Tim Welty, a pharmacist in Des Moines, Iowa, who specializes in epilepsy drugs, agreed that the issue of medication costs needs to be addressed.
“I absolutely think physicians and others need to advocate for transparency in pricing,” he said. It’s not unusual for physician requests to have newer ASMs covered for their patients to be denied, he added.
Welty also noted Congress is currently considering bills that address the lack of transparency in the way medications are reimbursed.
This new study doesn’t reveal what patients are paying for their medications, he said. “These data tell me the national average of the cost to the pharmacy, but don’t tell me what the patient is actually paying, or what the insurance companies are actually paying for these medications.”
A “hot topic” in the industry is the role of pharmacy benefit managers, who are contracted by health insurance companies to manage medication portfolios, in influencing drug prices.
Drug pricing is a complicated topic. “There’s a lot more behind this; this is just like a tip of the iceberg,” said Welty.
Also commenting, Jacqueline French, MD, professor, NYU Comprehensive Epilepsy Center, New York City, said the much higher ASM prices are “very problematic,” particularly for drugs that don’t have a generic.
“I wonder how much the drugs for orphan indications, which are usually higher priced, influenced the numbers.”
The good news, though, is that many people “can safely take generics if they’re available,” said French.
The investigators and Welty reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — results of a new study showed.
These findings highlight an “urgent need” to examine ASM pricing, said study investigator Pradeep Javarayee, MD, MBA, assistant professor, Department of Neurology, Medical College of Wisconsin, Milwaukee.
“The price disparity between generic and brand-name anti-seizure medications is growing,” said Javarayee. “Understanding these trends is essential for clinicians to make cost-conscious prescribing decisions and to advocate for policies that ensure equitable access to treatment for patients with epilepsy.”
The findings were presented at American Epilepsy Society (AES) 78th Annual Meeting 2024.
Concerning Trends
Researchers analyzed prices of ASMs using National Average Drug Acquisition Cost (NADAC) data provided by the Centers for Medicare & Medicaid Services from November 2013 to July 2023.
A publicly available resource, NADAC is widely regarded as the most reliable benchmark for drug reimbursement in the United States, said Javarayee. It is based on the price/unit of Medicaid-covered outpatient drugs collected though monthly surveys of retail community pharmacies across the United States.
The database includes medication names, strengths, formulations, and National Drug Codes.
The study examined 23 US Food and Drug Administration–approved ASMs, encompassing 223 oral formulations, which included 112 brand-name and 111 generic products.
To account for inflation, researchers adjusted ASM prices using the Consumer Price Index for Medicinal Drugs–Seasonally Adjusted. They also explored the effects of the COVID-19 pandemic on drug pricing.
The study uncovered trends that Javarayee found concerning. For example, between 2013 and 2023, the average price of brand-name ASMs increased from $8.71 to $15.43, whereas the average price of generic ASMs decreased from $1.39 to $1.26.
Most generic ASMs remained in the low-cost range ($0-$0.25) during the study period, whereas the proportion of higher-priced brand-name ASMs ($10-$50) increased.
The number of brand-name ASMs with a mean price exceeding $15 rose from two (2013-2016) to six (2017-2019) and then to eight (2020-2023).
Unsustainable Price Increases
The study uncovered examples of what Javarayee called “extreme” price differences. For instance, matched brand-name and generic ASMs with price differences of 1000%-9999% increased from 32.88% in 2013-2016 to 41.43% in 2020-2023.
Among brand-name ASMs, cenobamate (Xcopri), which is approved in the United States for partial-onset seizures, had the highest mean price between 2020 and 2023 ($35.59). For generic ASMs, topiramate had the highest mean price in the same time period ($6.64).
Looking at formulation-based cost differences, the study found generic immediate-release formulations were significantly cheaper than extended-release or delayed-release counterparts, with cost differences reaching as high as 7751.20%.
The study also showed the COVID-19 pandemic led to a 24.4% increase in brand-name ASM prices and a 23.1% decrease in generic ASM prices.
The results underscore the need to raise awareness of drug pricing dynamics and call for targeted policy interventions to alleviate the rising cost burden on patients, said Javarayee.
He emphasized that such price increases are unsustainable. “Addressing these disparities is critical not only for improving patient adherence and outcomes but also for reducing the overall economic strain on the healthcare system.”
‘Tip of the Iceberg’
Reached for a comment, Tim Welty, a pharmacist in Des Moines, Iowa, who specializes in epilepsy drugs, agreed that the issue of medication costs needs to be addressed.
“I absolutely think physicians and others need to advocate for transparency in pricing,” he said. It’s not unusual for physician requests to have newer ASMs covered for their patients to be denied, he added.
Welty also noted Congress is currently considering bills that address the lack of transparency in the way medications are reimbursed.
This new study doesn’t reveal what patients are paying for their medications, he said. “These data tell me the national average of the cost to the pharmacy, but don’t tell me what the patient is actually paying, or what the insurance companies are actually paying for these medications.”
A “hot topic” in the industry is the role of pharmacy benefit managers, who are contracted by health insurance companies to manage medication portfolios, in influencing drug prices.
Drug pricing is a complicated topic. “There’s a lot more behind this; this is just like a tip of the iceberg,” said Welty.
Also commenting, Jacqueline French, MD, professor, NYU Comprehensive Epilepsy Center, New York City, said the much higher ASM prices are “very problematic,” particularly for drugs that don’t have a generic.
“I wonder how much the drugs for orphan indications, which are usually higher priced, influenced the numbers.”
The good news, though, is that many people “can safely take generics if they’re available,” said French.
The investigators and Welty reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM AES 2024
How Exactly Does One Map the Human Gut?
There was a recent flurry of excitement when UK researchers from the Wellcome Sanger Institute, a nonprofit genomics and genetics research organization in Cambridge, England, announced their creation of the most detailed cell map of the human gastrointestinal (GI) tract up to this point. Using spatial and single-cell data from 1.6 million cells (from 271 donors), the scientists’ work, published in Nature, yields valuable information about the gut’s health and disease states.
“We now have a nice idea of what cell types we can find in the gut,” said co-author Rasa Elmentaite, PhD, co-founder and head of Genomics and Data Science at Ensocell.
No small question: How, exactly, does one go about mapping the human gut?
Most of all, Elmentaite said, it has taken the scientists involved down paths they never anticipated.
How It Began
Over the past 5-7 years, there have been many individual publications across institutes where research labs have created snippets of what the cells in the gut look like, said Elmentaite, referring to the GI tract, which in this case encompasses the mouth, throat, esophagus, stomach, small intestine, large intestine, rectum, and anus.
Labs studying gut cells often focus on one specific region, for example, the small intestine or the large intestine, if they’re working on Crohn’s disease research. “It makes sense. The GI tract is really regionalized,” she said.
In 2019 and 2021, Elmentaite and her colleagues published papers that mapped some cells in the human gut, and their work garnered attention from other scientists around the world. That’s how they decided to take on the challenge of creating a more comprehensive map of the cells in both the healthy gut and in GI tracts where disease is present.
“We realized there are so many other labs interested in understanding the intestinal tract holistically,” she said. “We thought it would be really interesting to look at the cells in the context of the whole GI system.”
Not a Bad ‘Lockdown Project’
During the pandemic, while the rest of society was playing with sourdough starter, Elmentaite’s lab decided to pool their datasets with data from other labs to see what happened. They had more than 20 datasets at the time and wanted to generate more to fill gaps where there was less information available (eg, data on the cells in the stomach).
“It required getting samples from surgeons, going into the lab and processing those samples into single cells, and then processing that data bioinformatically,” said Elmentaite.
She explained that generating more datasets was not a job for one person and “required convincing a lot of scientists that it was worthwhile,” including a cancer biologist and a mucosal immunologist. They also brought in more technical bioinformatics expertise and recruited an IT team — several people who only worked on processing data and clearing it, “so it was aligned very specifically, and processed very uniformly, across the study,” Elmentaite said.
In the end, with researchers coming together on many Zoom calls from Australia, Germany, Norway, Spain, and numerous locations across the United Kingdom, they were able to integrate 25 single-cell RNA sequencing datasets that encompassed the entire healthy GI tract in development and in adults, leading to a healthy gut reference atlas that includes about 1.1 million cells and 136 cell subgroups.
How to Build a Two-Dimensional (2D) Map of the Gut
Here’s where the weeds get taller: Raw sequencing reads — bits of different RNA that the researchers sequenced from individual biological samples — needed to be mapped back to genes so that the researchers could understand what kinds of genes were expressed in the samples.
“There is a lot of curation there that needs to happen because the versions of transcriptome [a complete set of RNA molecules in a single cell or tissue], and what the genome looks like, is evolving constantly. So we have to map it back to the same transcriptomic reference,” Elmentaite said.
Once they knew all the different genes active in a cell, the researchers were able, using bioinformatics, to pull all of the datasets together and visualize them in a 2D space — essentially, a representation of a map.
“The cells that are transcriptionally more similar to each other, they will cluster together. And the ones that are more distinct transcriptionally will be farther away from each other,” Elmentaite said.
For decades, GI tract researchers had individually studied which types of genes are activated in an epithelial cell vs a T cell vs a B cell, she said, and “then suddenly you’re seeing it on your screen all at once. It’s amazing to see.”
In Brutal Detail
One of the biggest challenges in interpreting the data involved many people who made sure that there were no technical differences between the samples, Elmentaite said.
For example, samples processed in different labs may have sequencing differences between them. Or the kind of enzymes used to process the tissue might have been different from lab to lab. Sometimes they’d even record down to the detail what time of the day a sample was collected, if that information was available.
“Computationally, we considered all of these variables and tried to regress as much of that as possible. And then, if we saw clusters that resembled gene expression that we know is consistent with some of the cell types, then we knew that we’d regressed all the batch effects,” said Elmentaite.
Before ‘Eureka’ Comes a Few ‘Aha’ Moments
There were many “aha moments,” but also some puzzling ones, she said. One of the biggest surprises was seeing that the identity of a cell believed to be set from development can actually change if a person has a lot of irritation and inflammation, as occurs in inflammatory bowel disease. Epithelial cell metaplasia was one of the surprises.
“Metaplasia describes an activation or differentiation of one differentiated cell type into another differentiated cell type. And we knew that that exists in some of the upper GI diseases, but we didn’t realize that the same sort of mechanism exists in the small intestine,” Elmentaite said.
Epithelial cells are among the most abundant cells in the body. The researchers knew from established research that these cells act a bit like first responders and provide healing to the gut. “We could see that they were producing a lot of mucous that helps to potentially flush down the microbes that are triggering inflammation. But the ‘aha moment’ for us was that actually there’s a dual function in these cells,” she said.
They could see in the transcriptional profile a significant production of chemokines (a family of proteins that play a role in the body’s immune responses) and major histocompatibility complex class II molecules (cell surface proteins involved in the body’s immune response), and the epithelial cells seemed to attract neutrophils and monocytes and to interact with certain T cells — adding to the cycle of chronic inflammation.
“I think for a lot of us, this was a surprise because we think of epithelial cells as more like a barrier, just a passive player in, for example, inflammatory bowel disease,” said Elmentaite.
In addition to reporting their findings on epithelial cell metaplasia, the researchers processed 12 GI disease datasets, including celiac disease, Crohn’s disease, GI-related cancers, and ulcerative colitis.
A Gut Cell Atlas for the People (Well, Scientific People)
“The Gut Cell Atlas is usable for everyone, and everyone has a chance to contribute,” said Elmentaite. But 1.6 million cells is only a start and more data are needed, she said, and efforts are being spearheaded at the broader Human Cell Atlas project to collect it. There are also efforts to get all researchers using the same cell annotation, research-wide standards that will make the atlas truly usable for everyone.
Keith Summa, MD, PhD, assistant professor of medicine in the Division of Gastroenterology and Hepatology at Feinberg School of Medicine, Northwestern University, Chicago, focuses much of his work on inflammatory bowel disease as well as disorders of the gut-brain interaction. He conducts basic and translational research using experimental models of intestinal inflammation.
At Northwestern University, they have a tissue biorepository. It includes colon and intestine tissue samples from healthy individuals as well as individuals with different disease states. “One potential area where I could see this being a useful tool for us is that we could utilize the Gut Cell Atlas in the analysis of our tissue samples to see if we find commonalities between what’s described in the atlas and then what we’re observing,” said Summa, who was not involved in the UK-based project.
He said Northwestern University’s biorepository has details about what medications people were on and the extent and severity of their disease.
“We may be able to utilize the Gut Cell Atlas to help us look at specific factors in terms of how people are responding to different treatments, how different cell types are affected by different treatments, or how they are active or not active in different severities of disease. It may help us provide more precision to our understanding of these different conditions,” said Summa.
He also noted how GI specialists use “Crohn’s disease” as a single diagnosis, “but that encompasses a pretty wide spectrum of phenotypes and behaviors,” he said. “I think looking at such a cell-specific level may help to better identify some of the different pathways that are active and the different phenotypes or behaviors of this disease.”
Next Step: Visualize It in a Three-Dimensional (3D) Space
The next stage for Elmentaite and her colleagues is to evolve the 2D map into a 3D map so they can visualize which cells are where and how they are organized in space.
“The next step, which I think is super exciting, is understanding how these cells depend on each other,” she said. “Really functionally understanding if some of them are essential and others are not. And doing AI modeling to understand what we can learn from this vast amount of data that we’re generating. And of course, that includes how we use this knowledge to create precision therapies.”
A version of this article appeared on Medscape.com.
There was a recent flurry of excitement when UK researchers from the Wellcome Sanger Institute, a nonprofit genomics and genetics research organization in Cambridge, England, announced their creation of the most detailed cell map of the human gastrointestinal (GI) tract up to this point. Using spatial and single-cell data from 1.6 million cells (from 271 donors), the scientists’ work, published in Nature, yields valuable information about the gut’s health and disease states.
“We now have a nice idea of what cell types we can find in the gut,” said co-author Rasa Elmentaite, PhD, co-founder and head of Genomics and Data Science at Ensocell.
No small question: How, exactly, does one go about mapping the human gut?
Most of all, Elmentaite said, it has taken the scientists involved down paths they never anticipated.
How It Began
Over the past 5-7 years, there have been many individual publications across institutes where research labs have created snippets of what the cells in the gut look like, said Elmentaite, referring to the GI tract, which in this case encompasses the mouth, throat, esophagus, stomach, small intestine, large intestine, rectum, and anus.
Labs studying gut cells often focus on one specific region, for example, the small intestine or the large intestine, if they’re working on Crohn’s disease research. “It makes sense. The GI tract is really regionalized,” she said.
In 2019 and 2021, Elmentaite and her colleagues published papers that mapped some cells in the human gut, and their work garnered attention from other scientists around the world. That’s how they decided to take on the challenge of creating a more comprehensive map of the cells in both the healthy gut and in GI tracts where disease is present.
“We realized there are so many other labs interested in understanding the intestinal tract holistically,” she said. “We thought it would be really interesting to look at the cells in the context of the whole GI system.”
Not a Bad ‘Lockdown Project’
During the pandemic, while the rest of society was playing with sourdough starter, Elmentaite’s lab decided to pool their datasets with data from other labs to see what happened. They had more than 20 datasets at the time and wanted to generate more to fill gaps where there was less information available (eg, data on the cells in the stomach).
“It required getting samples from surgeons, going into the lab and processing those samples into single cells, and then processing that data bioinformatically,” said Elmentaite.
She explained that generating more datasets was not a job for one person and “required convincing a lot of scientists that it was worthwhile,” including a cancer biologist and a mucosal immunologist. They also brought in more technical bioinformatics expertise and recruited an IT team — several people who only worked on processing data and clearing it, “so it was aligned very specifically, and processed very uniformly, across the study,” Elmentaite said.
In the end, with researchers coming together on many Zoom calls from Australia, Germany, Norway, Spain, and numerous locations across the United Kingdom, they were able to integrate 25 single-cell RNA sequencing datasets that encompassed the entire healthy GI tract in development and in adults, leading to a healthy gut reference atlas that includes about 1.1 million cells and 136 cell subgroups.
How to Build a Two-Dimensional (2D) Map of the Gut
Here’s where the weeds get taller: Raw sequencing reads — bits of different RNA that the researchers sequenced from individual biological samples — needed to be mapped back to genes so that the researchers could understand what kinds of genes were expressed in the samples.
“There is a lot of curation there that needs to happen because the versions of transcriptome [a complete set of RNA molecules in a single cell or tissue], and what the genome looks like, is evolving constantly. So we have to map it back to the same transcriptomic reference,” Elmentaite said.
Once they knew all the different genes active in a cell, the researchers were able, using bioinformatics, to pull all of the datasets together and visualize them in a 2D space — essentially, a representation of a map.
“The cells that are transcriptionally more similar to each other, they will cluster together. And the ones that are more distinct transcriptionally will be farther away from each other,” Elmentaite said.
For decades, GI tract researchers had individually studied which types of genes are activated in an epithelial cell vs a T cell vs a B cell, she said, and “then suddenly you’re seeing it on your screen all at once. It’s amazing to see.”
In Brutal Detail
One of the biggest challenges in interpreting the data involved many people who made sure that there were no technical differences between the samples, Elmentaite said.
For example, samples processed in different labs may have sequencing differences between them. Or the kind of enzymes used to process the tissue might have been different from lab to lab. Sometimes they’d even record down to the detail what time of the day a sample was collected, if that information was available.
“Computationally, we considered all of these variables and tried to regress as much of that as possible. And then, if we saw clusters that resembled gene expression that we know is consistent with some of the cell types, then we knew that we’d regressed all the batch effects,” said Elmentaite.
Before ‘Eureka’ Comes a Few ‘Aha’ Moments
There were many “aha moments,” but also some puzzling ones, she said. One of the biggest surprises was seeing that the identity of a cell believed to be set from development can actually change if a person has a lot of irritation and inflammation, as occurs in inflammatory bowel disease. Epithelial cell metaplasia was one of the surprises.
“Metaplasia describes an activation or differentiation of one differentiated cell type into another differentiated cell type. And we knew that that exists in some of the upper GI diseases, but we didn’t realize that the same sort of mechanism exists in the small intestine,” Elmentaite said.
Epithelial cells are among the most abundant cells in the body. The researchers knew from established research that these cells act a bit like first responders and provide healing to the gut. “We could see that they were producing a lot of mucous that helps to potentially flush down the microbes that are triggering inflammation. But the ‘aha moment’ for us was that actually there’s a dual function in these cells,” she said.
They could see in the transcriptional profile a significant production of chemokines (a family of proteins that play a role in the body’s immune responses) and major histocompatibility complex class II molecules (cell surface proteins involved in the body’s immune response), and the epithelial cells seemed to attract neutrophils and monocytes and to interact with certain T cells — adding to the cycle of chronic inflammation.
“I think for a lot of us, this was a surprise because we think of epithelial cells as more like a barrier, just a passive player in, for example, inflammatory bowel disease,” said Elmentaite.
In addition to reporting their findings on epithelial cell metaplasia, the researchers processed 12 GI disease datasets, including celiac disease, Crohn’s disease, GI-related cancers, and ulcerative colitis.
A Gut Cell Atlas for the People (Well, Scientific People)
“The Gut Cell Atlas is usable for everyone, and everyone has a chance to contribute,” said Elmentaite. But 1.6 million cells is only a start and more data are needed, she said, and efforts are being spearheaded at the broader Human Cell Atlas project to collect it. There are also efforts to get all researchers using the same cell annotation, research-wide standards that will make the atlas truly usable for everyone.
Keith Summa, MD, PhD, assistant professor of medicine in the Division of Gastroenterology and Hepatology at Feinberg School of Medicine, Northwestern University, Chicago, focuses much of his work on inflammatory bowel disease as well as disorders of the gut-brain interaction. He conducts basic and translational research using experimental models of intestinal inflammation.
At Northwestern University, they have a tissue biorepository. It includes colon and intestine tissue samples from healthy individuals as well as individuals with different disease states. “One potential area where I could see this being a useful tool for us is that we could utilize the Gut Cell Atlas in the analysis of our tissue samples to see if we find commonalities between what’s described in the atlas and then what we’re observing,” said Summa, who was not involved in the UK-based project.
He said Northwestern University’s biorepository has details about what medications people were on and the extent and severity of their disease.
“We may be able to utilize the Gut Cell Atlas to help us look at specific factors in terms of how people are responding to different treatments, how different cell types are affected by different treatments, or how they are active or not active in different severities of disease. It may help us provide more precision to our understanding of these different conditions,” said Summa.
He also noted how GI specialists use “Crohn’s disease” as a single diagnosis, “but that encompasses a pretty wide spectrum of phenotypes and behaviors,” he said. “I think looking at such a cell-specific level may help to better identify some of the different pathways that are active and the different phenotypes or behaviors of this disease.”
Next Step: Visualize It in a Three-Dimensional (3D) Space
The next stage for Elmentaite and her colleagues is to evolve the 2D map into a 3D map so they can visualize which cells are where and how they are organized in space.
“The next step, which I think is super exciting, is understanding how these cells depend on each other,” she said. “Really functionally understanding if some of them are essential and others are not. And doing AI modeling to understand what we can learn from this vast amount of data that we’re generating. And of course, that includes how we use this knowledge to create precision therapies.”
A version of this article appeared on Medscape.com.
There was a recent flurry of excitement when UK researchers from the Wellcome Sanger Institute, a nonprofit genomics and genetics research organization in Cambridge, England, announced their creation of the most detailed cell map of the human gastrointestinal (GI) tract up to this point. Using spatial and single-cell data from 1.6 million cells (from 271 donors), the scientists’ work, published in Nature, yields valuable information about the gut’s health and disease states.
“We now have a nice idea of what cell types we can find in the gut,” said co-author Rasa Elmentaite, PhD, co-founder and head of Genomics and Data Science at Ensocell.
No small question: How, exactly, does one go about mapping the human gut?
Most of all, Elmentaite said, it has taken the scientists involved down paths they never anticipated.
How It Began
Over the past 5-7 years, there have been many individual publications across institutes where research labs have created snippets of what the cells in the gut look like, said Elmentaite, referring to the GI tract, which in this case encompasses the mouth, throat, esophagus, stomach, small intestine, large intestine, rectum, and anus.
Labs studying gut cells often focus on one specific region, for example, the small intestine or the large intestine, if they’re working on Crohn’s disease research. “It makes sense. The GI tract is really regionalized,” she said.
In 2019 and 2021, Elmentaite and her colleagues published papers that mapped some cells in the human gut, and their work garnered attention from other scientists around the world. That’s how they decided to take on the challenge of creating a more comprehensive map of the cells in both the healthy gut and in GI tracts where disease is present.
“We realized there are so many other labs interested in understanding the intestinal tract holistically,” she said. “We thought it would be really interesting to look at the cells in the context of the whole GI system.”
Not a Bad ‘Lockdown Project’
During the pandemic, while the rest of society was playing with sourdough starter, Elmentaite’s lab decided to pool their datasets with data from other labs to see what happened. They had more than 20 datasets at the time and wanted to generate more to fill gaps where there was less information available (eg, data on the cells in the stomach).
“It required getting samples from surgeons, going into the lab and processing those samples into single cells, and then processing that data bioinformatically,” said Elmentaite.
She explained that generating more datasets was not a job for one person and “required convincing a lot of scientists that it was worthwhile,” including a cancer biologist and a mucosal immunologist. They also brought in more technical bioinformatics expertise and recruited an IT team — several people who only worked on processing data and clearing it, “so it was aligned very specifically, and processed very uniformly, across the study,” Elmentaite said.
In the end, with researchers coming together on many Zoom calls from Australia, Germany, Norway, Spain, and numerous locations across the United Kingdom, they were able to integrate 25 single-cell RNA sequencing datasets that encompassed the entire healthy GI tract in development and in adults, leading to a healthy gut reference atlas that includes about 1.1 million cells and 136 cell subgroups.
How to Build a Two-Dimensional (2D) Map of the Gut
Here’s where the weeds get taller: Raw sequencing reads — bits of different RNA that the researchers sequenced from individual biological samples — needed to be mapped back to genes so that the researchers could understand what kinds of genes were expressed in the samples.
“There is a lot of curation there that needs to happen because the versions of transcriptome [a complete set of RNA molecules in a single cell or tissue], and what the genome looks like, is evolving constantly. So we have to map it back to the same transcriptomic reference,” Elmentaite said.
Once they knew all the different genes active in a cell, the researchers were able, using bioinformatics, to pull all of the datasets together and visualize them in a 2D space — essentially, a representation of a map.
“The cells that are transcriptionally more similar to each other, they will cluster together. And the ones that are more distinct transcriptionally will be farther away from each other,” Elmentaite said.
For decades, GI tract researchers had individually studied which types of genes are activated in an epithelial cell vs a T cell vs a B cell, she said, and “then suddenly you’re seeing it on your screen all at once. It’s amazing to see.”
In Brutal Detail
One of the biggest challenges in interpreting the data involved many people who made sure that there were no technical differences between the samples, Elmentaite said.
For example, samples processed in different labs may have sequencing differences between them. Or the kind of enzymes used to process the tissue might have been different from lab to lab. Sometimes they’d even record down to the detail what time of the day a sample was collected, if that information was available.
“Computationally, we considered all of these variables and tried to regress as much of that as possible. And then, if we saw clusters that resembled gene expression that we know is consistent with some of the cell types, then we knew that we’d regressed all the batch effects,” said Elmentaite.
Before ‘Eureka’ Comes a Few ‘Aha’ Moments
There were many “aha moments,” but also some puzzling ones, she said. One of the biggest surprises was seeing that the identity of a cell believed to be set from development can actually change if a person has a lot of irritation and inflammation, as occurs in inflammatory bowel disease. Epithelial cell metaplasia was one of the surprises.
“Metaplasia describes an activation or differentiation of one differentiated cell type into another differentiated cell type. And we knew that that exists in some of the upper GI diseases, but we didn’t realize that the same sort of mechanism exists in the small intestine,” Elmentaite said.
Epithelial cells are among the most abundant cells in the body. The researchers knew from established research that these cells act a bit like first responders and provide healing to the gut. “We could see that they were producing a lot of mucous that helps to potentially flush down the microbes that are triggering inflammation. But the ‘aha moment’ for us was that actually there’s a dual function in these cells,” she said.
They could see in the transcriptional profile a significant production of chemokines (a family of proteins that play a role in the body’s immune responses) and major histocompatibility complex class II molecules (cell surface proteins involved in the body’s immune response), and the epithelial cells seemed to attract neutrophils and monocytes and to interact with certain T cells — adding to the cycle of chronic inflammation.
“I think for a lot of us, this was a surprise because we think of epithelial cells as more like a barrier, just a passive player in, for example, inflammatory bowel disease,” said Elmentaite.
In addition to reporting their findings on epithelial cell metaplasia, the researchers processed 12 GI disease datasets, including celiac disease, Crohn’s disease, GI-related cancers, and ulcerative colitis.
A Gut Cell Atlas for the People (Well, Scientific People)
“The Gut Cell Atlas is usable for everyone, and everyone has a chance to contribute,” said Elmentaite. But 1.6 million cells is only a start and more data are needed, she said, and efforts are being spearheaded at the broader Human Cell Atlas project to collect it. There are also efforts to get all researchers using the same cell annotation, research-wide standards that will make the atlas truly usable for everyone.
Keith Summa, MD, PhD, assistant professor of medicine in the Division of Gastroenterology and Hepatology at Feinberg School of Medicine, Northwestern University, Chicago, focuses much of his work on inflammatory bowel disease as well as disorders of the gut-brain interaction. He conducts basic and translational research using experimental models of intestinal inflammation.
At Northwestern University, they have a tissue biorepository. It includes colon and intestine tissue samples from healthy individuals as well as individuals with different disease states. “One potential area where I could see this being a useful tool for us is that we could utilize the Gut Cell Atlas in the analysis of our tissue samples to see if we find commonalities between what’s described in the atlas and then what we’re observing,” said Summa, who was not involved in the UK-based project.
He said Northwestern University’s biorepository has details about what medications people were on and the extent and severity of their disease.
“We may be able to utilize the Gut Cell Atlas to help us look at specific factors in terms of how people are responding to different treatments, how different cell types are affected by different treatments, or how they are active or not active in different severities of disease. It may help us provide more precision to our understanding of these different conditions,” said Summa.
He also noted how GI specialists use “Crohn’s disease” as a single diagnosis, “but that encompasses a pretty wide spectrum of phenotypes and behaviors,” he said. “I think looking at such a cell-specific level may help to better identify some of the different pathways that are active and the different phenotypes or behaviors of this disease.”
Next Step: Visualize It in a Three-Dimensional (3D) Space
The next stage for Elmentaite and her colleagues is to evolve the 2D map into a 3D map so they can visualize which cells are where and how they are organized in space.
“The next step, which I think is super exciting, is understanding how these cells depend on each other,” she said. “Really functionally understanding if some of them are essential and others are not. And doing AI modeling to understand what we can learn from this vast amount of data that we’re generating. And of course, that includes how we use this knowledge to create precision therapies.”
A version of this article appeared on Medscape.com.
Patients With Refractory Systemic Sclerosis Have Early Success With CAR T-Cell Therapy
TOPLINE:
CD19-targeting chimeric antigen receptor (CAR) T-cell therapy shows potential to intercept fibrotic organ manifestations and improve disease measures in patients with diffuse cutaneous systemic sclerosis (SSc) who had disease progression despite multiple previous treatments.
METHODOLOGY:
- Researchers conducted a case series to examine the effect of CD19-targeting CAR T-cell therapy on fibrotic and vascular organ manifestations in six patients with diffuse cutaneous SSc (median age, 42 years; four men and two women) who had an insufficient response to at least two previous treatments.
- Participants received CD19-targeting CAR T-cell treatment at a dose of 1 × 106 CAR T cells per kilogram of body weight after lymphodepletion with fludarabine and cyclophosphamide.
- The primary outcome was event-free time or treatment intensification after study entry, with events defined as the progression of interstitial lung disease, onset of congestive heart or renal failure or arterial hypertension, or initiation of new therapy.
- The secondary outcomes included changes in the modified Rodnan skin score (mRSS), imaging and laboratory assessments, patient-reported outcomes, and the modified American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline and 3, 6, 9, and 12 months after treatment.
TAKEAWAY:
- No progression of organ manifestations or new lung, cardiac, or renal events occurred within the median follow-up period of 487 days.
- The probability of improvement in the ACR-CRISS score increased to a median value of 100% within 6 and 12 months of CAR T-cell treatment compared with baseline.
- Skin involvement improved in all the patients after CAR T-cell treatment, with a median mRSS decrease of 8 points within 100 days; the improvements were maintained throughout the 1-year follow-up period.
- This treatment also led to a depletion of antinuclear antibodies and SSc-specific autoantibodies.
IN PRACTICE:
“This case series highlights the potential of CAR T-cell therapy to address a crucial unmet need in refractory systemic sclerosis treatment. The study’s most significant contribution is the demonstration that CD19-targeting CAR T-cell therapy can halt or reverse aspects of fibrosis in systemic sclerosis,” Jérôme Avouac, Service de Rhumatologie, Hôpital Cochin, AP-HP Centre-Université Paris Cité, Paris, France, wrote in an accompanying editorial.
SOURCE:
The study was led by Janina Auth, MD, Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen in Germany, and was published online on November 11, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study lacked a control group, which limited the ability to draw definitive conclusions about the efficacy of CD19-targeting CAR T-cell therapy compared with standard treatments. The unpredictable nature of SSc, in which periods of stability can occur spontaneously, makes it difficult to attribute the improvements merely to the intervention. Moreover, the effect of CAR T-cell therapy on other disease manifestations, such as pulmonary hypertension, myocardial involvement, and scleroderma renal crisis, remains unclear.
DISCLOSURES:
The study was funded by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN Foundation Erlangen, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, and the European Union. Some authors reported receiving research grants, consulting fees, speaker fees, honoraria, or travel grants from Boehringer Ingelheim, Novartis, Almirall, and other pharmaceutical companies.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
CD19-targeting chimeric antigen receptor (CAR) T-cell therapy shows potential to intercept fibrotic organ manifestations and improve disease measures in patients with diffuse cutaneous systemic sclerosis (SSc) who had disease progression despite multiple previous treatments.
METHODOLOGY:
- Researchers conducted a case series to examine the effect of CD19-targeting CAR T-cell therapy on fibrotic and vascular organ manifestations in six patients with diffuse cutaneous SSc (median age, 42 years; four men and two women) who had an insufficient response to at least two previous treatments.
- Participants received CD19-targeting CAR T-cell treatment at a dose of 1 × 106 CAR T cells per kilogram of body weight after lymphodepletion with fludarabine and cyclophosphamide.
- The primary outcome was event-free time or treatment intensification after study entry, with events defined as the progression of interstitial lung disease, onset of congestive heart or renal failure or arterial hypertension, or initiation of new therapy.
- The secondary outcomes included changes in the modified Rodnan skin score (mRSS), imaging and laboratory assessments, patient-reported outcomes, and the modified American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline and 3, 6, 9, and 12 months after treatment.
TAKEAWAY:
- No progression of organ manifestations or new lung, cardiac, or renal events occurred within the median follow-up period of 487 days.
- The probability of improvement in the ACR-CRISS score increased to a median value of 100% within 6 and 12 months of CAR T-cell treatment compared with baseline.
- Skin involvement improved in all the patients after CAR T-cell treatment, with a median mRSS decrease of 8 points within 100 days; the improvements were maintained throughout the 1-year follow-up period.
- This treatment also led to a depletion of antinuclear antibodies and SSc-specific autoantibodies.
IN PRACTICE:
“This case series highlights the potential of CAR T-cell therapy to address a crucial unmet need in refractory systemic sclerosis treatment. The study’s most significant contribution is the demonstration that CD19-targeting CAR T-cell therapy can halt or reverse aspects of fibrosis in systemic sclerosis,” Jérôme Avouac, Service de Rhumatologie, Hôpital Cochin, AP-HP Centre-Université Paris Cité, Paris, France, wrote in an accompanying editorial.
SOURCE:
The study was led by Janina Auth, MD, Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen in Germany, and was published online on November 11, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study lacked a control group, which limited the ability to draw definitive conclusions about the efficacy of CD19-targeting CAR T-cell therapy compared with standard treatments. The unpredictable nature of SSc, in which periods of stability can occur spontaneously, makes it difficult to attribute the improvements merely to the intervention. Moreover, the effect of CAR T-cell therapy on other disease manifestations, such as pulmonary hypertension, myocardial involvement, and scleroderma renal crisis, remains unclear.
DISCLOSURES:
The study was funded by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN Foundation Erlangen, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, and the European Union. Some authors reported receiving research grants, consulting fees, speaker fees, honoraria, or travel grants from Boehringer Ingelheim, Novartis, Almirall, and other pharmaceutical companies.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
CD19-targeting chimeric antigen receptor (CAR) T-cell therapy shows potential to intercept fibrotic organ manifestations and improve disease measures in patients with diffuse cutaneous systemic sclerosis (SSc) who had disease progression despite multiple previous treatments.
METHODOLOGY:
- Researchers conducted a case series to examine the effect of CD19-targeting CAR T-cell therapy on fibrotic and vascular organ manifestations in six patients with diffuse cutaneous SSc (median age, 42 years; four men and two women) who had an insufficient response to at least two previous treatments.
- Participants received CD19-targeting CAR T-cell treatment at a dose of 1 × 106 CAR T cells per kilogram of body weight after lymphodepletion with fludarabine and cyclophosphamide.
- The primary outcome was event-free time or treatment intensification after study entry, with events defined as the progression of interstitial lung disease, onset of congestive heart or renal failure or arterial hypertension, or initiation of new therapy.
- The secondary outcomes included changes in the modified Rodnan skin score (mRSS), imaging and laboratory assessments, patient-reported outcomes, and the modified American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline and 3, 6, 9, and 12 months after treatment.
TAKEAWAY:
- No progression of organ manifestations or new lung, cardiac, or renal events occurred within the median follow-up period of 487 days.
- The probability of improvement in the ACR-CRISS score increased to a median value of 100% within 6 and 12 months of CAR T-cell treatment compared with baseline.
- Skin involvement improved in all the patients after CAR T-cell treatment, with a median mRSS decrease of 8 points within 100 days; the improvements were maintained throughout the 1-year follow-up period.
- This treatment also led to a depletion of antinuclear antibodies and SSc-specific autoantibodies.
IN PRACTICE:
“This case series highlights the potential of CAR T-cell therapy to address a crucial unmet need in refractory systemic sclerosis treatment. The study’s most significant contribution is the demonstration that CD19-targeting CAR T-cell therapy can halt or reverse aspects of fibrosis in systemic sclerosis,” Jérôme Avouac, Service de Rhumatologie, Hôpital Cochin, AP-HP Centre-Université Paris Cité, Paris, France, wrote in an accompanying editorial.
SOURCE:
The study was led by Janina Auth, MD, Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen in Germany, and was published online on November 11, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study lacked a control group, which limited the ability to draw definitive conclusions about the efficacy of CD19-targeting CAR T-cell therapy compared with standard treatments. The unpredictable nature of SSc, in which periods of stability can occur spontaneously, makes it difficult to attribute the improvements merely to the intervention. Moreover, the effect of CAR T-cell therapy on other disease manifestations, such as pulmonary hypertension, myocardial involvement, and scleroderma renal crisis, remains unclear.
DISCLOSURES:
The study was funded by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN Foundation Erlangen, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, and the European Union. Some authors reported receiving research grants, consulting fees, speaker fees, honoraria, or travel grants from Boehringer Ingelheim, Novartis, Almirall, and other pharmaceutical companies.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Which Biologics May Contribute to Cancer Risk in Patients With Rheumatoid Arthritis?
TOPLINE:
The initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), particularly rituximab and abatacept, is associated with an increased risk for incident cancer in patients with rheumatoid arthritis (RA) within 2 years of starting treatment.
METHODOLOGY:
- The researchers conducted a retrospective cohort study to assess the safety of tumor necrosis factor (TNF) inhibitors, non-TNF inhibitors, and Janus kinase (JAK) inhibitors in patients with RA using US administrative claims data from the Merative Marketscan Research Databases from November 2012 to December 2021.
- A total of 25,305 patients with RA (median age, 50 years; 79% women; 49% from the southern United States) were identified using diagnostic codes on or before treatment initiation.
- Treatment exposures, including the initiation of TNF inhibitors (adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab), non-TNF inhibitors (abatacept, interleukin 6 [IL-6] inhibitors, and rituximab), and JAK inhibitors (tofacitinib, baricitinib, and upadacitinib), were compared.
- The primary outcome was any incident cancer (excluding nonmelanoma skin cancer) occurring after a minimum of 90 days and within 2 years of treatment initiation.
- Sensitivity analyses used 1:1 propensity matching to compare cancer rates between populations treated with rituximab, IL-6 inhibitors, abatacept, or JAK inhibitors and matched reference populations treated with TNF inhibitors.
TAKEAWAY:
- Rituximab (adjusted hazard ratio [aHR], 1.91; 95% CI, 1.17-3.14) and abatacept (aHR, 1.47; 95% CI, 1.03-2.11) were significantly associated with an increased risk for incident cancer, compared with TNF inhibitors.
- In the propensity-matched analysis, a statistically significant increase in risk was observed in patients treated with rituximab (aHR, 4.37; 95% CI, 1.48-12.93) and abatacept (aHR, 3.12; 95%CI, 1.52-6.44).
- IL-6 inhibitors showed no significant association with cancer in the primary analysis, but a significantly increased risk was observed in the propensity-matched analysis (HR, 5.65; 95% CI, 1.11-28.79).
- JAK inhibitors were not associated with a significant increase in the risk for cancer, compared with TNF inhibitors.
IN PRACTICE:
“Given the limitations of using private insurance claims data and confounding by indication, it is likely that these patients may have a higher disease burden, resulting in channeling bias,” the authors wrote. “To understand these associations, larger studies with longer follow-up and more granular collection of data, including medication indications and RA disease activity measures, would be needed for better comparison of incident cancer risk among these drugs,” they added.
SOURCE:
The study was led by Xavier Sendaydiego, MD, University of Washington, Seattle. It was published online in JAMA Network Open.
LIMITATIONS:
A relatively small number of cancer outcomes may have affected the ability to adjust for confounders. The follow-up period was limited to 2 years, potentially missing long-term cancer risks. The use of US-specific administrative claims data, including only patients aged 18-64 years, may limit the generalizability of the findings. Additionally, the claims data lacked direct measures of disease activity or severity of RA, and information on treatment adherence was unavailable, leading to potential misclassification.
DISCLOSURES:
The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging. Some authors reported receiving personal fees, nonfinancial support, and grants from various pharmaceutical companies or government sources. One author reported having a pending patent and another author reported receiving a fellowship, travel reimbursement, and royalties outside the submitted work.
This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
The initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), particularly rituximab and abatacept, is associated with an increased risk for incident cancer in patients with rheumatoid arthritis (RA) within 2 years of starting treatment.
METHODOLOGY:
- The researchers conducted a retrospective cohort study to assess the safety of tumor necrosis factor (TNF) inhibitors, non-TNF inhibitors, and Janus kinase (JAK) inhibitors in patients with RA using US administrative claims data from the Merative Marketscan Research Databases from November 2012 to December 2021.
- A total of 25,305 patients with RA (median age, 50 years; 79% women; 49% from the southern United States) were identified using diagnostic codes on or before treatment initiation.
- Treatment exposures, including the initiation of TNF inhibitors (adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab), non-TNF inhibitors (abatacept, interleukin 6 [IL-6] inhibitors, and rituximab), and JAK inhibitors (tofacitinib, baricitinib, and upadacitinib), were compared.
- The primary outcome was any incident cancer (excluding nonmelanoma skin cancer) occurring after a minimum of 90 days and within 2 years of treatment initiation.
- Sensitivity analyses used 1:1 propensity matching to compare cancer rates between populations treated with rituximab, IL-6 inhibitors, abatacept, or JAK inhibitors and matched reference populations treated with TNF inhibitors.
TAKEAWAY:
- Rituximab (adjusted hazard ratio [aHR], 1.91; 95% CI, 1.17-3.14) and abatacept (aHR, 1.47; 95% CI, 1.03-2.11) were significantly associated with an increased risk for incident cancer, compared with TNF inhibitors.
- In the propensity-matched analysis, a statistically significant increase in risk was observed in patients treated with rituximab (aHR, 4.37; 95% CI, 1.48-12.93) and abatacept (aHR, 3.12; 95%CI, 1.52-6.44).
- IL-6 inhibitors showed no significant association with cancer in the primary analysis, but a significantly increased risk was observed in the propensity-matched analysis (HR, 5.65; 95% CI, 1.11-28.79).
- JAK inhibitors were not associated with a significant increase in the risk for cancer, compared with TNF inhibitors.
IN PRACTICE:
“Given the limitations of using private insurance claims data and confounding by indication, it is likely that these patients may have a higher disease burden, resulting in channeling bias,” the authors wrote. “To understand these associations, larger studies with longer follow-up and more granular collection of data, including medication indications and RA disease activity measures, would be needed for better comparison of incident cancer risk among these drugs,” they added.
SOURCE:
The study was led by Xavier Sendaydiego, MD, University of Washington, Seattle. It was published online in JAMA Network Open.
LIMITATIONS:
A relatively small number of cancer outcomes may have affected the ability to adjust for confounders. The follow-up period was limited to 2 years, potentially missing long-term cancer risks. The use of US-specific administrative claims data, including only patients aged 18-64 years, may limit the generalizability of the findings. Additionally, the claims data lacked direct measures of disease activity or severity of RA, and information on treatment adherence was unavailable, leading to potential misclassification.
DISCLOSURES:
The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging. Some authors reported receiving personal fees, nonfinancial support, and grants from various pharmaceutical companies or government sources. One author reported having a pending patent and another author reported receiving a fellowship, travel reimbursement, and royalties outside the submitted work.
This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
The initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), particularly rituximab and abatacept, is associated with an increased risk for incident cancer in patients with rheumatoid arthritis (RA) within 2 years of starting treatment.
METHODOLOGY:
- The researchers conducted a retrospective cohort study to assess the safety of tumor necrosis factor (TNF) inhibitors, non-TNF inhibitors, and Janus kinase (JAK) inhibitors in patients with RA using US administrative claims data from the Merative Marketscan Research Databases from November 2012 to December 2021.
- A total of 25,305 patients with RA (median age, 50 years; 79% women; 49% from the southern United States) were identified using diagnostic codes on or before treatment initiation.
- Treatment exposures, including the initiation of TNF inhibitors (adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab), non-TNF inhibitors (abatacept, interleukin 6 [IL-6] inhibitors, and rituximab), and JAK inhibitors (tofacitinib, baricitinib, and upadacitinib), were compared.
- The primary outcome was any incident cancer (excluding nonmelanoma skin cancer) occurring after a minimum of 90 days and within 2 years of treatment initiation.
- Sensitivity analyses used 1:1 propensity matching to compare cancer rates between populations treated with rituximab, IL-6 inhibitors, abatacept, or JAK inhibitors and matched reference populations treated with TNF inhibitors.
TAKEAWAY:
- Rituximab (adjusted hazard ratio [aHR], 1.91; 95% CI, 1.17-3.14) and abatacept (aHR, 1.47; 95% CI, 1.03-2.11) were significantly associated with an increased risk for incident cancer, compared with TNF inhibitors.
- In the propensity-matched analysis, a statistically significant increase in risk was observed in patients treated with rituximab (aHR, 4.37; 95% CI, 1.48-12.93) and abatacept (aHR, 3.12; 95%CI, 1.52-6.44).
- IL-6 inhibitors showed no significant association with cancer in the primary analysis, but a significantly increased risk was observed in the propensity-matched analysis (HR, 5.65; 95% CI, 1.11-28.79).
- JAK inhibitors were not associated with a significant increase in the risk for cancer, compared with TNF inhibitors.
IN PRACTICE:
“Given the limitations of using private insurance claims data and confounding by indication, it is likely that these patients may have a higher disease burden, resulting in channeling bias,” the authors wrote. “To understand these associations, larger studies with longer follow-up and more granular collection of data, including medication indications and RA disease activity measures, would be needed for better comparison of incident cancer risk among these drugs,” they added.
SOURCE:
The study was led by Xavier Sendaydiego, MD, University of Washington, Seattle. It was published online in JAMA Network Open.
LIMITATIONS:
A relatively small number of cancer outcomes may have affected the ability to adjust for confounders. The follow-up period was limited to 2 years, potentially missing long-term cancer risks. The use of US-specific administrative claims data, including only patients aged 18-64 years, may limit the generalizability of the findings. Additionally, the claims data lacked direct measures of disease activity or severity of RA, and information on treatment adherence was unavailable, leading to potential misclassification.
DISCLOSURES:
The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging. Some authors reported receiving personal fees, nonfinancial support, and grants from various pharmaceutical companies or government sources. One author reported having a pending patent and another author reported receiving a fellowship, travel reimbursement, and royalties outside the submitted work.
This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Is a Xanthine Oxidase Inhibitor or a Mechanism-Based Approach Best for First-Line Gout Treatment?
For gout, xanthine oxidase (XO) inhibitors are the choice for first-line urate-lowering therapy (ULT) according to the 2020 American College of Rheumatology Guideline for the Management of Gout, which endorsed allopurinol, but should that be the approach for all patients, or should first-line therapy be tailored to the mechanism of each patient’s hyperuricemia? Two gout experts, Lisa Stamp, MBChB, PhD, a rheumatologist and professor of medicine at the University of Otago in Christchurch, New Zealand, and Fernando Pérez-Ruiz, MD, PhD, consultant in the Rheumatology Division of Cruces University Hospital, Barakaldo, head of the Investigation Group for Arthritis at Biocruces Health Research Institute, Barakaldo, and associate professor in the Department of Medicine at the Faculty of Medicine and Nursing at the University of the Basque Country in Leioa, Spain, debated this question recently at the annual research symposium of the Gout, Hyperuricemia and Crystal-Associated Disease Network.
Before the debate began, audience members voted on the question and 56% favored using XO inhibitors as a first-line therapy for all rather than tailoring first-line therapy to disease mechanism.
Up first, Stamp argued that XO inhibitors should be first-line therapy for all patients with gout. She said that XO inhibitors have been demonstrated to work regardless of the cause of hyperuricemia and degree of kidney function, and they are cheap, readily available, and easy to administer. She showed results from a study published by her debate opponent, Pérez-Ruiz, which demonstrated efficacy of XO inhibitors in both under-excreters and over-excreters of uric acid. That study compared the efficacy of the XO inhibitor allopurinol to the uricosuric agent benzbromarone and found the latter to be more effective, but Stamp argued that the allopurinol dose used in the study — 300 mg/d — “may not be enough for many patients who have gout. Dose-restricting allopurinol is one way to demonstrate that an alternative agent is superior,” she said.
A more recent study showed low-dose benzbromarone was better than low-dose febuxostat, another XO inhibitor. “I think we do need to have clinical trials that reflect real-world practice. I accept that this may have reflected [accepted practice where the studies] were undertaken, but these [XO inhibitor] doses don’t represent what many of us would do in other parts of the world,” Stamp said.
One concern is the utility of a ULT in patients with impaired renal function. Stamp cited her own post hoc analysis of a randomized, controlled trial showing that allopurinol is effective irrespective of renal function, as long as the dose is escalated to achieve target urate level, and a meta-analysis of observational studies suggesting that febuxostat is effective irrespective of renal function.
On the other hand, she showed data from a 1994 study of benzbromarone in renal transplant recipients, which showed that the drug’s effect on decreasing plasma uric acid dropped off significantly with lower creatinine clearance. “It does work, but the efficacy really drops off as renal function decreases. Benzbromarone is probably the most effective uricosuric in patients with renal impairment, but this agent is not readily available,” Stamp said.
The uricosuric agent probenecid, which is generally available across the world, led to only about 30% success in achieving target levels of uric acid among patients with an estimated glomerular filtration rate < 50 mL/min/1.73 m2. “I think we can all agree that getting 30% of our patients to target uric acid is not an acceptable outcome,” she said.
Stamp emphasized the importance of drug availability and noted that allopurinol is also the only medication for gout that is on the World Health Organization list of essential medications. “I think we should be recommending medications that are readily available, irrespective of where you live,” she said, noting that this is true of allopurinol, febuxostat, and probenecid.
Stamp also addressed the mechanism of action of ULTs. “Does the cause of hyperuricemia affect treatment response? I don’t think it does. Most people respond to allopurinol whether they’re a normal excreter or an under-excreter. Everyone who is lacking uricase will respond to allopurinol. Not everyone will respond to a uricosuric [agent], particularly in the setting of comorbidities such as renal impairment, which many of our patients with gout have,” she said.
Counterargument: Combine Therapies With Different Mechanisms of Action
In his counterargument, Pérez-Ruiz contended that gout is not in fact a metabolic disease and suggested that combining therapies with different mechanisms of action could be the best approach for difficult-to-treat gout. “The problem we face in clinical practice is how to treat difficult-to-treat patients,” he said. He referenced his own PhD thesis, which showed both high urinary uric acid output and underexcretion among patients with gout.
Pérez-Ruiz agreed that XO inhibitors should be used as first-line therapy but noted that the effect of allopurinol tapers off at higher doses. “If you use very high doses of allopurinol, you cannot expect to get much more effect,” he said. This is also true of febuxostat, he said.
He showed another study that illustrated difficulties in achieving target serum urate level with intensive therapy. “Even using a high dose of allopurinol, if you would like to get lower than 3 mg/dL for intensive therapy, close to 50% of patients will fail,” he said.
Pérez-Ruiz described a strategy of combining XO inhibitors with a uricosuric therapy, creating what he called a “uricase-like effect” on serum uric acid levels. Ruiz-Perez uses high-dose febuxostat in patients with chronic kidney disease who cannot be given uricosuric agents. “You can go to very low [serum urate levels] by raising up the doses,” he said.
He does not believe that allopurinol is the best agent for combination therapy in the treatment of tophaceous deposits. Instead, he favors combinations with febuxostat. He presented his own experience with 12 patients with very severe tophaceous gout who he treated with a combination of febuxostat and benzbromarone, which reduced serum urate to just over 2 mg/dL. “So this is a pegloticase-like effect [that is] very useful for tophaceous gout,” he said.
In her response, Stamp noted that most of the studies presented by Pérez-Ruiz showed XO inhibitors as first-line therapies, with other medications added on. “I think I heard Fernando agree with me. In just about all of those slides, he showed that a xanthine oxidase inhibitor was the first-line therapy, and subsequently a uricosuric was added,” she said.
Still, Stamp took issue with the idea that serum urate needs to get as low as Pérez-Ruiz advocated for. “What’s the risk associated with getting a serum urate to that level? I’m not sure that a sustained serum urate of around 1 [mg/dL] is necessarily good in the long term,” she said.
Stamp also pointed out the potential risks of polypharmacy, along with adherence issues. “If we can give our patients one therapy, one drug that’s going to get them to a target that we know is going to have beneficial long-term effects, that’s going to help improve our adherence. Maybe we are coming to a new era of [treatment, with] remission induction driving the serum urate very low, and then a maintenance therapy where we can back off. But irrespective, if you use that strategy, Fernando nicely showed that every time you’re going to start with a xanthine oxidase inhibitor,” she said.
After the debate, audience members voted again, and this time the result was 66% in favor of XO inhibitors as a first-line treatment.
Pérez-Ruiz is an adviser for Arthrosi, LG, Novartis, Protalix, and SOBI. He is a speaker for Menarini Central America and the Spanish Foundation for Rheumatology and has received funding from Cruces Rheumatology Association. Stamp did not disclose any financial relationships.
A version of this article first appeared on Medscape.com.
For gout, xanthine oxidase (XO) inhibitors are the choice for first-line urate-lowering therapy (ULT) according to the 2020 American College of Rheumatology Guideline for the Management of Gout, which endorsed allopurinol, but should that be the approach for all patients, or should first-line therapy be tailored to the mechanism of each patient’s hyperuricemia? Two gout experts, Lisa Stamp, MBChB, PhD, a rheumatologist and professor of medicine at the University of Otago in Christchurch, New Zealand, and Fernando Pérez-Ruiz, MD, PhD, consultant in the Rheumatology Division of Cruces University Hospital, Barakaldo, head of the Investigation Group for Arthritis at Biocruces Health Research Institute, Barakaldo, and associate professor in the Department of Medicine at the Faculty of Medicine and Nursing at the University of the Basque Country in Leioa, Spain, debated this question recently at the annual research symposium of the Gout, Hyperuricemia and Crystal-Associated Disease Network.
Before the debate began, audience members voted on the question and 56% favored using XO inhibitors as a first-line therapy for all rather than tailoring first-line therapy to disease mechanism.
Up first, Stamp argued that XO inhibitors should be first-line therapy for all patients with gout. She said that XO inhibitors have been demonstrated to work regardless of the cause of hyperuricemia and degree of kidney function, and they are cheap, readily available, and easy to administer. She showed results from a study published by her debate opponent, Pérez-Ruiz, which demonstrated efficacy of XO inhibitors in both under-excreters and over-excreters of uric acid. That study compared the efficacy of the XO inhibitor allopurinol to the uricosuric agent benzbromarone and found the latter to be more effective, but Stamp argued that the allopurinol dose used in the study — 300 mg/d — “may not be enough for many patients who have gout. Dose-restricting allopurinol is one way to demonstrate that an alternative agent is superior,” she said.
A more recent study showed low-dose benzbromarone was better than low-dose febuxostat, another XO inhibitor. “I think we do need to have clinical trials that reflect real-world practice. I accept that this may have reflected [accepted practice where the studies] were undertaken, but these [XO inhibitor] doses don’t represent what many of us would do in other parts of the world,” Stamp said.
One concern is the utility of a ULT in patients with impaired renal function. Stamp cited her own post hoc analysis of a randomized, controlled trial showing that allopurinol is effective irrespective of renal function, as long as the dose is escalated to achieve target urate level, and a meta-analysis of observational studies suggesting that febuxostat is effective irrespective of renal function.
On the other hand, she showed data from a 1994 study of benzbromarone in renal transplant recipients, which showed that the drug’s effect on decreasing plasma uric acid dropped off significantly with lower creatinine clearance. “It does work, but the efficacy really drops off as renal function decreases. Benzbromarone is probably the most effective uricosuric in patients with renal impairment, but this agent is not readily available,” Stamp said.
The uricosuric agent probenecid, which is generally available across the world, led to only about 30% success in achieving target levels of uric acid among patients with an estimated glomerular filtration rate < 50 mL/min/1.73 m2. “I think we can all agree that getting 30% of our patients to target uric acid is not an acceptable outcome,” she said.
Stamp emphasized the importance of drug availability and noted that allopurinol is also the only medication for gout that is on the World Health Organization list of essential medications. “I think we should be recommending medications that are readily available, irrespective of where you live,” she said, noting that this is true of allopurinol, febuxostat, and probenecid.
Stamp also addressed the mechanism of action of ULTs. “Does the cause of hyperuricemia affect treatment response? I don’t think it does. Most people respond to allopurinol whether they’re a normal excreter or an under-excreter. Everyone who is lacking uricase will respond to allopurinol. Not everyone will respond to a uricosuric [agent], particularly in the setting of comorbidities such as renal impairment, which many of our patients with gout have,” she said.
Counterargument: Combine Therapies With Different Mechanisms of Action
In his counterargument, Pérez-Ruiz contended that gout is not in fact a metabolic disease and suggested that combining therapies with different mechanisms of action could be the best approach for difficult-to-treat gout. “The problem we face in clinical practice is how to treat difficult-to-treat patients,” he said. He referenced his own PhD thesis, which showed both high urinary uric acid output and underexcretion among patients with gout.
Pérez-Ruiz agreed that XO inhibitors should be used as first-line therapy but noted that the effect of allopurinol tapers off at higher doses. “If you use very high doses of allopurinol, you cannot expect to get much more effect,” he said. This is also true of febuxostat, he said.
He showed another study that illustrated difficulties in achieving target serum urate level with intensive therapy. “Even using a high dose of allopurinol, if you would like to get lower than 3 mg/dL for intensive therapy, close to 50% of patients will fail,” he said.
Pérez-Ruiz described a strategy of combining XO inhibitors with a uricosuric therapy, creating what he called a “uricase-like effect” on serum uric acid levels. Ruiz-Perez uses high-dose febuxostat in patients with chronic kidney disease who cannot be given uricosuric agents. “You can go to very low [serum urate levels] by raising up the doses,” he said.
He does not believe that allopurinol is the best agent for combination therapy in the treatment of tophaceous deposits. Instead, he favors combinations with febuxostat. He presented his own experience with 12 patients with very severe tophaceous gout who he treated with a combination of febuxostat and benzbromarone, which reduced serum urate to just over 2 mg/dL. “So this is a pegloticase-like effect [that is] very useful for tophaceous gout,” he said.
In her response, Stamp noted that most of the studies presented by Pérez-Ruiz showed XO inhibitors as first-line therapies, with other medications added on. “I think I heard Fernando agree with me. In just about all of those slides, he showed that a xanthine oxidase inhibitor was the first-line therapy, and subsequently a uricosuric was added,” she said.
Still, Stamp took issue with the idea that serum urate needs to get as low as Pérez-Ruiz advocated for. “What’s the risk associated with getting a serum urate to that level? I’m not sure that a sustained serum urate of around 1 [mg/dL] is necessarily good in the long term,” she said.
Stamp also pointed out the potential risks of polypharmacy, along with adherence issues. “If we can give our patients one therapy, one drug that’s going to get them to a target that we know is going to have beneficial long-term effects, that’s going to help improve our adherence. Maybe we are coming to a new era of [treatment, with] remission induction driving the serum urate very low, and then a maintenance therapy where we can back off. But irrespective, if you use that strategy, Fernando nicely showed that every time you’re going to start with a xanthine oxidase inhibitor,” she said.
After the debate, audience members voted again, and this time the result was 66% in favor of XO inhibitors as a first-line treatment.
Pérez-Ruiz is an adviser for Arthrosi, LG, Novartis, Protalix, and SOBI. He is a speaker for Menarini Central America and the Spanish Foundation for Rheumatology and has received funding from Cruces Rheumatology Association. Stamp did not disclose any financial relationships.
A version of this article first appeared on Medscape.com.
For gout, xanthine oxidase (XO) inhibitors are the choice for first-line urate-lowering therapy (ULT) according to the 2020 American College of Rheumatology Guideline for the Management of Gout, which endorsed allopurinol, but should that be the approach for all patients, or should first-line therapy be tailored to the mechanism of each patient’s hyperuricemia? Two gout experts, Lisa Stamp, MBChB, PhD, a rheumatologist and professor of medicine at the University of Otago in Christchurch, New Zealand, and Fernando Pérez-Ruiz, MD, PhD, consultant in the Rheumatology Division of Cruces University Hospital, Barakaldo, head of the Investigation Group for Arthritis at Biocruces Health Research Institute, Barakaldo, and associate professor in the Department of Medicine at the Faculty of Medicine and Nursing at the University of the Basque Country in Leioa, Spain, debated this question recently at the annual research symposium of the Gout, Hyperuricemia and Crystal-Associated Disease Network.
Before the debate began, audience members voted on the question and 56% favored using XO inhibitors as a first-line therapy for all rather than tailoring first-line therapy to disease mechanism.
Up first, Stamp argued that XO inhibitors should be first-line therapy for all patients with gout. She said that XO inhibitors have been demonstrated to work regardless of the cause of hyperuricemia and degree of kidney function, and they are cheap, readily available, and easy to administer. She showed results from a study published by her debate opponent, Pérez-Ruiz, which demonstrated efficacy of XO inhibitors in both under-excreters and over-excreters of uric acid. That study compared the efficacy of the XO inhibitor allopurinol to the uricosuric agent benzbromarone and found the latter to be more effective, but Stamp argued that the allopurinol dose used in the study — 300 mg/d — “may not be enough for many patients who have gout. Dose-restricting allopurinol is one way to demonstrate that an alternative agent is superior,” she said.
A more recent study showed low-dose benzbromarone was better than low-dose febuxostat, another XO inhibitor. “I think we do need to have clinical trials that reflect real-world practice. I accept that this may have reflected [accepted practice where the studies] were undertaken, but these [XO inhibitor] doses don’t represent what many of us would do in other parts of the world,” Stamp said.
One concern is the utility of a ULT in patients with impaired renal function. Stamp cited her own post hoc analysis of a randomized, controlled trial showing that allopurinol is effective irrespective of renal function, as long as the dose is escalated to achieve target urate level, and a meta-analysis of observational studies suggesting that febuxostat is effective irrespective of renal function.
On the other hand, she showed data from a 1994 study of benzbromarone in renal transplant recipients, which showed that the drug’s effect on decreasing plasma uric acid dropped off significantly with lower creatinine clearance. “It does work, but the efficacy really drops off as renal function decreases. Benzbromarone is probably the most effective uricosuric in patients with renal impairment, but this agent is not readily available,” Stamp said.
The uricosuric agent probenecid, which is generally available across the world, led to only about 30% success in achieving target levels of uric acid among patients with an estimated glomerular filtration rate < 50 mL/min/1.73 m2. “I think we can all agree that getting 30% of our patients to target uric acid is not an acceptable outcome,” she said.
Stamp emphasized the importance of drug availability and noted that allopurinol is also the only medication for gout that is on the World Health Organization list of essential medications. “I think we should be recommending medications that are readily available, irrespective of where you live,” she said, noting that this is true of allopurinol, febuxostat, and probenecid.
Stamp also addressed the mechanism of action of ULTs. “Does the cause of hyperuricemia affect treatment response? I don’t think it does. Most people respond to allopurinol whether they’re a normal excreter or an under-excreter. Everyone who is lacking uricase will respond to allopurinol. Not everyone will respond to a uricosuric [agent], particularly in the setting of comorbidities such as renal impairment, which many of our patients with gout have,” she said.
Counterargument: Combine Therapies With Different Mechanisms of Action
In his counterargument, Pérez-Ruiz contended that gout is not in fact a metabolic disease and suggested that combining therapies with different mechanisms of action could be the best approach for difficult-to-treat gout. “The problem we face in clinical practice is how to treat difficult-to-treat patients,” he said. He referenced his own PhD thesis, which showed both high urinary uric acid output and underexcretion among patients with gout.
Pérez-Ruiz agreed that XO inhibitors should be used as first-line therapy but noted that the effect of allopurinol tapers off at higher doses. “If you use very high doses of allopurinol, you cannot expect to get much more effect,” he said. This is also true of febuxostat, he said.
He showed another study that illustrated difficulties in achieving target serum urate level with intensive therapy. “Even using a high dose of allopurinol, if you would like to get lower than 3 mg/dL for intensive therapy, close to 50% of patients will fail,” he said.
Pérez-Ruiz described a strategy of combining XO inhibitors with a uricosuric therapy, creating what he called a “uricase-like effect” on serum uric acid levels. Ruiz-Perez uses high-dose febuxostat in patients with chronic kidney disease who cannot be given uricosuric agents. “You can go to very low [serum urate levels] by raising up the doses,” he said.
He does not believe that allopurinol is the best agent for combination therapy in the treatment of tophaceous deposits. Instead, he favors combinations with febuxostat. He presented his own experience with 12 patients with very severe tophaceous gout who he treated with a combination of febuxostat and benzbromarone, which reduced serum urate to just over 2 mg/dL. “So this is a pegloticase-like effect [that is] very useful for tophaceous gout,” he said.
In her response, Stamp noted that most of the studies presented by Pérez-Ruiz showed XO inhibitors as first-line therapies, with other medications added on. “I think I heard Fernando agree with me. In just about all of those slides, he showed that a xanthine oxidase inhibitor was the first-line therapy, and subsequently a uricosuric was added,” she said.
Still, Stamp took issue with the idea that serum urate needs to get as low as Pérez-Ruiz advocated for. “What’s the risk associated with getting a serum urate to that level? I’m not sure that a sustained serum urate of around 1 [mg/dL] is necessarily good in the long term,” she said.
Stamp also pointed out the potential risks of polypharmacy, along with adherence issues. “If we can give our patients one therapy, one drug that’s going to get them to a target that we know is going to have beneficial long-term effects, that’s going to help improve our adherence. Maybe we are coming to a new era of [treatment, with] remission induction driving the serum urate very low, and then a maintenance therapy where we can back off. But irrespective, if you use that strategy, Fernando nicely showed that every time you’re going to start with a xanthine oxidase inhibitor,” she said.
After the debate, audience members voted again, and this time the result was 66% in favor of XO inhibitors as a first-line treatment.
Pérez-Ruiz is an adviser for Arthrosi, LG, Novartis, Protalix, and SOBI. He is a speaker for Menarini Central America and the Spanish Foundation for Rheumatology and has received funding from Cruces Rheumatology Association. Stamp did not disclose any financial relationships.
A version of this article first appeared on Medscape.com.
FROM G-CAN 2024
Topical Tapinarof Approved for Treating Atopic Dermatitis, Ages 2 and Up
An aryl hydrocarbon receptor agonist, tapinarof cream, 1% was first approved in May 2022 for the topical treatment of plaque psoriasis in adults.
According to a press release from the manufacturer, Organon — which markets tapinarof cream, 1%, under the brand name VTAMA — the new indication for AD is based on results from the ADORING pivotal studies. In ADORING 1, the proportion of patients in the tapinarof cream, 1% treatment group who achieved a score of clear (0) or almost clear (1) and a minimum 2-grade improvement from baseline at week 8 on the Validated Investigator Global Assessment for AD was 45.4%, compared with 13.9% of patients who received vehicle alone. ADORING 2 yielded similar results (46.4% vs 18.0%, respectively; P < .0001 for both associations).
Secondary endpoints measured at week 8 also significantly favored the treatment group over the vehicle group, including the Eczema Area and Severity Index score improvement of at least 75% from baseline and achievement of a ≥ 4-point improvement in the patient-reported Peak Pruritus Numerical Rating Scale from baseline.
The most common adverse reactions (incidence ≥ 1%) were upper respiratory tract infection (12%), folliculitis (9%), lower respiratory tract infection (5%), headache (4%), asthma (2%), vomiting (2%), ear infection (2%), pain in extremity (2%), and abdominal pain (1%), according to the release.
Among 728 patients in the ADORING studies who enrolled in an open-label 48-week extension trial (ADORING 3), 378 entered with or achieved complete disease clearance and discontinued treatment. In this subset of patients, the mean duration of the first treatment-free interval was approximately 80 consecutive days, according to the release.
A version of this article first appeared on Medscape.com.
An aryl hydrocarbon receptor agonist, tapinarof cream, 1% was first approved in May 2022 for the topical treatment of plaque psoriasis in adults.
According to a press release from the manufacturer, Organon — which markets tapinarof cream, 1%, under the brand name VTAMA — the new indication for AD is based on results from the ADORING pivotal studies. In ADORING 1, the proportion of patients in the tapinarof cream, 1% treatment group who achieved a score of clear (0) or almost clear (1) and a minimum 2-grade improvement from baseline at week 8 on the Validated Investigator Global Assessment for AD was 45.4%, compared with 13.9% of patients who received vehicle alone. ADORING 2 yielded similar results (46.4% vs 18.0%, respectively; P < .0001 for both associations).
Secondary endpoints measured at week 8 also significantly favored the treatment group over the vehicle group, including the Eczema Area and Severity Index score improvement of at least 75% from baseline and achievement of a ≥ 4-point improvement in the patient-reported Peak Pruritus Numerical Rating Scale from baseline.
The most common adverse reactions (incidence ≥ 1%) were upper respiratory tract infection (12%), folliculitis (9%), lower respiratory tract infection (5%), headache (4%), asthma (2%), vomiting (2%), ear infection (2%), pain in extremity (2%), and abdominal pain (1%), according to the release.
Among 728 patients in the ADORING studies who enrolled in an open-label 48-week extension trial (ADORING 3), 378 entered with or achieved complete disease clearance and discontinued treatment. In this subset of patients, the mean duration of the first treatment-free interval was approximately 80 consecutive days, according to the release.
A version of this article first appeared on Medscape.com.
An aryl hydrocarbon receptor agonist, tapinarof cream, 1% was first approved in May 2022 for the topical treatment of plaque psoriasis in adults.
According to a press release from the manufacturer, Organon — which markets tapinarof cream, 1%, under the brand name VTAMA — the new indication for AD is based on results from the ADORING pivotal studies. In ADORING 1, the proportion of patients in the tapinarof cream, 1% treatment group who achieved a score of clear (0) or almost clear (1) and a minimum 2-grade improvement from baseline at week 8 on the Validated Investigator Global Assessment for AD was 45.4%, compared with 13.9% of patients who received vehicle alone. ADORING 2 yielded similar results (46.4% vs 18.0%, respectively; P < .0001 for both associations).
Secondary endpoints measured at week 8 also significantly favored the treatment group over the vehicle group, including the Eczema Area and Severity Index score improvement of at least 75% from baseline and achievement of a ≥ 4-point improvement in the patient-reported Peak Pruritus Numerical Rating Scale from baseline.
The most common adverse reactions (incidence ≥ 1%) were upper respiratory tract infection (12%), folliculitis (9%), lower respiratory tract infection (5%), headache (4%), asthma (2%), vomiting (2%), ear infection (2%), pain in extremity (2%), and abdominal pain (1%), according to the release.
Among 728 patients in the ADORING studies who enrolled in an open-label 48-week extension trial (ADORING 3), 378 entered with or achieved complete disease clearance and discontinued treatment. In this subset of patients, the mean duration of the first treatment-free interval was approximately 80 consecutive days, according to the release.
A version of this article first appeared on Medscape.com.
Daratumumab Confirmed as SOC for AL Amyloidosis
Adding DARA to VCd (D-VCd; Darzalex Faspro; Janssen Biotech) provided deeper and more rapid hematologic response and clinically meaningful and statistically significant improvement in overall survival (OS) and major organ deterioration progression-free survival (MOD-PFS), combined with 40.7% cardiac complete response (CR), first author Efstathios Kastritis, MD, said during presentation of an oral abstract at the American Society of Hematology (ASH) 2024 Annual Meeting.
“The Andromeda study is the first comparing two contemporary regimens that shows a significant survival improvement for patients with AL amyloidosis,” said Kastritis, an associate professor at the National and Kapodistrian University of Athens in Greece. “These findings reaffirm frontline D-VCd as the standard of care in this difficult-to-treat disease.”
The regimen was approved for this indication in 2021 based on prior earlier findings from the Andromeda trial. The current results are from a preplanned analysis for MOD-PFS and OS.
At a median follow-up of 61.4 months, the overall hematologic CR rates were 59.5% and 19.2% among 388 patients randomized to receive D-VCd or VCd, respectively (odds ratio, 6.03), which showed continued improvement with additional DARA vs the 53.3% and 18.1% rates observed at the primary analysis, Kastritis reported.
Time to hematologic CR was 67.5 days and 85.0 days in the treatment groups, respectively, and median duration of hematologic CR was not reached in either group.
A significant 56% improvement was also observed in MOD-PFS (hazard ratio [HR], 0.44). Median MOD-PFS was not reached in the D-VCd group and was 30.3 months in the VCd group.
A significant 38% improvement was observed in OS (HR, 0.62), 5-year OS was 76.1% vs 64.7% in the D-VCd and VCd groups, respectively, he said.
“[The OS] benefit occurred even though more than 70% of the patients in the VCd arm who received a subsequent therapy were treated with a DARA-based regimen,” he stressed. “This further emphasizes the importance of using DSTS in the frontline setting.”
Trial participants had newly diagnosed AL amyloidosis with measurable hematologic disease, one or more involved organs, cardiac stage I-IIIA, estimated glomerular filtration rate of at least 20 mL/min, and absence of symptomatic multiple myeloma. They were randomized 1:1 to the two treatment groups. All patients received 1.3 mg/m2 of bortezomib by weekly injection, 300 mg/m2 of cyclophosphamide either by weekly oral or intravenous administration, and 20-40 mg of dexamethasone by weekly oral or intravenous administration for six 28-day cycles.
Those in the D-VCd group also received 1800 mg of DARA coformulated with rHuPH20 as a weekly injection in cycles 1-2, as a biweekly injection in cycles 3-6, and by injection every 4 weeks thereafter for up to 24 28-day cycles.
The median duration of treatment was 21.3 months for D-VCd and 5.3 months for VCd, and of 122 patients who received subsequent therapy, 82 (67%) received subsequent DARA.
Patients who achieved hematologic CR had better MOD-PFS and OS (HR, 0.30 and 0.41, respectively), regardless of the treatment received, he noted, adding that “this further supports that complete hematologic response is a valid early endpoint for the evaluation of anti-monoclonal therapies in AL amyloidosis.”
“I think this is very important for the further development of new treatments in this disease,” he said.
Of note, cardiac and renal response rates in the D-VCd group were about two to three times greater than those in the VCd group at 6, 12, 24, 36, and 48 months, Kastritis said.
Among 235 patients with an evaluable cardiac response, 113 achieved a very good partial response or better, including 76 of 118 (64.4%) in the D-VCd group and 37 of 117 (31.6%) in the VCd group. Of these, 48 (40.7%) and 16 (13.7%) achieved a cardiac CR.
Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurring in at least 5% of patients in the D-VCd and VCd groups, respectively, were lymphopenia (13% and 10%), pneumonia (8% and 4%), hypokalemia (2% and 5%), and peripheral edema (3% and 6%), he noted, adding that systemic administration-related reactions occurred in 14 (7%) of patients receiving D-VCd; all were grade 1 or 2 and most (86%) occurred after the first injection. TEAEs led to treatment discontinuation in 5% and 4% of patients in the groups, respectively.
No new safety signals were observed during the extended follow-up, he said.
Kastritis reported relationships with Pfizer, Genesis Pharma, Sanofi, AbbVie, GSK, Prothena, Janssen, and Amgen.
A version of this article first appeared on Medscape.com.
Adding DARA to VCd (D-VCd; Darzalex Faspro; Janssen Biotech) provided deeper and more rapid hematologic response and clinically meaningful and statistically significant improvement in overall survival (OS) and major organ deterioration progression-free survival (MOD-PFS), combined with 40.7% cardiac complete response (CR), first author Efstathios Kastritis, MD, said during presentation of an oral abstract at the American Society of Hematology (ASH) 2024 Annual Meeting.
“The Andromeda study is the first comparing two contemporary regimens that shows a significant survival improvement for patients with AL amyloidosis,” said Kastritis, an associate professor at the National and Kapodistrian University of Athens in Greece. “These findings reaffirm frontline D-VCd as the standard of care in this difficult-to-treat disease.”
The regimen was approved for this indication in 2021 based on prior earlier findings from the Andromeda trial. The current results are from a preplanned analysis for MOD-PFS and OS.
At a median follow-up of 61.4 months, the overall hematologic CR rates were 59.5% and 19.2% among 388 patients randomized to receive D-VCd or VCd, respectively (odds ratio, 6.03), which showed continued improvement with additional DARA vs the 53.3% and 18.1% rates observed at the primary analysis, Kastritis reported.
Time to hematologic CR was 67.5 days and 85.0 days in the treatment groups, respectively, and median duration of hematologic CR was not reached in either group.
A significant 56% improvement was also observed in MOD-PFS (hazard ratio [HR], 0.44). Median MOD-PFS was not reached in the D-VCd group and was 30.3 months in the VCd group.
A significant 38% improvement was observed in OS (HR, 0.62), 5-year OS was 76.1% vs 64.7% in the D-VCd and VCd groups, respectively, he said.
“[The OS] benefit occurred even though more than 70% of the patients in the VCd arm who received a subsequent therapy were treated with a DARA-based regimen,” he stressed. “This further emphasizes the importance of using DSTS in the frontline setting.”
Trial participants had newly diagnosed AL amyloidosis with measurable hematologic disease, one or more involved organs, cardiac stage I-IIIA, estimated glomerular filtration rate of at least 20 mL/min, and absence of symptomatic multiple myeloma. They were randomized 1:1 to the two treatment groups. All patients received 1.3 mg/m2 of bortezomib by weekly injection, 300 mg/m2 of cyclophosphamide either by weekly oral or intravenous administration, and 20-40 mg of dexamethasone by weekly oral or intravenous administration for six 28-day cycles.
Those in the D-VCd group also received 1800 mg of DARA coformulated with rHuPH20 as a weekly injection in cycles 1-2, as a biweekly injection in cycles 3-6, and by injection every 4 weeks thereafter for up to 24 28-day cycles.
The median duration of treatment was 21.3 months for D-VCd and 5.3 months for VCd, and of 122 patients who received subsequent therapy, 82 (67%) received subsequent DARA.
Patients who achieved hematologic CR had better MOD-PFS and OS (HR, 0.30 and 0.41, respectively), regardless of the treatment received, he noted, adding that “this further supports that complete hematologic response is a valid early endpoint for the evaluation of anti-monoclonal therapies in AL amyloidosis.”
“I think this is very important for the further development of new treatments in this disease,” he said.
Of note, cardiac and renal response rates in the D-VCd group were about two to three times greater than those in the VCd group at 6, 12, 24, 36, and 48 months, Kastritis said.
Among 235 patients with an evaluable cardiac response, 113 achieved a very good partial response or better, including 76 of 118 (64.4%) in the D-VCd group and 37 of 117 (31.6%) in the VCd group. Of these, 48 (40.7%) and 16 (13.7%) achieved a cardiac CR.
Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurring in at least 5% of patients in the D-VCd and VCd groups, respectively, were lymphopenia (13% and 10%), pneumonia (8% and 4%), hypokalemia (2% and 5%), and peripheral edema (3% and 6%), he noted, adding that systemic administration-related reactions occurred in 14 (7%) of patients receiving D-VCd; all were grade 1 or 2 and most (86%) occurred after the first injection. TEAEs led to treatment discontinuation in 5% and 4% of patients in the groups, respectively.
No new safety signals were observed during the extended follow-up, he said.
Kastritis reported relationships with Pfizer, Genesis Pharma, Sanofi, AbbVie, GSK, Prothena, Janssen, and Amgen.
A version of this article first appeared on Medscape.com.
Adding DARA to VCd (D-VCd; Darzalex Faspro; Janssen Biotech) provided deeper and more rapid hematologic response and clinically meaningful and statistically significant improvement in overall survival (OS) and major organ deterioration progression-free survival (MOD-PFS), combined with 40.7% cardiac complete response (CR), first author Efstathios Kastritis, MD, said during presentation of an oral abstract at the American Society of Hematology (ASH) 2024 Annual Meeting.
“The Andromeda study is the first comparing two contemporary regimens that shows a significant survival improvement for patients with AL amyloidosis,” said Kastritis, an associate professor at the National and Kapodistrian University of Athens in Greece. “These findings reaffirm frontline D-VCd as the standard of care in this difficult-to-treat disease.”
The regimen was approved for this indication in 2021 based on prior earlier findings from the Andromeda trial. The current results are from a preplanned analysis for MOD-PFS and OS.
At a median follow-up of 61.4 months, the overall hematologic CR rates were 59.5% and 19.2% among 388 patients randomized to receive D-VCd or VCd, respectively (odds ratio, 6.03), which showed continued improvement with additional DARA vs the 53.3% and 18.1% rates observed at the primary analysis, Kastritis reported.
Time to hematologic CR was 67.5 days and 85.0 days in the treatment groups, respectively, and median duration of hematologic CR was not reached in either group.
A significant 56% improvement was also observed in MOD-PFS (hazard ratio [HR], 0.44). Median MOD-PFS was not reached in the D-VCd group and was 30.3 months in the VCd group.
A significant 38% improvement was observed in OS (HR, 0.62), 5-year OS was 76.1% vs 64.7% in the D-VCd and VCd groups, respectively, he said.
“[The OS] benefit occurred even though more than 70% of the patients in the VCd arm who received a subsequent therapy were treated with a DARA-based regimen,” he stressed. “This further emphasizes the importance of using DSTS in the frontline setting.”
Trial participants had newly diagnosed AL amyloidosis with measurable hematologic disease, one or more involved organs, cardiac stage I-IIIA, estimated glomerular filtration rate of at least 20 mL/min, and absence of symptomatic multiple myeloma. They were randomized 1:1 to the two treatment groups. All patients received 1.3 mg/m2 of bortezomib by weekly injection, 300 mg/m2 of cyclophosphamide either by weekly oral or intravenous administration, and 20-40 mg of dexamethasone by weekly oral or intravenous administration for six 28-day cycles.
Those in the D-VCd group also received 1800 mg of DARA coformulated with rHuPH20 as a weekly injection in cycles 1-2, as a biweekly injection in cycles 3-6, and by injection every 4 weeks thereafter for up to 24 28-day cycles.
The median duration of treatment was 21.3 months for D-VCd and 5.3 months for VCd, and of 122 patients who received subsequent therapy, 82 (67%) received subsequent DARA.
Patients who achieved hematologic CR had better MOD-PFS and OS (HR, 0.30 and 0.41, respectively), regardless of the treatment received, he noted, adding that “this further supports that complete hematologic response is a valid early endpoint for the evaluation of anti-monoclonal therapies in AL amyloidosis.”
“I think this is very important for the further development of new treatments in this disease,” he said.
Of note, cardiac and renal response rates in the D-VCd group were about two to three times greater than those in the VCd group at 6, 12, 24, 36, and 48 months, Kastritis said.
Among 235 patients with an evaluable cardiac response, 113 achieved a very good partial response or better, including 76 of 118 (64.4%) in the D-VCd group and 37 of 117 (31.6%) in the VCd group. Of these, 48 (40.7%) and 16 (13.7%) achieved a cardiac CR.
Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurring in at least 5% of patients in the D-VCd and VCd groups, respectively, were lymphopenia (13% and 10%), pneumonia (8% and 4%), hypokalemia (2% and 5%), and peripheral edema (3% and 6%), he noted, adding that systemic administration-related reactions occurred in 14 (7%) of patients receiving D-VCd; all were grade 1 or 2 and most (86%) occurred after the first injection. TEAEs led to treatment discontinuation in 5% and 4% of patients in the groups, respectively.
No new safety signals were observed during the extended follow-up, he said.
Kastritis reported relationships with Pfizer, Genesis Pharma, Sanofi, AbbVie, GSK, Prothena, Janssen, and Amgen.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
Upfront Therapy for ITP in Children: New Drug a Game-Changer?
“This is the first time in 30 years that a new drug is being tested for newly diagnosed pediatric ITP,” said the study’s lead author, Kristin A. Shimano, MD, professor of pediatrics at the Benioff Children’s Hospital, University of California San Francisco, in a press statement for the study, presented at the American Society of Hematology (ASH) 2024 Annual Meeting earlier this month.
“We really think that this has the potential to transform the approach to the management of ITP in the newly diagnosed phase with the use of a therapy that can provide sustained hemostatic platelet counts to bridge the time that patients are at risk of bleeding events with the goal to wean off the medication for patients who have a natural resolution of their disease,” Shimano said in her talk.
While children with ITP, a rare autoimmune blood disorder, very often improve without the need for any treatment, some do require intervention, and the condition can become chronic. First-line therapies for those patients commonly include corticosteroids, intravenous immunoglobulin (IVIg), and anti-D globulin; however, side effects can be undesirable, and with their efficacy often temporary, patients can require monitoring and juggling of treatments.
Eltrombopag, an oral, daily thrombopoietin receptor agonist, was approved by the US Food and Drug Administration for children and adults with chronic ITP in 2015; however, research has been lacking on the benefits of the therapy for newly diagnosed pediatric patients.
To investigate the drug’s efficacy at that stage, Shimano and colleagues with the ITP Consortium of North America launched the prospective, open-label Pediatric ITP Newly diagnosed pts Epag vs Standard therapy (PINES) trial, enrolling 118 patients at 23 institutions between May 2019 and January 2024.
All enrollees had been diagnosed with ITP within 3 months and had been determined by their treating hematologist to require pharmacologic treatment.
Of the patients, about 40% were untreated, and 60% had been treated with at least one medication prior to the trial but did not have a lasting response.
The patients were stratified by age and prior treatment and randomized 2:1 to receive either eltrombopag (n = 78) or the investigator’s choice of one of three standard first-line therapies, including prednisone, IVIg, or anti-D globulin at specified doses (n = 40). Overall, 29 in the standard-of-care arm received prednisone and 11 received IVIg. The patients had a median age of 8 years.
For the study’s primary endpoint, patients in the eltrombopag group had a significantly greater sustained response at 12 weeks, defined as having at least three of four platelet counts > 50 × 109/L during weeks 6-12 without the need for rescue treatment, with a rate of 63% vs 35% in the standard-of-care group (P = .0054).
There were no significant differences between the two groups in terms of the proportion of patients with a high bleeding score at weeks 1-4 and week 12.
However, those in the eltrombopag arm had a significantly lower rate of receiving rescue therapy (18% vs 38% with the standard of care; P = .02).
Both groups showed clinically meaningful improvements from baseline in terms of health-related quality of life, as assessed by parent proxy-reported KIT overall scores.
Twenty adverse events that were grade 3 or higher, including six serious adverse events, occurred in each of the study’s arms, with the most common events including headache and epistaxis.
Treatment-related serious adverse events occurred among six patients in the eltrombopag group and one in the control group, but importantly, no thromboembolic events were reported.
One intracranial hemorrhage occurred in the eltrombopag arm.
With eltrombopag having a slower effect than some other treatments, Shimano cautioned that the therapy is not recommended for patients with severe bleeding.
“Patients with grade 4 or 5 bleeding at the time of screening were specifically excluded from the study, so for patients who have very severe bleeding who need to get their platelets up very quickly, this would not be the ideal therapy for them,” she noted.
On the basis of results, the trial was recommended to close early due to efficacy; however, the participants are being followed for a total of 12 months to determine the durability of the responses, including in terms of bleeding events, quality of life, or the development of chronic ITP.
“We have shown that in pediatric patients with newly diagnosed ITP requiring pharmacologic treatment, eltrombopag resulted in a significant, clinically relevant higher rate of a durable platelet response in the absence of rescue treatment as compared with standard first-line therapies,” Shimano said.
“Eltrombopag could certainly be added to the medication choices hematologists consider as they are making treatment decisions with families, and it is an option that could potentially raise platelets for a more sustained period in children with ITP in the newly diagnosed period, which is one of the most difficult times for patients with regard to the impact of the disease on bleeding symptoms and quality of life,” she added.
Commenting on the study, James B. Bussel, MD, emeritus professor of pediatrics, medicine and obstetrics and gynecology at Weill Cornell Medicine in New York City, commented that “generally, a short-term increase in platelets is the biggest challenge, which is getting the patient to the point of not requiring future treatment to get better.”
“If more children can be shown to be going into remission earlier, that would be great,” he said.
While eltrombopag is known to be effective in chronic ITP, a key caveat of its use in newly diagnosed patients is the question of whether patients will get better on their own and feasibly be able to be spared the cost and burden of treatment in the first place.
However, identifying which patients will fit that profile isn’t always easy.
“Exactly which child needs treatment can be hard to determine, and there is some debate about that,” Bussel noted.
“The theoretic standard is that the platelet count doesn’t matter — only whether the patient is bleeding a lot, and then there is debate over treatment based on bleeding scores,” he said.
Quality-of-life issues, such as patients’ ability to take part in activities, are also a key consideration.
“It would be great if eltrombopag can support children who really need it and provide clear unequivocal benefit beyond just increasing the platelet count, but also leading to better quality of life,” Bussel said.
The new findings are “a very encouraging start, but I’d really like to see what the story is at 1 year.”
The study was funded by Novartis, maker of eltrombopag, and sponsored by the ITP Consortium of North America. Shimano disclosed ties with Sanofi, Sobi, Daiichi Sankyo, Novartis, and Pfizer. Bussel reported a relationship with Novartis that ended more than 2 years ago.
A version of this article first appeared on Medscape.com.
“This is the first time in 30 years that a new drug is being tested for newly diagnosed pediatric ITP,” said the study’s lead author, Kristin A. Shimano, MD, professor of pediatrics at the Benioff Children’s Hospital, University of California San Francisco, in a press statement for the study, presented at the American Society of Hematology (ASH) 2024 Annual Meeting earlier this month.
“We really think that this has the potential to transform the approach to the management of ITP in the newly diagnosed phase with the use of a therapy that can provide sustained hemostatic platelet counts to bridge the time that patients are at risk of bleeding events with the goal to wean off the medication for patients who have a natural resolution of their disease,” Shimano said in her talk.
While children with ITP, a rare autoimmune blood disorder, very often improve without the need for any treatment, some do require intervention, and the condition can become chronic. First-line therapies for those patients commonly include corticosteroids, intravenous immunoglobulin (IVIg), and anti-D globulin; however, side effects can be undesirable, and with their efficacy often temporary, patients can require monitoring and juggling of treatments.
Eltrombopag, an oral, daily thrombopoietin receptor agonist, was approved by the US Food and Drug Administration for children and adults with chronic ITP in 2015; however, research has been lacking on the benefits of the therapy for newly diagnosed pediatric patients.
To investigate the drug’s efficacy at that stage, Shimano and colleagues with the ITP Consortium of North America launched the prospective, open-label Pediatric ITP Newly diagnosed pts Epag vs Standard therapy (PINES) trial, enrolling 118 patients at 23 institutions between May 2019 and January 2024.
All enrollees had been diagnosed with ITP within 3 months and had been determined by their treating hematologist to require pharmacologic treatment.
Of the patients, about 40% were untreated, and 60% had been treated with at least one medication prior to the trial but did not have a lasting response.
The patients were stratified by age and prior treatment and randomized 2:1 to receive either eltrombopag (n = 78) or the investigator’s choice of one of three standard first-line therapies, including prednisone, IVIg, or anti-D globulin at specified doses (n = 40). Overall, 29 in the standard-of-care arm received prednisone and 11 received IVIg. The patients had a median age of 8 years.
For the study’s primary endpoint, patients in the eltrombopag group had a significantly greater sustained response at 12 weeks, defined as having at least three of four platelet counts > 50 × 109/L during weeks 6-12 without the need for rescue treatment, with a rate of 63% vs 35% in the standard-of-care group (P = .0054).
There were no significant differences between the two groups in terms of the proportion of patients with a high bleeding score at weeks 1-4 and week 12.
However, those in the eltrombopag arm had a significantly lower rate of receiving rescue therapy (18% vs 38% with the standard of care; P = .02).
Both groups showed clinically meaningful improvements from baseline in terms of health-related quality of life, as assessed by parent proxy-reported KIT overall scores.
Twenty adverse events that were grade 3 or higher, including six serious adverse events, occurred in each of the study’s arms, with the most common events including headache and epistaxis.
Treatment-related serious adverse events occurred among six patients in the eltrombopag group and one in the control group, but importantly, no thromboembolic events were reported.
One intracranial hemorrhage occurred in the eltrombopag arm.
With eltrombopag having a slower effect than some other treatments, Shimano cautioned that the therapy is not recommended for patients with severe bleeding.
“Patients with grade 4 or 5 bleeding at the time of screening were specifically excluded from the study, so for patients who have very severe bleeding who need to get their platelets up very quickly, this would not be the ideal therapy for them,” she noted.
On the basis of results, the trial was recommended to close early due to efficacy; however, the participants are being followed for a total of 12 months to determine the durability of the responses, including in terms of bleeding events, quality of life, or the development of chronic ITP.
“We have shown that in pediatric patients with newly diagnosed ITP requiring pharmacologic treatment, eltrombopag resulted in a significant, clinically relevant higher rate of a durable platelet response in the absence of rescue treatment as compared with standard first-line therapies,” Shimano said.
“Eltrombopag could certainly be added to the medication choices hematologists consider as they are making treatment decisions with families, and it is an option that could potentially raise platelets for a more sustained period in children with ITP in the newly diagnosed period, which is one of the most difficult times for patients with regard to the impact of the disease on bleeding symptoms and quality of life,” she added.
Commenting on the study, James B. Bussel, MD, emeritus professor of pediatrics, medicine and obstetrics and gynecology at Weill Cornell Medicine in New York City, commented that “generally, a short-term increase in platelets is the biggest challenge, which is getting the patient to the point of not requiring future treatment to get better.”
“If more children can be shown to be going into remission earlier, that would be great,” he said.
While eltrombopag is known to be effective in chronic ITP, a key caveat of its use in newly diagnosed patients is the question of whether patients will get better on their own and feasibly be able to be spared the cost and burden of treatment in the first place.
However, identifying which patients will fit that profile isn’t always easy.
“Exactly which child needs treatment can be hard to determine, and there is some debate about that,” Bussel noted.
“The theoretic standard is that the platelet count doesn’t matter — only whether the patient is bleeding a lot, and then there is debate over treatment based on bleeding scores,” he said.
Quality-of-life issues, such as patients’ ability to take part in activities, are also a key consideration.
“It would be great if eltrombopag can support children who really need it and provide clear unequivocal benefit beyond just increasing the platelet count, but also leading to better quality of life,” Bussel said.
The new findings are “a very encouraging start, but I’d really like to see what the story is at 1 year.”
The study was funded by Novartis, maker of eltrombopag, and sponsored by the ITP Consortium of North America. Shimano disclosed ties with Sanofi, Sobi, Daiichi Sankyo, Novartis, and Pfizer. Bussel reported a relationship with Novartis that ended more than 2 years ago.
A version of this article first appeared on Medscape.com.
“This is the first time in 30 years that a new drug is being tested for newly diagnosed pediatric ITP,” said the study’s lead author, Kristin A. Shimano, MD, professor of pediatrics at the Benioff Children’s Hospital, University of California San Francisco, in a press statement for the study, presented at the American Society of Hematology (ASH) 2024 Annual Meeting earlier this month.
“We really think that this has the potential to transform the approach to the management of ITP in the newly diagnosed phase with the use of a therapy that can provide sustained hemostatic platelet counts to bridge the time that patients are at risk of bleeding events with the goal to wean off the medication for patients who have a natural resolution of their disease,” Shimano said in her talk.
While children with ITP, a rare autoimmune blood disorder, very often improve without the need for any treatment, some do require intervention, and the condition can become chronic. First-line therapies for those patients commonly include corticosteroids, intravenous immunoglobulin (IVIg), and anti-D globulin; however, side effects can be undesirable, and with their efficacy often temporary, patients can require monitoring and juggling of treatments.
Eltrombopag, an oral, daily thrombopoietin receptor agonist, was approved by the US Food and Drug Administration for children and adults with chronic ITP in 2015; however, research has been lacking on the benefits of the therapy for newly diagnosed pediatric patients.
To investigate the drug’s efficacy at that stage, Shimano and colleagues with the ITP Consortium of North America launched the prospective, open-label Pediatric ITP Newly diagnosed pts Epag vs Standard therapy (PINES) trial, enrolling 118 patients at 23 institutions between May 2019 and January 2024.
All enrollees had been diagnosed with ITP within 3 months and had been determined by their treating hematologist to require pharmacologic treatment.
Of the patients, about 40% were untreated, and 60% had been treated with at least one medication prior to the trial but did not have a lasting response.
The patients were stratified by age and prior treatment and randomized 2:1 to receive either eltrombopag (n = 78) or the investigator’s choice of one of three standard first-line therapies, including prednisone, IVIg, or anti-D globulin at specified doses (n = 40). Overall, 29 in the standard-of-care arm received prednisone and 11 received IVIg. The patients had a median age of 8 years.
For the study’s primary endpoint, patients in the eltrombopag group had a significantly greater sustained response at 12 weeks, defined as having at least three of four platelet counts > 50 × 109/L during weeks 6-12 without the need for rescue treatment, with a rate of 63% vs 35% in the standard-of-care group (P = .0054).
There were no significant differences between the two groups in terms of the proportion of patients with a high bleeding score at weeks 1-4 and week 12.
However, those in the eltrombopag arm had a significantly lower rate of receiving rescue therapy (18% vs 38% with the standard of care; P = .02).
Both groups showed clinically meaningful improvements from baseline in terms of health-related quality of life, as assessed by parent proxy-reported KIT overall scores.
Twenty adverse events that were grade 3 or higher, including six serious adverse events, occurred in each of the study’s arms, with the most common events including headache and epistaxis.
Treatment-related serious adverse events occurred among six patients in the eltrombopag group and one in the control group, but importantly, no thromboembolic events were reported.
One intracranial hemorrhage occurred in the eltrombopag arm.
With eltrombopag having a slower effect than some other treatments, Shimano cautioned that the therapy is not recommended for patients with severe bleeding.
“Patients with grade 4 or 5 bleeding at the time of screening were specifically excluded from the study, so for patients who have very severe bleeding who need to get their platelets up very quickly, this would not be the ideal therapy for them,” she noted.
On the basis of results, the trial was recommended to close early due to efficacy; however, the participants are being followed for a total of 12 months to determine the durability of the responses, including in terms of bleeding events, quality of life, or the development of chronic ITP.
“We have shown that in pediatric patients with newly diagnosed ITP requiring pharmacologic treatment, eltrombopag resulted in a significant, clinically relevant higher rate of a durable platelet response in the absence of rescue treatment as compared with standard first-line therapies,” Shimano said.
“Eltrombopag could certainly be added to the medication choices hematologists consider as they are making treatment decisions with families, and it is an option that could potentially raise platelets for a more sustained period in children with ITP in the newly diagnosed period, which is one of the most difficult times for patients with regard to the impact of the disease on bleeding symptoms and quality of life,” she added.
Commenting on the study, James B. Bussel, MD, emeritus professor of pediatrics, medicine and obstetrics and gynecology at Weill Cornell Medicine in New York City, commented that “generally, a short-term increase in platelets is the biggest challenge, which is getting the patient to the point of not requiring future treatment to get better.”
“If more children can be shown to be going into remission earlier, that would be great,” he said.
While eltrombopag is known to be effective in chronic ITP, a key caveat of its use in newly diagnosed patients is the question of whether patients will get better on their own and feasibly be able to be spared the cost and burden of treatment in the first place.
However, identifying which patients will fit that profile isn’t always easy.
“Exactly which child needs treatment can be hard to determine, and there is some debate about that,” Bussel noted.
“The theoretic standard is that the platelet count doesn’t matter — only whether the patient is bleeding a lot, and then there is debate over treatment based on bleeding scores,” he said.
Quality-of-life issues, such as patients’ ability to take part in activities, are also a key consideration.
“It would be great if eltrombopag can support children who really need it and provide clear unequivocal benefit beyond just increasing the platelet count, but also leading to better quality of life,” Bussel said.
The new findings are “a very encouraging start, but I’d really like to see what the story is at 1 year.”
The study was funded by Novartis, maker of eltrombopag, and sponsored by the ITP Consortium of North America. Shimano disclosed ties with Sanofi, Sobi, Daiichi Sankyo, Novartis, and Pfizer. Bussel reported a relationship with Novartis that ended more than 2 years ago.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
Camrelizumab Plus Chemotherapy Boosts Response in Triple-Negative Breast Cancer
TOPLINE:
The combination shows consistent benefits across patient subgroups with a manageable safety profile.
METHODOLOGY:
- A randomized, double-blind, phase 3 trial enrolled 441 females (median age, 48 years) with early or locally advanced triple-negative breast cancer from 40 hospitals in China between November 2020 and May 2023.
- Participants were randomized 1:1 to receive either camrelizumab 200 mg (n = 222) or placebo (n = 219) combined with chemotherapy every 2 weeks, with median follow-up period of 14.4 months.
- Treatment included nab-paclitaxel (100 mg/m²) plus carboplatin (area under curve, 1.5) on days 1, 8, and 15 in 28-day cycles for 16 weeks, followed by epirubicin (90 mg/m²) and cyclophosphamide (500 mg/m²) every 2 weeks for 8 weeks.
- The primary endpoint was pathological complete response, defined as no invasive tumor in breast and lymph nodes.
TAKEAWAY:
- Pathological complete response was achieved in 56.8% (95% CI, 50.0%-63.4%) of patients in the camrelizumab-chemotherapy group vs 44.7% (95% CI, 38.0%-51.6%) in the placebo-chemotherapy group (rate difference, 12.2%; 95% CI, 3.3%-21.2%; P = .004).
- Grade 3 or higher adverse events occurred in 89.2% of camrelizumab-chemotherapy group vs 83.1% in placebo-chemotherapy group, with serious adverse events in 34.7% vs 22.8%, respectively.
- Event-free survival rate at 18 months was 86.6% (95% CI, 79.9%-91.1%) with camrelizumab-chemotherapy vs 83.6% (95% CI, 76.2%-88.9%) with placebo-chemotherapy (hazard ratio [HR], 0.80; 95% CI, 0.46-1.42).
- Disease-free survival rate at 12 months reached 91.9% (95% CI, 85.5%-95.5%) with camrelizumab-chemotherapy compared with 87.8% (95% CI, 80.3%-92.6%) with placebo-chemotherapy (HR, 0.58; 95% CI, 0.27-1.24).
IN PRACTICE:
“The addition of camrelizumab to neoadjuvant chemotherapy significantly improved pathological complete response... The benefits of camrelizumab-chemotherapy with respect to pCR were generally consistent across subgroups,” wrote the authors of the study.
SOURCE:
The study was led by Zhi-Ming Shao, MD, Fudan University Shanghai Cancer Center in Shanghai, China. It was published online on December 13 in JAMA.
LIMITATIONS:
According to the authors, the study’s limitations include short follow-up duration preventing assessment of mature survival data and long-term safety profile, uncertainty about optimal duration of adjuvant camrelizumab treatment, small sample sizes in some subgroups warranting cautious interpretation, and potential limited generalizability as the study was conducted only in Chinese patients with triple-negative breast cancer.
DISCLOSURES:
The study was supported by Jiangsu Hengrui Pharmaceuticals. The authors and funder were involved in data collection, analysis, and interpretation and guaranteed the accuracy, completeness of the data, writing of the report, and the decision to submit the manuscript for publication.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
The combination shows consistent benefits across patient subgroups with a manageable safety profile.
METHODOLOGY:
- A randomized, double-blind, phase 3 trial enrolled 441 females (median age, 48 years) with early or locally advanced triple-negative breast cancer from 40 hospitals in China between November 2020 and May 2023.
- Participants were randomized 1:1 to receive either camrelizumab 200 mg (n = 222) or placebo (n = 219) combined with chemotherapy every 2 weeks, with median follow-up period of 14.4 months.
- Treatment included nab-paclitaxel (100 mg/m²) plus carboplatin (area under curve, 1.5) on days 1, 8, and 15 in 28-day cycles for 16 weeks, followed by epirubicin (90 mg/m²) and cyclophosphamide (500 mg/m²) every 2 weeks for 8 weeks.
- The primary endpoint was pathological complete response, defined as no invasive tumor in breast and lymph nodes.
TAKEAWAY:
- Pathological complete response was achieved in 56.8% (95% CI, 50.0%-63.4%) of patients in the camrelizumab-chemotherapy group vs 44.7% (95% CI, 38.0%-51.6%) in the placebo-chemotherapy group (rate difference, 12.2%; 95% CI, 3.3%-21.2%; P = .004).
- Grade 3 or higher adverse events occurred in 89.2% of camrelizumab-chemotherapy group vs 83.1% in placebo-chemotherapy group, with serious adverse events in 34.7% vs 22.8%, respectively.
- Event-free survival rate at 18 months was 86.6% (95% CI, 79.9%-91.1%) with camrelizumab-chemotherapy vs 83.6% (95% CI, 76.2%-88.9%) with placebo-chemotherapy (hazard ratio [HR], 0.80; 95% CI, 0.46-1.42).
- Disease-free survival rate at 12 months reached 91.9% (95% CI, 85.5%-95.5%) with camrelizumab-chemotherapy compared with 87.8% (95% CI, 80.3%-92.6%) with placebo-chemotherapy (HR, 0.58; 95% CI, 0.27-1.24).
IN PRACTICE:
“The addition of camrelizumab to neoadjuvant chemotherapy significantly improved pathological complete response... The benefits of camrelizumab-chemotherapy with respect to pCR were generally consistent across subgroups,” wrote the authors of the study.
SOURCE:
The study was led by Zhi-Ming Shao, MD, Fudan University Shanghai Cancer Center in Shanghai, China. It was published online on December 13 in JAMA.
LIMITATIONS:
According to the authors, the study’s limitations include short follow-up duration preventing assessment of mature survival data and long-term safety profile, uncertainty about optimal duration of adjuvant camrelizumab treatment, small sample sizes in some subgroups warranting cautious interpretation, and potential limited generalizability as the study was conducted only in Chinese patients with triple-negative breast cancer.
DISCLOSURES:
The study was supported by Jiangsu Hengrui Pharmaceuticals. The authors and funder were involved in data collection, analysis, and interpretation and guaranteed the accuracy, completeness of the data, writing of the report, and the decision to submit the manuscript for publication.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
The combination shows consistent benefits across patient subgroups with a manageable safety profile.
METHODOLOGY:
- A randomized, double-blind, phase 3 trial enrolled 441 females (median age, 48 years) with early or locally advanced triple-negative breast cancer from 40 hospitals in China between November 2020 and May 2023.
- Participants were randomized 1:1 to receive either camrelizumab 200 mg (n = 222) or placebo (n = 219) combined with chemotherapy every 2 weeks, with median follow-up period of 14.4 months.
- Treatment included nab-paclitaxel (100 mg/m²) plus carboplatin (area under curve, 1.5) on days 1, 8, and 15 in 28-day cycles for 16 weeks, followed by epirubicin (90 mg/m²) and cyclophosphamide (500 mg/m²) every 2 weeks for 8 weeks.
- The primary endpoint was pathological complete response, defined as no invasive tumor in breast and lymph nodes.
TAKEAWAY:
- Pathological complete response was achieved in 56.8% (95% CI, 50.0%-63.4%) of patients in the camrelizumab-chemotherapy group vs 44.7% (95% CI, 38.0%-51.6%) in the placebo-chemotherapy group (rate difference, 12.2%; 95% CI, 3.3%-21.2%; P = .004).
- Grade 3 or higher adverse events occurred in 89.2% of camrelizumab-chemotherapy group vs 83.1% in placebo-chemotherapy group, with serious adverse events in 34.7% vs 22.8%, respectively.
- Event-free survival rate at 18 months was 86.6% (95% CI, 79.9%-91.1%) with camrelizumab-chemotherapy vs 83.6% (95% CI, 76.2%-88.9%) with placebo-chemotherapy (hazard ratio [HR], 0.80; 95% CI, 0.46-1.42).
- Disease-free survival rate at 12 months reached 91.9% (95% CI, 85.5%-95.5%) with camrelizumab-chemotherapy compared with 87.8% (95% CI, 80.3%-92.6%) with placebo-chemotherapy (HR, 0.58; 95% CI, 0.27-1.24).
IN PRACTICE:
“The addition of camrelizumab to neoadjuvant chemotherapy significantly improved pathological complete response... The benefits of camrelizumab-chemotherapy with respect to pCR were generally consistent across subgroups,” wrote the authors of the study.
SOURCE:
The study was led by Zhi-Ming Shao, MD, Fudan University Shanghai Cancer Center in Shanghai, China. It was published online on December 13 in JAMA.
LIMITATIONS:
According to the authors, the study’s limitations include short follow-up duration preventing assessment of mature survival data and long-term safety profile, uncertainty about optimal duration of adjuvant camrelizumab treatment, small sample sizes in some subgroups warranting cautious interpretation, and potential limited generalizability as the study was conducted only in Chinese patients with triple-negative breast cancer.
DISCLOSURES:
The study was supported by Jiangsu Hengrui Pharmaceuticals. The authors and funder were involved in data collection, analysis, and interpretation and guaranteed the accuracy, completeness of the data, writing of the report, and the decision to submit the manuscript for publication.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Surveillance Instead of Surgery for Low-Risk DCIS?
At 2 years, investigators on the COMET trial found no clinically meaningful difference in the rates of ipsilateral invasive breast cancer among women randomized to active surveillance vs standard upfront surgery with or without radiation.
The 2-year findings suggest that surveillance is safe in the short term.
“While these results are provocative, I don’t think they’re quite practice-changing yet,” said lead investigator Shelley Hwang, MD, a surgical breast oncologist at Duke University in Durham, North Carolina, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024.
For one thing, it generally takes longer than 2 years for DCIS to convert to invasive cancer, so it will be important to wait for the planned analyses at 5, 7, and 10 years to make sure there isn’t an excess number of invasive breast cancers in the surveillance arm, Hwang said.
If the results prove durable, however, the findings will likely be “practice-changing” for women who were at least 40 years old and had grade 1 or 2 hormone receptor–positive DCIS at low risk for conversion, Hwang said.
The goal of active surveillance is to prevent unnecessary treatment. During surveillance, lesions are monitored for changes that indicate conversion to more advanced disease, at which point guideline-concordant care begins.
Although DCIS can convert to invasive breast cancer, this doesn’t always happen. As a result, upfront surgery and radiation aren’t necessary for some women.
The COMET trial aimed to determine the short-term safety of an active monitoring approach compared with guideline-concordant care in patients with low-risk DCIS.
The prospective, randomized noninferiority trial included women aged 40 years or older with a new diagnosis of HR–positive grade 1 or grade 2 DCIS without invasive cancer from 100 US Alliance Cancer Cooperative Group clinical trial sites.
In the trial, 484 women with DCIS were randomized to active surveillance — breast mammography and physical exam every 6 months — and 473 were randomized to standard upfront surgery with or without radiation. Overall, 15.7% of participants were Black and 75.0% were White.
Patients in either group could elect to have endocrine therapy, typically over a 5-year period (71% of women in the active monitoring group and 65.5% in the surgery group opted for endocrine therapy).
At 2 years, the cumulative rate of ipsilateral invasive breast cancer was 4.2% in the surveillance group vs 5.9% in the upfront surgery arm.
The study also included a planned per-protocol analysis among 673 patients who strictly followed the study protocol — 246 in the guideline-concordant care group who had received surgery by 6 months and 427 in the surveillance group who initiated the active monitoring protocol at 6 months.
With almost half of patients randomized to surgery declined to have it, which indicates that patients are interested in active monitoring, Hwang said.
At 2 years, the cumulative rate of invasive breast cancer was 3.1% in the active surveillance group vs 8.7% in the upfront surgery arm.
Among patients receiving endocrine therapy, the rate of invasive cancer was 7.15% in the surgery group and 3.21% in the surveillance arm.
Endocrine therapy “may have resulted in a reduced rate of invasive cancer in the active monitoring group,” the study authors noted.
These findings bring up the question of whether endocrine therapy might be just as good as surgery for low-risk DCIS, Hwang added. Given that one third of women undergo mastectomy for DCIS, “I think it’s not an inconsequential question,” Hwang said.
The findings, however, also suggest that surveillance sometimes leaves invasive cancer behind, Hwang explained. Nearly all invasive cancers in the surgery group were found during the initial operation , which may explain the slightly higher rates of invasive cancers in this group. Had the active monitoring group undergone surgery as well, the incidence of invasive cancer may have been the same in both arms, Hwang said.
However, when invasive cancers were removed, there were no significant differences in tumor size, node status, or tumor grade between the two groups, suggesting that there might not be a clinical penalty for delayed intervention with active monitoring, Hwang said.
With more than 10% of patients in the surgery group opting for mastectomy, compared with 1.8% in the active monitoring group, the active monitoring approach may not increase the likelihood of an eventual need for more extensive surgery, the COMET authors explained.
What Strategy Do Patients Prefer?
A companion analysis of patient-reported outcomes in COMET found no meaningful differences in quality of life, symptoms, or anxiety among patients who opted for surveillance over surgery. Results from questionnaires on quality of life, anxiety, depression, and breast cancer concerns were comparable between the two groups, with no evidence of a substantial impact of one approach over the other at 2 years.
“The results of this secondary analysis suggest that the lived experiences of individuals with low-risk DCIS are similar during early follow-up regardless of treatment allocation,” the COMET investigators concluded.
Overall, the findings from COMET provide reassuring short-term data, said Neil Iyengar, MD, a medical breast oncologist at Memorial Sloan Kettering Cancer Center in New York City.
DCIS is not an aggressive cancer, and it’s not going to invade any time soon, so patients have time to consider their options, Iyengar told Medscape Medical News.
The 2-year findings from COMET also help inform patient discussions. “I can tell patients if they decide not to have surgery what the likelihood is that they are going to convert into invasive cancer” after 2 years, he said.
COMET was published in JAMA, and the PRO analysis was published in JAMA Oncology to coincide with the study presentations.
COMET is funded by the Patient-Centered Outcomes Research Institute and others. Hwang is a consultant for Merck and on the advisory board of Clinetic, Exai Bio, and Havah Therapeutics. Iyengar is an advisor and/or researcher for AstraZeneca, Novartis, Pfizer, and other companies.
A version of this article first appeared on Medscape.com.
At 2 years, investigators on the COMET trial found no clinically meaningful difference in the rates of ipsilateral invasive breast cancer among women randomized to active surveillance vs standard upfront surgery with or without radiation.
The 2-year findings suggest that surveillance is safe in the short term.
“While these results are provocative, I don’t think they’re quite practice-changing yet,” said lead investigator Shelley Hwang, MD, a surgical breast oncologist at Duke University in Durham, North Carolina, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024.
For one thing, it generally takes longer than 2 years for DCIS to convert to invasive cancer, so it will be important to wait for the planned analyses at 5, 7, and 10 years to make sure there isn’t an excess number of invasive breast cancers in the surveillance arm, Hwang said.
If the results prove durable, however, the findings will likely be “practice-changing” for women who were at least 40 years old and had grade 1 or 2 hormone receptor–positive DCIS at low risk for conversion, Hwang said.
The goal of active surveillance is to prevent unnecessary treatment. During surveillance, lesions are monitored for changes that indicate conversion to more advanced disease, at which point guideline-concordant care begins.
Although DCIS can convert to invasive breast cancer, this doesn’t always happen. As a result, upfront surgery and radiation aren’t necessary for some women.
The COMET trial aimed to determine the short-term safety of an active monitoring approach compared with guideline-concordant care in patients with low-risk DCIS.
The prospective, randomized noninferiority trial included women aged 40 years or older with a new diagnosis of HR–positive grade 1 or grade 2 DCIS without invasive cancer from 100 US Alliance Cancer Cooperative Group clinical trial sites.
In the trial, 484 women with DCIS were randomized to active surveillance — breast mammography and physical exam every 6 months — and 473 were randomized to standard upfront surgery with or without radiation. Overall, 15.7% of participants were Black and 75.0% were White.
Patients in either group could elect to have endocrine therapy, typically over a 5-year period (71% of women in the active monitoring group and 65.5% in the surgery group opted for endocrine therapy).
At 2 years, the cumulative rate of ipsilateral invasive breast cancer was 4.2% in the surveillance group vs 5.9% in the upfront surgery arm.
The study also included a planned per-protocol analysis among 673 patients who strictly followed the study protocol — 246 in the guideline-concordant care group who had received surgery by 6 months and 427 in the surveillance group who initiated the active monitoring protocol at 6 months.
With almost half of patients randomized to surgery declined to have it, which indicates that patients are interested in active monitoring, Hwang said.
At 2 years, the cumulative rate of invasive breast cancer was 3.1% in the active surveillance group vs 8.7% in the upfront surgery arm.
Among patients receiving endocrine therapy, the rate of invasive cancer was 7.15% in the surgery group and 3.21% in the surveillance arm.
Endocrine therapy “may have resulted in a reduced rate of invasive cancer in the active monitoring group,” the study authors noted.
These findings bring up the question of whether endocrine therapy might be just as good as surgery for low-risk DCIS, Hwang added. Given that one third of women undergo mastectomy for DCIS, “I think it’s not an inconsequential question,” Hwang said.
The findings, however, also suggest that surveillance sometimes leaves invasive cancer behind, Hwang explained. Nearly all invasive cancers in the surgery group were found during the initial operation , which may explain the slightly higher rates of invasive cancers in this group. Had the active monitoring group undergone surgery as well, the incidence of invasive cancer may have been the same in both arms, Hwang said.
However, when invasive cancers were removed, there were no significant differences in tumor size, node status, or tumor grade between the two groups, suggesting that there might not be a clinical penalty for delayed intervention with active monitoring, Hwang said.
With more than 10% of patients in the surgery group opting for mastectomy, compared with 1.8% in the active monitoring group, the active monitoring approach may not increase the likelihood of an eventual need for more extensive surgery, the COMET authors explained.
What Strategy Do Patients Prefer?
A companion analysis of patient-reported outcomes in COMET found no meaningful differences in quality of life, symptoms, or anxiety among patients who opted for surveillance over surgery. Results from questionnaires on quality of life, anxiety, depression, and breast cancer concerns were comparable between the two groups, with no evidence of a substantial impact of one approach over the other at 2 years.
“The results of this secondary analysis suggest that the lived experiences of individuals with low-risk DCIS are similar during early follow-up regardless of treatment allocation,” the COMET investigators concluded.
Overall, the findings from COMET provide reassuring short-term data, said Neil Iyengar, MD, a medical breast oncologist at Memorial Sloan Kettering Cancer Center in New York City.
DCIS is not an aggressive cancer, and it’s not going to invade any time soon, so patients have time to consider their options, Iyengar told Medscape Medical News.
The 2-year findings from COMET also help inform patient discussions. “I can tell patients if they decide not to have surgery what the likelihood is that they are going to convert into invasive cancer” after 2 years, he said.
COMET was published in JAMA, and the PRO analysis was published in JAMA Oncology to coincide with the study presentations.
COMET is funded by the Patient-Centered Outcomes Research Institute and others. Hwang is a consultant for Merck and on the advisory board of Clinetic, Exai Bio, and Havah Therapeutics. Iyengar is an advisor and/or researcher for AstraZeneca, Novartis, Pfizer, and other companies.
A version of this article first appeared on Medscape.com.
At 2 years, investigators on the COMET trial found no clinically meaningful difference in the rates of ipsilateral invasive breast cancer among women randomized to active surveillance vs standard upfront surgery with or without radiation.
The 2-year findings suggest that surveillance is safe in the short term.
“While these results are provocative, I don’t think they’re quite practice-changing yet,” said lead investigator Shelley Hwang, MD, a surgical breast oncologist at Duke University in Durham, North Carolina, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024.
For one thing, it generally takes longer than 2 years for DCIS to convert to invasive cancer, so it will be important to wait for the planned analyses at 5, 7, and 10 years to make sure there isn’t an excess number of invasive breast cancers in the surveillance arm, Hwang said.
If the results prove durable, however, the findings will likely be “practice-changing” for women who were at least 40 years old and had grade 1 or 2 hormone receptor–positive DCIS at low risk for conversion, Hwang said.
The goal of active surveillance is to prevent unnecessary treatment. During surveillance, lesions are monitored for changes that indicate conversion to more advanced disease, at which point guideline-concordant care begins.
Although DCIS can convert to invasive breast cancer, this doesn’t always happen. As a result, upfront surgery and radiation aren’t necessary for some women.
The COMET trial aimed to determine the short-term safety of an active monitoring approach compared with guideline-concordant care in patients with low-risk DCIS.
The prospective, randomized noninferiority trial included women aged 40 years or older with a new diagnosis of HR–positive grade 1 or grade 2 DCIS without invasive cancer from 100 US Alliance Cancer Cooperative Group clinical trial sites.
In the trial, 484 women with DCIS were randomized to active surveillance — breast mammography and physical exam every 6 months — and 473 were randomized to standard upfront surgery with or without radiation. Overall, 15.7% of participants were Black and 75.0% were White.
Patients in either group could elect to have endocrine therapy, typically over a 5-year period (71% of women in the active monitoring group and 65.5% in the surgery group opted for endocrine therapy).
At 2 years, the cumulative rate of ipsilateral invasive breast cancer was 4.2% in the surveillance group vs 5.9% in the upfront surgery arm.
The study also included a planned per-protocol analysis among 673 patients who strictly followed the study protocol — 246 in the guideline-concordant care group who had received surgery by 6 months and 427 in the surveillance group who initiated the active monitoring protocol at 6 months.
With almost half of patients randomized to surgery declined to have it, which indicates that patients are interested in active monitoring, Hwang said.
At 2 years, the cumulative rate of invasive breast cancer was 3.1% in the active surveillance group vs 8.7% in the upfront surgery arm.
Among patients receiving endocrine therapy, the rate of invasive cancer was 7.15% in the surgery group and 3.21% in the surveillance arm.
Endocrine therapy “may have resulted in a reduced rate of invasive cancer in the active monitoring group,” the study authors noted.
These findings bring up the question of whether endocrine therapy might be just as good as surgery for low-risk DCIS, Hwang added. Given that one third of women undergo mastectomy for DCIS, “I think it’s not an inconsequential question,” Hwang said.
The findings, however, also suggest that surveillance sometimes leaves invasive cancer behind, Hwang explained. Nearly all invasive cancers in the surgery group were found during the initial operation , which may explain the slightly higher rates of invasive cancers in this group. Had the active monitoring group undergone surgery as well, the incidence of invasive cancer may have been the same in both arms, Hwang said.
However, when invasive cancers were removed, there were no significant differences in tumor size, node status, or tumor grade between the two groups, suggesting that there might not be a clinical penalty for delayed intervention with active monitoring, Hwang said.
With more than 10% of patients in the surgery group opting for mastectomy, compared with 1.8% in the active monitoring group, the active monitoring approach may not increase the likelihood of an eventual need for more extensive surgery, the COMET authors explained.
What Strategy Do Patients Prefer?
A companion analysis of patient-reported outcomes in COMET found no meaningful differences in quality of life, symptoms, or anxiety among patients who opted for surveillance over surgery. Results from questionnaires on quality of life, anxiety, depression, and breast cancer concerns were comparable between the two groups, with no evidence of a substantial impact of one approach over the other at 2 years.
“The results of this secondary analysis suggest that the lived experiences of individuals with low-risk DCIS are similar during early follow-up regardless of treatment allocation,” the COMET investigators concluded.
Overall, the findings from COMET provide reassuring short-term data, said Neil Iyengar, MD, a medical breast oncologist at Memorial Sloan Kettering Cancer Center in New York City.
DCIS is not an aggressive cancer, and it’s not going to invade any time soon, so patients have time to consider their options, Iyengar told Medscape Medical News.
The 2-year findings from COMET also help inform patient discussions. “I can tell patients if they decide not to have surgery what the likelihood is that they are going to convert into invasive cancer” after 2 years, he said.
COMET was published in JAMA, and the PRO analysis was published in JAMA Oncology to coincide with the study presentations.
COMET is funded by the Patient-Centered Outcomes Research Institute and others. Hwang is a consultant for Merck and on the advisory board of Clinetic, Exai Bio, and Havah Therapeutics. Iyengar is an advisor and/or researcher for AstraZeneca, Novartis, Pfizer, and other companies.
A version of this article first appeared on Medscape.com.
FROM SABCS 2024