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An international consortium of Huntington’s disease experts has developed the first-ever staging system for the genetic neurologic condition – an important step toward developing new therapeutics to treat the disease before symptoms present.

Researchers liken the Huntington’s disease Integrated Staging System (HD-ISS) to the system currently used to stage cancer. It groups patients according to their underlying biological, clinical, and functional characteristics.

It also includes criteria to biologically define Huntington’s disease stages across the entire disease spectrum, from birth to death, which is something that has not been done before. For now, the HD-ISS is only intended for research, but it could one day be modified for use in the clinic, investigators wrote.

“This systematization is of critical importance to select the most appropriate target population for clinical trials and studies,” said co-investigator Cristina Sampaio, MD, chief medical officer at the CHDI Foundation, Princeton, N.J.

“By providing a methodology to precisely define cases early in the neurodegenerative process, the HD-ISS will be instrumental in conducting trials in the very early disease stages,” Dr. Sampaio added.

The position paper was published in the July issue of the Lancet Neurology.
 

New approach needed

There is no approved therapy to slow Huntington’s disease progression. Clinical trials currently enroll patients with demonstrable symptoms, which limits the ability to test therapeutics that could delay or prevent neurodegeneration.

Huntington’s disease is rare, occurring in about 2.7 per 100,000 individuals worldwide. It is caused by a mutation in the HTT gene involving a DNA segment known as a CAG trinucleotide repeat.

Currently, Huntington’s disease is diagnosed on the basis of clinical signs that emerge late in the disease course, an approach developed before the discovery of the HTT gene and the development of the genetic test for the CAG mutation.

The disease phase prior to diagnosis has been described as presymptomatic, premanifest, or prodromal. However, the three terms have varying definitions that make it difficult to compare study results across trials.

Because drug development had focused on the overt motor sign phase of the disease, there was no real need for an evidence-based staging system that classified disease phases from birth, the investigators noted.

“Now, the research community and regulators recognize that it is critical to conduct trials early in the disease when no signs or overt symptoms are measurable,” Dr. Sampaio said.
 

Defining disease stages

Work on the staging system was done through the Huntington’s Disease Regulatory Science Consortium, an international project begun in 2018 among biotech and pharma companies, academic institutions, and nonprofit research and advocacy organizations.

Overall, more than 50 clinicians and researchers were involved in developing the HD-ISS.

Using modeling data from four large observational studies that included patients with Huntington’s disease and control groups, researchers identified four different stages of Huntington’s disease:

• Stage 0: Begins at birth with identification of HTT gene mutations but no detectable pathologic changes.
• Stage 1: Begins when biomarker changes are detected via MRI by a volume decrease in six brain areas.
• Stage 2: Begins when clinical signs of Huntington’s disease are present, as determined through motor and cognitive assessments.
• Stage 3: Begins when functional decline is evident, with worsening on the Independence Scale and the Total Functional Capacity of the Unified Huntington’s Disease Rating Scale.

Applying the HD-ISS to clinical trials requires the collection of information routinely recorded in Huntington’s disease research, as well as some additional data, but researchers say its application is straightforward.

The HD-ISS uses a numerical staging system similar to that used in the U.S. Food and Drug Administration’s guidance for Alzheimer’s disease (AD) and integrates the prodromal, presymptomatic, or premanifest phase of the disease. This distinguishes it from earlier classification systems.

The HD-ISS can be adapted if new Huntington’s disease biomarkers are identified.

“As research results are generated, this will further validate the HD-ISS and potentially lead to the development of a derivative, and possibly simplified, system for clinical practice,” Dr. Sampaio said.

The new system goes further than a more recent proposal from the Movement Disorder Society task force, which addresses earlier stages in Huntington’s disease but doesn’t consider objective biomarker data.
 

Question of timing

Commenting on the findings, Erin Furr-Stimming, MD, neurologist and director of the Huntington’s Disease Society of America Center of Excellence with McGovern Medical School, UTHealth, Houston, said targeting early-stage disease will be key.

“Similar to more common neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, there is a period of at least a decade when changes are occurring in the nervous system, prior to the manifestation of clinical symptoms and signs significant enough to warrant a clinical diagnosis,” Dr. Furr-Stimming said.

She noted that multiple trials of disease-modifying agents for Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have failed for a multitude of reasons, “but one consistent question that is relevant to all these diseases is that of timing: Should we intervene and test these therapies earlier?

“The premanifest or prodromal period may be the ideal time to intervene with a disease-modifying therapy, prior to onset of any neurodegeneration,” Dr. Furr-Stimming said.

The CHDI Foundation provided financial support to the Critical Path Institute for the Huntington’s Disease Regulatory Science Consortium, including all working group efforts. Dr. Sampio is an employee of and receives salary from CHDI Management. She has also received consultancy honorariums (unrelated to HD) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. A full list of disclosures for the other researchers is in the original article. Dr. Furr-Stimming reported no relevant financial relationships.

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

An international consortium of Huntington’s disease experts has developed the first-ever staging system for the genetic neurologic condition – an important step toward developing new therapeutics to treat the disease before symptoms present.

Researchers liken the Huntington’s disease Integrated Staging System (HD-ISS) to the system currently used to stage cancer. It groups patients according to their underlying biological, clinical, and functional characteristics.

It also includes criteria to biologically define Huntington’s disease stages across the entire disease spectrum, from birth to death, which is something that has not been done before. For now, the HD-ISS is only intended for research, but it could one day be modified for use in the clinic, investigators wrote.

“This systematization is of critical importance to select the most appropriate target population for clinical trials and studies,” said co-investigator Cristina Sampaio, MD, chief medical officer at the CHDI Foundation, Princeton, N.J.

“By providing a methodology to precisely define cases early in the neurodegenerative process, the HD-ISS will be instrumental in conducting trials in the very early disease stages,” Dr. Sampaio added.

The position paper was published in the July issue of the Lancet Neurology.
 

New approach needed

There is no approved therapy to slow Huntington’s disease progression. Clinical trials currently enroll patients with demonstrable symptoms, which limits the ability to test therapeutics that could delay or prevent neurodegeneration.

Huntington’s disease is rare, occurring in about 2.7 per 100,000 individuals worldwide. It is caused by a mutation in the HTT gene involving a DNA segment known as a CAG trinucleotide repeat.

Currently, Huntington’s disease is diagnosed on the basis of clinical signs that emerge late in the disease course, an approach developed before the discovery of the HTT gene and the development of the genetic test for the CAG mutation.

The disease phase prior to diagnosis has been described as presymptomatic, premanifest, or prodromal. However, the three terms have varying definitions that make it difficult to compare study results across trials.

Because drug development had focused on the overt motor sign phase of the disease, there was no real need for an evidence-based staging system that classified disease phases from birth, the investigators noted.

“Now, the research community and regulators recognize that it is critical to conduct trials early in the disease when no signs or overt symptoms are measurable,” Dr. Sampaio said.
 

Defining disease stages

Work on the staging system was done through the Huntington’s Disease Regulatory Science Consortium, an international project begun in 2018 among biotech and pharma companies, academic institutions, and nonprofit research and advocacy organizations.

Overall, more than 50 clinicians and researchers were involved in developing the HD-ISS.

Using modeling data from four large observational studies that included patients with Huntington’s disease and control groups, researchers identified four different stages of Huntington’s disease:

• Stage 0: Begins at birth with identification of HTT gene mutations but no detectable pathologic changes.
• Stage 1: Begins when biomarker changes are detected via MRI by a volume decrease in six brain areas.
• Stage 2: Begins when clinical signs of Huntington’s disease are present, as determined through motor and cognitive assessments.
• Stage 3: Begins when functional decline is evident, with worsening on the Independence Scale and the Total Functional Capacity of the Unified Huntington’s Disease Rating Scale.

Applying the HD-ISS to clinical trials requires the collection of information routinely recorded in Huntington’s disease research, as well as some additional data, but researchers say its application is straightforward.

The HD-ISS uses a numerical staging system similar to that used in the U.S. Food and Drug Administration’s guidance for Alzheimer’s disease (AD) and integrates the prodromal, presymptomatic, or premanifest phase of the disease. This distinguishes it from earlier classification systems.

The HD-ISS can be adapted if new Huntington’s disease biomarkers are identified.

“As research results are generated, this will further validate the HD-ISS and potentially lead to the development of a derivative, and possibly simplified, system for clinical practice,” Dr. Sampaio said.

The new system goes further than a more recent proposal from the Movement Disorder Society task force, which addresses earlier stages in Huntington’s disease but doesn’t consider objective biomarker data.
 

Question of timing

Commenting on the findings, Erin Furr-Stimming, MD, neurologist and director of the Huntington’s Disease Society of America Center of Excellence with McGovern Medical School, UTHealth, Houston, said targeting early-stage disease will be key.

“Similar to more common neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, there is a period of at least a decade when changes are occurring in the nervous system, prior to the manifestation of clinical symptoms and signs significant enough to warrant a clinical diagnosis,” Dr. Furr-Stimming said.

She noted that multiple trials of disease-modifying agents for Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have failed for a multitude of reasons, “but one consistent question that is relevant to all these diseases is that of timing: Should we intervene and test these therapies earlier?

“The premanifest or prodromal period may be the ideal time to intervene with a disease-modifying therapy, prior to onset of any neurodegeneration,” Dr. Furr-Stimming said.

The CHDI Foundation provided financial support to the Critical Path Institute for the Huntington’s Disease Regulatory Science Consortium, including all working group efforts. Dr. Sampio is an employee of and receives salary from CHDI Management. She has also received consultancy honorariums (unrelated to HD) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. A full list of disclosures for the other researchers is in the original article. Dr. Furr-Stimming reported no relevant financial relationships.

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

An international consortium of Huntington’s disease experts has developed the first-ever staging system for the genetic neurologic condition – an important step toward developing new therapeutics to treat the disease before symptoms present.

Researchers liken the Huntington’s disease Integrated Staging System (HD-ISS) to the system currently used to stage cancer. It groups patients according to their underlying biological, clinical, and functional characteristics.

It also includes criteria to biologically define Huntington’s disease stages across the entire disease spectrum, from birth to death, which is something that has not been done before. For now, the HD-ISS is only intended for research, but it could one day be modified for use in the clinic, investigators wrote.

“This systematization is of critical importance to select the most appropriate target population for clinical trials and studies,” said co-investigator Cristina Sampaio, MD, chief medical officer at the CHDI Foundation, Princeton, N.J.

“By providing a methodology to precisely define cases early in the neurodegenerative process, the HD-ISS will be instrumental in conducting trials in the very early disease stages,” Dr. Sampaio added.

The position paper was published in the July issue of the Lancet Neurology.
 

New approach needed

There is no approved therapy to slow Huntington’s disease progression. Clinical trials currently enroll patients with demonstrable symptoms, which limits the ability to test therapeutics that could delay or prevent neurodegeneration.

Huntington’s disease is rare, occurring in about 2.7 per 100,000 individuals worldwide. It is caused by a mutation in the HTT gene involving a DNA segment known as a CAG trinucleotide repeat.

Currently, Huntington’s disease is diagnosed on the basis of clinical signs that emerge late in the disease course, an approach developed before the discovery of the HTT gene and the development of the genetic test for the CAG mutation.

The disease phase prior to diagnosis has been described as presymptomatic, premanifest, or prodromal. However, the three terms have varying definitions that make it difficult to compare study results across trials.

Because drug development had focused on the overt motor sign phase of the disease, there was no real need for an evidence-based staging system that classified disease phases from birth, the investigators noted.

“Now, the research community and regulators recognize that it is critical to conduct trials early in the disease when no signs or overt symptoms are measurable,” Dr. Sampaio said.
 

Defining disease stages

Work on the staging system was done through the Huntington’s Disease Regulatory Science Consortium, an international project begun in 2018 among biotech and pharma companies, academic institutions, and nonprofit research and advocacy organizations.

Overall, more than 50 clinicians and researchers were involved in developing the HD-ISS.

Using modeling data from four large observational studies that included patients with Huntington’s disease and control groups, researchers identified four different stages of Huntington’s disease:

• Stage 0: Begins at birth with identification of HTT gene mutations but no detectable pathologic changes.
• Stage 1: Begins when biomarker changes are detected via MRI by a volume decrease in six brain areas.
• Stage 2: Begins when clinical signs of Huntington’s disease are present, as determined through motor and cognitive assessments.
• Stage 3: Begins when functional decline is evident, with worsening on the Independence Scale and the Total Functional Capacity of the Unified Huntington’s Disease Rating Scale.

Applying the HD-ISS to clinical trials requires the collection of information routinely recorded in Huntington’s disease research, as well as some additional data, but researchers say its application is straightforward.

The HD-ISS uses a numerical staging system similar to that used in the U.S. Food and Drug Administration’s guidance for Alzheimer’s disease (AD) and integrates the prodromal, presymptomatic, or premanifest phase of the disease. This distinguishes it from earlier classification systems.

The HD-ISS can be adapted if new Huntington’s disease biomarkers are identified.

“As research results are generated, this will further validate the HD-ISS and potentially lead to the development of a derivative, and possibly simplified, system for clinical practice,” Dr. Sampaio said.

The new system goes further than a more recent proposal from the Movement Disorder Society task force, which addresses earlier stages in Huntington’s disease but doesn’t consider objective biomarker data.
 

Question of timing

Commenting on the findings, Erin Furr-Stimming, MD, neurologist and director of the Huntington’s Disease Society of America Center of Excellence with McGovern Medical School, UTHealth, Houston, said targeting early-stage disease will be key.

“Similar to more common neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, there is a period of at least a decade when changes are occurring in the nervous system, prior to the manifestation of clinical symptoms and signs significant enough to warrant a clinical diagnosis,” Dr. Furr-Stimming said.

She noted that multiple trials of disease-modifying agents for Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have failed for a multitude of reasons, “but one consistent question that is relevant to all these diseases is that of timing: Should we intervene and test these therapies earlier?

“The premanifest or prodromal period may be the ideal time to intervene with a disease-modifying therapy, prior to onset of any neurodegeneration,” Dr. Furr-Stimming said.

The CHDI Foundation provided financial support to the Critical Path Institute for the Huntington’s Disease Regulatory Science Consortium, including all working group efforts. Dr. Sampio is an employee of and receives salary from CHDI Management. She has also received consultancy honorariums (unrelated to HD) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. A full list of disclosures for the other researchers is in the original article. Dr. Furr-Stimming reported no relevant financial relationships.

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

Wireless devices, like smart phones and tablets, appear to induce compulsive or even addictive use in many individuals, leading to adverse health consequences that are likely to be curtailed only through often difficult behavior modification, according to a pediatric endocrinologist’s take on the problem.

While the summary was based in part on the analysis of 234 published papers drawn from the medical literature, the lead author, Nidhi Gupta, MD, said the data reinforce her own clinical experience.

Lisa Nainggolin/MDedge News

“As a pediatric endocrinologist, the trend in smartphone-associated health disorders, such as obesity, sleep, and behavior issues, worries me,” Dr. Gupta, director of KAP Pediatric Endocrinology, Nashville, Tenn., said at the annual meeting of the Endocrine Society.

Based on her search of the medical literature, the available data raise concern. In one study she cited, for example, each hour per day of screen time was found to translate into a body mass index increase of 0.5 to 0.7 kg/m² (P < .001).

With this type of progressive rise in BMI comes prediabetes, dyslipidemia, and other metabolic disorders associated with major health risks, including cardiovascular disease. And there are others. Dr. Gupta cited data suggesting screen time before bed disturbs sleep, which has its own set of health risks.

“When I say health, it includes physical health, mental health, and emotional health,” said Dr. Gupta.

In the U.S. and other countries with a growing obesity epidemic, lack of physical activity and unhealthy eating are widely considered the major culprits. Excessive screen time contributes to both.

“When we are engaged with our devices, we are often snacking subconsciously and not very mindful that we are making unhealthy choices,” Dr. Gupta said.

The problem is that there is a vicious circle. Compulsive use of devices follows the same loop as other types of addictive behaviors, according to Dr. Gupta. She traced overuse of wireless devices to the dopaminergic system, which is a powerful neuroendocrine-mediated process of craving, response, and reward.

Like fat, sugar, and salt, which provoke a neuroendocrine reward signal, the chimes and buzzes of a cell phone provide their own cues for reward in the form of a dopamine surge. As a result, these become the “triggers of an irresistible and irrational urge to check our device that makes the dopamine go high in our brain,” Dr. Gupta explained.

Although the vicious cycle can be thwarted by turning off the device, Dr. Gupta characterized this as “impractical” when smartphones are so vital to daily communication. Rather, Dr. Gupta advocated a program of moderation, reserving the phone for useful tasks without succumbing to the siren song of apps that waste time.

The most conspicuous culprit is social media, which Dr. Gupta considers to be among the most Pavlovian triggers of cell phone addiction. However, she acknowledged that participation in social media has its justifications.

“I, myself, use social media for my own branding and marketing,” Dr. Gupta said.

The problem that users have is distinguishing between screen time that does and does not have value, according to Dr. Gupta. She indicated that many of those overusing their smart devices are being driven by the dopaminergic reward system, which is generally divorced from the real goals of life, such as personal satisfaction and activity that is rewarding monetarily or in other ways.

“I am not asking for these devices to be thrown out the window. I am advocating for moderation, balance, and real-life engagement,” Dr. Gupta said at the meeting, held in Atlanta and virtually.

She outlined a long list of practical suggestions, including turning off the alarms, chimes, and messages that engage the user into the vicious dopaminergic-reward system loop. She suggested mindfulness so that the user can distinguish between valuable device use and activity that is simply procrastination.

“The devices are designed to be addictive. They are designed to manipulate our brain,” she said. “Eliminate the reward. Let’s try to make our devices boring, unappealing, or enticing so that they only work as tools.”

The medical literature is filled with data that support the potential harms of excessive screen use, leading many others to make some of the same points. In 2017, Thomas N. Robinson, MD, professor of child health at Stanford (Calif.) University, reviewed data showing an association between screen media exposure and obesity in children and adolescents.

“This is an area crying out for more research,” Dr. Robinson said in an interview. The problem of screen time, sedentary behavior, and weight gain has been an issue since the television was invented, which was the point he made in his 2017 paper, but he agreed that the problem is only getting worse.

“Digital technology has become ubiquitous, touching nearly every aspect of people’s lives,” he said. Yet, as evidence grows that overuse of this technology can be harmful, it is creating a problem without a clear solution.

“There are few data about the efficacy of specific strategies to reduce harmful impacts of digital screen use,” he said.

While some of the solutions that Dr. Gupta described make sense, they are more easily described than executed. The dopaminergic reward system is strong and largely experienced subconsciously. Recruiting patients to recognize that dopaminergic rewards are not rewards in any true sense is already a challenge. Enlisting patients to take the difficult steps to avoid the behavioral cues might be even more difficult.

Dr. Gupta and Dr. Robinson report no potential conflicts of interest.

Wireless devices, like smart phones and tablets, appear to induce compulsive or even addictive use in many individuals, leading to adverse health consequences that are likely to be curtailed only through often difficult behavior modification, according to a pediatric endocrinologist’s take on the problem.

While the summary was based in part on the analysis of 234 published papers drawn from the medical literature, the lead author, Nidhi Gupta, MD, said the data reinforce her own clinical experience.

Lisa Nainggolin/MDedge News

“As a pediatric endocrinologist, the trend in smartphone-associated health disorders, such as obesity, sleep, and behavior issues, worries me,” Dr. Gupta, director of KAP Pediatric Endocrinology, Nashville, Tenn., said at the annual meeting of the Endocrine Society.

Based on her search of the medical literature, the available data raise concern. In one study she cited, for example, each hour per day of screen time was found to translate into a body mass index increase of 0.5 to 0.7 kg/m² (P < .001).

With this type of progressive rise in BMI comes prediabetes, dyslipidemia, and other metabolic disorders associated with major health risks, including cardiovascular disease. And there are others. Dr. Gupta cited data suggesting screen time before bed disturbs sleep, which has its own set of health risks.

“When I say health, it includes physical health, mental health, and emotional health,” said Dr. Gupta.

In the U.S. and other countries with a growing obesity epidemic, lack of physical activity and unhealthy eating are widely considered the major culprits. Excessive screen time contributes to both.

“When we are engaged with our devices, we are often snacking subconsciously and not very mindful that we are making unhealthy choices,” Dr. Gupta said.

The problem is that there is a vicious circle. Compulsive use of devices follows the same loop as other types of addictive behaviors, according to Dr. Gupta. She traced overuse of wireless devices to the dopaminergic system, which is a powerful neuroendocrine-mediated process of craving, response, and reward.

Like fat, sugar, and salt, which provoke a neuroendocrine reward signal, the chimes and buzzes of a cell phone provide their own cues for reward in the form of a dopamine surge. As a result, these become the “triggers of an irresistible and irrational urge to check our device that makes the dopamine go high in our brain,” Dr. Gupta explained.

Although the vicious cycle can be thwarted by turning off the device, Dr. Gupta characterized this as “impractical” when smartphones are so vital to daily communication. Rather, Dr. Gupta advocated a program of moderation, reserving the phone for useful tasks without succumbing to the siren song of apps that waste time.

The most conspicuous culprit is social media, which Dr. Gupta considers to be among the most Pavlovian triggers of cell phone addiction. However, she acknowledged that participation in social media has its justifications.

“I, myself, use social media for my own branding and marketing,” Dr. Gupta said.

The problem that users have is distinguishing between screen time that does and does not have value, according to Dr. Gupta. She indicated that many of those overusing their smart devices are being driven by the dopaminergic reward system, which is generally divorced from the real goals of life, such as personal satisfaction and activity that is rewarding monetarily or in other ways.

“I am not asking for these devices to be thrown out the window. I am advocating for moderation, balance, and real-life engagement,” Dr. Gupta said at the meeting, held in Atlanta and virtually.

She outlined a long list of practical suggestions, including turning off the alarms, chimes, and messages that engage the user into the vicious dopaminergic-reward system loop. She suggested mindfulness so that the user can distinguish between valuable device use and activity that is simply procrastination.

“The devices are designed to be addictive. They are designed to manipulate our brain,” she said. “Eliminate the reward. Let’s try to make our devices boring, unappealing, or enticing so that they only work as tools.”

The medical literature is filled with data that support the potential harms of excessive screen use, leading many others to make some of the same points. In 2017, Thomas N. Robinson, MD, professor of child health at Stanford (Calif.) University, reviewed data showing an association between screen media exposure and obesity in children and adolescents.

“This is an area crying out for more research,” Dr. Robinson said in an interview. The problem of screen time, sedentary behavior, and weight gain has been an issue since the television was invented, which was the point he made in his 2017 paper, but he agreed that the problem is only getting worse.

“Digital technology has become ubiquitous, touching nearly every aspect of people’s lives,” he said. Yet, as evidence grows that overuse of this technology can be harmful, it is creating a problem without a clear solution.

“There are few data about the efficacy of specific strategies to reduce harmful impacts of digital screen use,” he said.

While some of the solutions that Dr. Gupta described make sense, they are more easily described than executed. The dopaminergic reward system is strong and largely experienced subconsciously. Recruiting patients to recognize that dopaminergic rewards are not rewards in any true sense is already a challenge. Enlisting patients to take the difficult steps to avoid the behavioral cues might be even more difficult.

Dr. Gupta and Dr. Robinson report no potential conflicts of interest.

Wireless devices, like smart phones and tablets, appear to induce compulsive or even addictive use in many individuals, leading to adverse health consequences that are likely to be curtailed only through often difficult behavior modification, according to a pediatric endocrinologist’s take on the problem.

While the summary was based in part on the analysis of 234 published papers drawn from the medical literature, the lead author, Nidhi Gupta, MD, said the data reinforce her own clinical experience.

Lisa Nainggolin/MDedge News

“As a pediatric endocrinologist, the trend in smartphone-associated health disorders, such as obesity, sleep, and behavior issues, worries me,” Dr. Gupta, director of KAP Pediatric Endocrinology, Nashville, Tenn., said at the annual meeting of the Endocrine Society.

Based on her search of the medical literature, the available data raise concern. In one study she cited, for example, each hour per day of screen time was found to translate into a body mass index increase of 0.5 to 0.7 kg/m² (P < .001).

With this type of progressive rise in BMI comes prediabetes, dyslipidemia, and other metabolic disorders associated with major health risks, including cardiovascular disease. And there are others. Dr. Gupta cited data suggesting screen time before bed disturbs sleep, which has its own set of health risks.

“When I say health, it includes physical health, mental health, and emotional health,” said Dr. Gupta.

In the U.S. and other countries with a growing obesity epidemic, lack of physical activity and unhealthy eating are widely considered the major culprits. Excessive screen time contributes to both.

“When we are engaged with our devices, we are often snacking subconsciously and not very mindful that we are making unhealthy choices,” Dr. Gupta said.

The problem is that there is a vicious circle. Compulsive use of devices follows the same loop as other types of addictive behaviors, according to Dr. Gupta. She traced overuse of wireless devices to the dopaminergic system, which is a powerful neuroendocrine-mediated process of craving, response, and reward.

Like fat, sugar, and salt, which provoke a neuroendocrine reward signal, the chimes and buzzes of a cell phone provide their own cues for reward in the form of a dopamine surge. As a result, these become the “triggers of an irresistible and irrational urge to check our device that makes the dopamine go high in our brain,” Dr. Gupta explained.

Although the vicious cycle can be thwarted by turning off the device, Dr. Gupta characterized this as “impractical” when smartphones are so vital to daily communication. Rather, Dr. Gupta advocated a program of moderation, reserving the phone for useful tasks without succumbing to the siren song of apps that waste time.

The most conspicuous culprit is social media, which Dr. Gupta considers to be among the most Pavlovian triggers of cell phone addiction. However, she acknowledged that participation in social media has its justifications.

“I, myself, use social media for my own branding and marketing,” Dr. Gupta said.

The problem that users have is distinguishing between screen time that does and does not have value, according to Dr. Gupta. She indicated that many of those overusing their smart devices are being driven by the dopaminergic reward system, which is generally divorced from the real goals of life, such as personal satisfaction and activity that is rewarding monetarily or in other ways.

“I am not asking for these devices to be thrown out the window. I am advocating for moderation, balance, and real-life engagement,” Dr. Gupta said at the meeting, held in Atlanta and virtually.

She outlined a long list of practical suggestions, including turning off the alarms, chimes, and messages that engage the user into the vicious dopaminergic-reward system loop. She suggested mindfulness so that the user can distinguish between valuable device use and activity that is simply procrastination.

“The devices are designed to be addictive. They are designed to manipulate our brain,” she said. “Eliminate the reward. Let’s try to make our devices boring, unappealing, or enticing so that they only work as tools.”

The medical literature is filled with data that support the potential harms of excessive screen use, leading many others to make some of the same points. In 2017, Thomas N. Robinson, MD, professor of child health at Stanford (Calif.) University, reviewed data showing an association between screen media exposure and obesity in children and adolescents.

“This is an area crying out for more research,” Dr. Robinson said in an interview. The problem of screen time, sedentary behavior, and weight gain has been an issue since the television was invented, which was the point he made in his 2017 paper, but he agreed that the problem is only getting worse.

“Digital technology has become ubiquitous, touching nearly every aspect of people’s lives,” he said. Yet, as evidence grows that overuse of this technology can be harmful, it is creating a problem without a clear solution.

“There are few data about the efficacy of specific strategies to reduce harmful impacts of digital screen use,” he said.

While some of the solutions that Dr. Gupta described make sense, they are more easily described than executed. The dopaminergic reward system is strong and largely experienced subconsciously. Recruiting patients to recognize that dopaminergic rewards are not rewards in any true sense is already a challenge. Enlisting patients to take the difficult steps to avoid the behavioral cues might be even more difficult.

Dr. Gupta and Dr. Robinson report no potential conflicts of interest.

People with diabetes who had a poor-quality diet and food insecurity were significantly more likely to have poor glycemic and cholesterol control than were those with a healthier diet and food security, based on data from a national study of more than 2,000 individuals.

The American Diabetes Association recommends a high-quality diet for people with diabetes (PWD) to achieve treatment goals; however, roughly 18% of PWD in the United States are food insecure and/or have a poor-quality diet, Sarah S. Casagrande, PhD, of DLH Corporation, Silver Spring, Md., and colleagues wrote in a poster presented at the annual scientific sessions of the ADA in New Orleans.

To examine the impact of food insecurity and diet quality on diabetes and lipid management, the researchers reviewed data from 2,075 adults with self-reported diabetes who completed the National Health and Nutrition Examination Surveys between 2013 and 2018.

Diet quality was divided into quartiles based on the 2015 Healthy Eating Index. Food insecurity was assessed using a standard 10-item questionnaire including questions about running out of food and not being able to afford more, reducing meal sizes, eating less or not at all, and going hungry because of lack of money for food.

The logistic regression analysis controlled for factors including sociodemographics, health care use, smoking, diabetes medications, blood pressure medication use, cholesterol medication use, and body mass index.

Overall, 17.6% of the participants were food insecure and had a low-quality diet, 14.2% were food insecure with a high-quality diet, 33.1% were food secure with a low-quality diet, and 35.2% were food secure with a high-quality diet.

PWD in the food insecure/low-quality diet group were significantly more likely to be younger, non-Hispanic black or Hispanic, and uninsured compared to those in the food secure/high-quality diet group (P < .001 for all).

When the researchers examined glycemic control, they found that PWD in the food insecurity/low-quality diet groups were significantly more likely than were those with food security/high-quality diets to have hemoglobin A1c of at least 7.0% (adjusted odds ratio, 1.85), A1c of at least 8.0% (aOR, 1.79), low HDL cholesterol (aOR, 1.69), and high triglycerides (aOR, 3.26).

PWD with food insecurity but a high-quality diet also were significantly more likely than were those with food security and a high quality diet to have A1c of at least 7.0% (aOR, 1.69), A1c of at least 8.0% (aOR, 1.83), and high triglycerides (aOR, 2.44). PWD with food security but a low-quality diet were significantly more likely than was the food security/high-quality diet group to have A1c of at least 7% (aOR, 1.55).

The study findings were limited by several factors including the cross-sectional design, reliance on self-reports, and inability to distinguish between type 1 and type 2 diabetes, the researchers wrote.

However, the results were strengthened by the large, nationally representative sample and the inclusion of multiple clinical outcomes in the patient assessment, they said.

The results suggest that food insecurity had a significant impact on both glycemic control and cholesterol management independent of diet quality, the researchers noted. Based on these findings, health care providers treating PWD may wish to assess their patients’ food security status, and “interventions could address disparities in food security,” they concluded.
 

Food insecurity a growing problem

“With more communities being pushed into state of war, drought, and famine globally, it is important to track impact of food insecurity and low quality food on common medical conditions like diabetes in our vulnerable communities,” Romesh K. Khardori, MD, professor of medicine: endocrinology, and metabolism at Eastern Virginia Medical School, Norfolk, said in an interview.

Dr. Khardori, who was not involved in the study, said he was not surprised by the current study findings.

“Type of food, amount of food, and quality of food have been stressed in diabetes management for more than 100 years,” he said. “Organizations charged with recommendations, such as the ADA and American Dietetic Association, have regularly updated their recommendations,” he noted. “It was not surprising, therefore, to find food insecurity and low quality tied to poor glycemic control.”

The take-home message for clinicians is to consider the availability and quality of food that their patients are exposed to when evaluating barriers to proper glycemic control, Dr. Khardori emphasized.

However, additional research is needed to explore whether the prescription of a sufficient amount of good quality food would alleviate the adverse impact seen in the current study, he said.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers and Dr. Khardori had no financial conflicts to disclose.

People with diabetes who had a poor-quality diet and food insecurity were significantly more likely to have poor glycemic and cholesterol control than were those with a healthier diet and food security, based on data from a national study of more than 2,000 individuals.

The American Diabetes Association recommends a high-quality diet for people with diabetes (PWD) to achieve treatment goals; however, roughly 18% of PWD in the United States are food insecure and/or have a poor-quality diet, Sarah S. Casagrande, PhD, of DLH Corporation, Silver Spring, Md., and colleagues wrote in a poster presented at the annual scientific sessions of the ADA in New Orleans.

To examine the impact of food insecurity and diet quality on diabetes and lipid management, the researchers reviewed data from 2,075 adults with self-reported diabetes who completed the National Health and Nutrition Examination Surveys between 2013 and 2018.

Diet quality was divided into quartiles based on the 2015 Healthy Eating Index. Food insecurity was assessed using a standard 10-item questionnaire including questions about running out of food and not being able to afford more, reducing meal sizes, eating less or not at all, and going hungry because of lack of money for food.

The logistic regression analysis controlled for factors including sociodemographics, health care use, smoking, diabetes medications, blood pressure medication use, cholesterol medication use, and body mass index.

Overall, 17.6% of the participants were food insecure and had a low-quality diet, 14.2% were food insecure with a high-quality diet, 33.1% were food secure with a low-quality diet, and 35.2% were food secure with a high-quality diet.

PWD in the food insecure/low-quality diet group were significantly more likely to be younger, non-Hispanic black or Hispanic, and uninsured compared to those in the food secure/high-quality diet group (P < .001 for all).

When the researchers examined glycemic control, they found that PWD in the food insecurity/low-quality diet groups were significantly more likely than were those with food security/high-quality diets to have hemoglobin A1c of at least 7.0% (adjusted odds ratio, 1.85), A1c of at least 8.0% (aOR, 1.79), low HDL cholesterol (aOR, 1.69), and high triglycerides (aOR, 3.26).

PWD with food insecurity but a high-quality diet also were significantly more likely than were those with food security and a high quality diet to have A1c of at least 7.0% (aOR, 1.69), A1c of at least 8.0% (aOR, 1.83), and high triglycerides (aOR, 2.44). PWD with food security but a low-quality diet were significantly more likely than was the food security/high-quality diet group to have A1c of at least 7% (aOR, 1.55).

The study findings were limited by several factors including the cross-sectional design, reliance on self-reports, and inability to distinguish between type 1 and type 2 diabetes, the researchers wrote.

However, the results were strengthened by the large, nationally representative sample and the inclusion of multiple clinical outcomes in the patient assessment, they said.

The results suggest that food insecurity had a significant impact on both glycemic control and cholesterol management independent of diet quality, the researchers noted. Based on these findings, health care providers treating PWD may wish to assess their patients’ food security status, and “interventions could address disparities in food security,” they concluded.
 

Food insecurity a growing problem

“With more communities being pushed into state of war, drought, and famine globally, it is important to track impact of food insecurity and low quality food on common medical conditions like diabetes in our vulnerable communities,” Romesh K. Khardori, MD, professor of medicine: endocrinology, and metabolism at Eastern Virginia Medical School, Norfolk, said in an interview.

Dr. Khardori, who was not involved in the study, said he was not surprised by the current study findings.

“Type of food, amount of food, and quality of food have been stressed in diabetes management for more than 100 years,” he said. “Organizations charged with recommendations, such as the ADA and American Dietetic Association, have regularly updated their recommendations,” he noted. “It was not surprising, therefore, to find food insecurity and low quality tied to poor glycemic control.”

The take-home message for clinicians is to consider the availability and quality of food that their patients are exposed to when evaluating barriers to proper glycemic control, Dr. Khardori emphasized.

However, additional research is needed to explore whether the prescription of a sufficient amount of good quality food would alleviate the adverse impact seen in the current study, he said.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers and Dr. Khardori had no financial conflicts to disclose.

People with diabetes who had a poor-quality diet and food insecurity were significantly more likely to have poor glycemic and cholesterol control than were those with a healthier diet and food security, based on data from a national study of more than 2,000 individuals.

The American Diabetes Association recommends a high-quality diet for people with diabetes (PWD) to achieve treatment goals; however, roughly 18% of PWD in the United States are food insecure and/or have a poor-quality diet, Sarah S. Casagrande, PhD, of DLH Corporation, Silver Spring, Md., and colleagues wrote in a poster presented at the annual scientific sessions of the ADA in New Orleans.

To examine the impact of food insecurity and diet quality on diabetes and lipid management, the researchers reviewed data from 2,075 adults with self-reported diabetes who completed the National Health and Nutrition Examination Surveys between 2013 and 2018.

Diet quality was divided into quartiles based on the 2015 Healthy Eating Index. Food insecurity was assessed using a standard 10-item questionnaire including questions about running out of food and not being able to afford more, reducing meal sizes, eating less or not at all, and going hungry because of lack of money for food.

The logistic regression analysis controlled for factors including sociodemographics, health care use, smoking, diabetes medications, blood pressure medication use, cholesterol medication use, and body mass index.

Overall, 17.6% of the participants were food insecure and had a low-quality diet, 14.2% were food insecure with a high-quality diet, 33.1% were food secure with a low-quality diet, and 35.2% were food secure with a high-quality diet.

PWD in the food insecure/low-quality diet group were significantly more likely to be younger, non-Hispanic black or Hispanic, and uninsured compared to those in the food secure/high-quality diet group (P < .001 for all).

When the researchers examined glycemic control, they found that PWD in the food insecurity/low-quality diet groups were significantly more likely than were those with food security/high-quality diets to have hemoglobin A1c of at least 7.0% (adjusted odds ratio, 1.85), A1c of at least 8.0% (aOR, 1.79), low HDL cholesterol (aOR, 1.69), and high triglycerides (aOR, 3.26).

PWD with food insecurity but a high-quality diet also were significantly more likely than were those with food security and a high quality diet to have A1c of at least 7.0% (aOR, 1.69), A1c of at least 8.0% (aOR, 1.83), and high triglycerides (aOR, 2.44). PWD with food security but a low-quality diet were significantly more likely than was the food security/high-quality diet group to have A1c of at least 7% (aOR, 1.55).

The study findings were limited by several factors including the cross-sectional design, reliance on self-reports, and inability to distinguish between type 1 and type 2 diabetes, the researchers wrote.

However, the results were strengthened by the large, nationally representative sample and the inclusion of multiple clinical outcomes in the patient assessment, they said.

The results suggest that food insecurity had a significant impact on both glycemic control and cholesterol management independent of diet quality, the researchers noted. Based on these findings, health care providers treating PWD may wish to assess their patients’ food security status, and “interventions could address disparities in food security,” they concluded.
 

Food insecurity a growing problem

“With more communities being pushed into state of war, drought, and famine globally, it is important to track impact of food insecurity and low quality food on common medical conditions like diabetes in our vulnerable communities,” Romesh K. Khardori, MD, professor of medicine: endocrinology, and metabolism at Eastern Virginia Medical School, Norfolk, said in an interview.

Dr. Khardori, who was not involved in the study, said he was not surprised by the current study findings.

“Type of food, amount of food, and quality of food have been stressed in diabetes management for more than 100 years,” he said. “Organizations charged with recommendations, such as the ADA and American Dietetic Association, have regularly updated their recommendations,” he noted. “It was not surprising, therefore, to find food insecurity and low quality tied to poor glycemic control.”

The take-home message for clinicians is to consider the availability and quality of food that their patients are exposed to when evaluating barriers to proper glycemic control, Dr. Khardori emphasized.

However, additional research is needed to explore whether the prescription of a sufficient amount of good quality food would alleviate the adverse impact seen in the current study, he said.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers and Dr. Khardori had no financial conflicts to disclose.

The American College of Cardiology and the American Heart Association have jointly issued a comprehensive set of data standards to help clarify definitions of the cardiovascular (CV) and non-CV complications of COVID-19.

It’s the work of the ACC/AHA Task Force on Clinical Data Standards and has been endorsed by the Heart Failure Society of America and Society for Cardiac Angiography and Interventions.

There is increased importance to understanding the acute and long-term impact of COVID-19 on CV health, the writing group notes. Until now, however, there has not been “clarity or consensus” on definitions of CV conditions related to COVID-19, with different diagnostic terminologies being used for overlapping conditions, such as “myocardial injury,” “myocarditis,” “type Il myocardial infarction,” “stress cardiomyopathy,” and “inflammatory cardiomyopathy,” they point out.

Floaria Bicher/iStock/Getty Images Plus

“We, as a research community, did some things right and some things wrong surrounding the COVID pandemic,” Sandeep Das, MD, MPH, vice chair of the writing group, noted in an interview with this news organization.

“The things that we really did right is that everybody responded with enthusiasm, kind of all hands on deck with a massive crisis response, and that was fantastic,” Dr. Das said.

“However, because of the need to hurry, we didn’t structure and organize in the way that we typically would for something that was sort of a slow burn kind of problem rather than an emergency. One of the consequences of that was fragmentation of how things are collected, reported, et cetera, and that leads to confusion,” he added.

The report was published simultaneously June 23 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.
 

A necessary but not glamorous project

The new data standards for COVID-19 will help standardize definitions and set the framework to capture and better understand how COVID-19 affects CV health.

“It wasn’t exactly a glamorous-type project but, at the same time, it’s super necessary to kind of get everybody on the same page and working together,” Dr. Das said. 

Broad agreement on common vocabulary and definitions will help with efforts to pool or compare data from electronic health records, clinical registries, administrative datasets, and other databases, and determine whether these data apply to clinical practice and research endeavors, the writing group says.

They considered data elements relevant to the full range of care provided to COVID-19 patients in all care settings. Among the key items included in the document are:

• Case definitions for confirmed, probable, and suspected acute COVID-19, as well as postacute sequelae of COVID-19.
• Definitions for acute CV complications related to COVID-19, including acute myocardial injury, heart failure, shock, arrhythmia, thromboembolic complications, and .
• Data elements related to COVID-19 vaccination status, comorbidities, and preexisting CV conditions.
• Definitions for postacute CV sequelae of SARS-CoV-2 infection and long-term CV complications of COVID-19.
• Data elements for CV mortality during acute COVID-19.
• Data elements for non-CV complications to help document severity of illness and other competing diagnoses and complications that might affect CV outcomes.
• A list of symptoms and signs related to COVID-19 and CV complications.
• Data elements for diagnostic and therapeutic strategies for COVID-19 and CV conditions.
• A discussion of advanced therapies, including , extracorporeal membrane oxygenation, and end-of-life management strategies.

These data standards will be useful for researchers, registry developers, and clinicians, and they are proposed as a framework for ICD-10 code development of COVID-19–related CV conditions, the writing group says.

The standards are also of “great importance” to patients, clinicians, investigators, scientists, administrators, public health officials, policymakers, and payers, the group says.

Dr. Das said that, although there is no formal plan in place to update the document, he could see sections that might be refined.

“For example, there’s a nice long list of all the various variants, and unfortunately, I suspect that that is going to change and evolve over time,” Dr. Das told this news organization.

“We tried very hard not to include things like specifying specific treatments so we didn’t get proscriptive. We wanted to make it descriptive, so hopefully it will stand the test of time pretty well,” he added.

This research had no commercial funding. The writing group has no relevant disclosures.

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

The American College of Cardiology and the American Heart Association have jointly issued a comprehensive set of data standards to help clarify definitions of the cardiovascular (CV) and non-CV complications of COVID-19.

It’s the work of the ACC/AHA Task Force on Clinical Data Standards and has been endorsed by the Heart Failure Society of America and Society for Cardiac Angiography and Interventions.

There is increased importance to understanding the acute and long-term impact of COVID-19 on CV health, the writing group notes. Until now, however, there has not been “clarity or consensus” on definitions of CV conditions related to COVID-19, with different diagnostic terminologies being used for overlapping conditions, such as “myocardial injury,” “myocarditis,” “type Il myocardial infarction,” “stress cardiomyopathy,” and “inflammatory cardiomyopathy,” they point out.

Floaria Bicher/iStock/Getty Images Plus

“We, as a research community, did some things right and some things wrong surrounding the COVID pandemic,” Sandeep Das, MD, MPH, vice chair of the writing group, noted in an interview with this news organization.

“The things that we really did right is that everybody responded with enthusiasm, kind of all hands on deck with a massive crisis response, and that was fantastic,” Dr. Das said.

“However, because of the need to hurry, we didn’t structure and organize in the way that we typically would for something that was sort of a slow burn kind of problem rather than an emergency. One of the consequences of that was fragmentation of how things are collected, reported, et cetera, and that leads to confusion,” he added.

The report was published simultaneously June 23 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.
 

A necessary but not glamorous project

The new data standards for COVID-19 will help standardize definitions and set the framework to capture and better understand how COVID-19 affects CV health.

“It wasn’t exactly a glamorous-type project but, at the same time, it’s super necessary to kind of get everybody on the same page and working together,” Dr. Das said. 

Broad agreement on common vocabulary and definitions will help with efforts to pool or compare data from electronic health records, clinical registries, administrative datasets, and other databases, and determine whether these data apply to clinical practice and research endeavors, the writing group says.

They considered data elements relevant to the full range of care provided to COVID-19 patients in all care settings. Among the key items included in the document are:

• Case definitions for confirmed, probable, and suspected acute COVID-19, as well as postacute sequelae of COVID-19.
• Definitions for acute CV complications related to COVID-19, including acute myocardial injury, heart failure, shock, arrhythmia, thromboembolic complications, and .
• Data elements related to COVID-19 vaccination status, comorbidities, and preexisting CV conditions.
• Definitions for postacute CV sequelae of SARS-CoV-2 infection and long-term CV complications of COVID-19.
• Data elements for CV mortality during acute COVID-19.
• Data elements for non-CV complications to help document severity of illness and other competing diagnoses and complications that might affect CV outcomes.
• A list of symptoms and signs related to COVID-19 and CV complications.
• Data elements for diagnostic and therapeutic strategies for COVID-19 and CV conditions.
• A discussion of advanced therapies, including , extracorporeal membrane oxygenation, and end-of-life management strategies.

These data standards will be useful for researchers, registry developers, and clinicians, and they are proposed as a framework for ICD-10 code development of COVID-19–related CV conditions, the writing group says.

The standards are also of “great importance” to patients, clinicians, investigators, scientists, administrators, public health officials, policymakers, and payers, the group says.

Dr. Das said that, although there is no formal plan in place to update the document, he could see sections that might be refined.

“For example, there’s a nice long list of all the various variants, and unfortunately, I suspect that that is going to change and evolve over time,” Dr. Das told this news organization.

“We tried very hard not to include things like specifying specific treatments so we didn’t get proscriptive. We wanted to make it descriptive, so hopefully it will stand the test of time pretty well,” he added.

This research had no commercial funding. The writing group has no relevant disclosures.

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

The American College of Cardiology and the American Heart Association have jointly issued a comprehensive set of data standards to help clarify definitions of the cardiovascular (CV) and non-CV complications of COVID-19.

It’s the work of the ACC/AHA Task Force on Clinical Data Standards and has been endorsed by the Heart Failure Society of America and Society for Cardiac Angiography and Interventions.

There is increased importance to understanding the acute and long-term impact of COVID-19 on CV health, the writing group notes. Until now, however, there has not been “clarity or consensus” on definitions of CV conditions related to COVID-19, with different diagnostic terminologies being used for overlapping conditions, such as “myocardial injury,” “myocarditis,” “type Il myocardial infarction,” “stress cardiomyopathy,” and “inflammatory cardiomyopathy,” they point out.

Floaria Bicher/iStock/Getty Images Plus

“We, as a research community, did some things right and some things wrong surrounding the COVID pandemic,” Sandeep Das, MD, MPH, vice chair of the writing group, noted in an interview with this news organization.

“The things that we really did right is that everybody responded with enthusiasm, kind of all hands on deck with a massive crisis response, and that was fantastic,” Dr. Das said.

“However, because of the need to hurry, we didn’t structure and organize in the way that we typically would for something that was sort of a slow burn kind of problem rather than an emergency. One of the consequences of that was fragmentation of how things are collected, reported, et cetera, and that leads to confusion,” he added.

The report was published simultaneously June 23 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.
 

A necessary but not glamorous project

The new data standards for COVID-19 will help standardize definitions and set the framework to capture and better understand how COVID-19 affects CV health.

“It wasn’t exactly a glamorous-type project but, at the same time, it’s super necessary to kind of get everybody on the same page and working together,” Dr. Das said. 

Broad agreement on common vocabulary and definitions will help with efforts to pool or compare data from electronic health records, clinical registries, administrative datasets, and other databases, and determine whether these data apply to clinical practice and research endeavors, the writing group says.

They considered data elements relevant to the full range of care provided to COVID-19 patients in all care settings. Among the key items included in the document are:

• Case definitions for confirmed, probable, and suspected acute COVID-19, as well as postacute sequelae of COVID-19.
• Definitions for acute CV complications related to COVID-19, including acute myocardial injury, heart failure, shock, arrhythmia, thromboembolic complications, and .
• Data elements related to COVID-19 vaccination status, comorbidities, and preexisting CV conditions.
• Definitions for postacute CV sequelae of SARS-CoV-2 infection and long-term CV complications of COVID-19.
• Data elements for CV mortality during acute COVID-19.
• Data elements for non-CV complications to help document severity of illness and other competing diagnoses and complications that might affect CV outcomes.
• A list of symptoms and signs related to COVID-19 and CV complications.
• Data elements for diagnostic and therapeutic strategies for COVID-19 and CV conditions.
• A discussion of advanced therapies, including , extracorporeal membrane oxygenation, and end-of-life management strategies.

These data standards will be useful for researchers, registry developers, and clinicians, and they are proposed as a framework for ICD-10 code development of COVID-19–related CV conditions, the writing group says.

The standards are also of “great importance” to patients, clinicians, investigators, scientists, administrators, public health officials, policymakers, and payers, the group says.

Dr. Das said that, although there is no formal plan in place to update the document, he could see sections that might be refined.

“For example, there’s a nice long list of all the various variants, and unfortunately, I suspect that that is going to change and evolve over time,” Dr. Das told this news organization.

“We tried very hard not to include things like specifying specific treatments so we didn’t get proscriptive. We wanted to make it descriptive, so hopefully it will stand the test of time pretty well,” he added.

This research had no commercial funding. The writing group has no relevant disclosures.

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

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

U.S. maternal deaths – those during pregnancy or within 42 days of pregnancy – increased substantially by 33.3% after March 2020 corresponding to the COVID-19 pandemic onset, according to new research published in JAMA Network Open.

Data from the National Center for Health Statistics (NCHS) revealed this rise in maternal deaths was higher than the 22% overall excess death estimate associated with the pandemic in 2020.

Increases were highest for Hispanic and non-Hispanic Black women, exacerbating already high rates of disparity in comparison with White women, wrote Marie E. Thoma, PhD, an associate professor at the University of Maryland, College Park, and Eugene R. Declercq, PhD, a professor at Boston University.

The authors noted that this spike in maternal deaths might be caused either by conditions directly related to COVID-19, such as respiratory or viral infections, or by conditions worsened by pandemic-associated health care disruptions including those for diabetes or cardiovascular disease.

The precise causes, however, could not be discerned from the data, the authors noted.

The NCHS reported an 18.4% increase in U.S. maternal mortality from 2019 to 2020. The relative increase was 44.4% among Hispanic, 25.7% among non-Hispanic Black, and 6.1% among non-Hispanic White women.

“The rise in maternal mortality among Hispanic women was unprecedented,” Dr. Thoma said in an interview. Given a 16.8% increase in overall U.S. mortality in 2020, largely attributed to the COVID-19 pandemic, the authors examined the pandemic’s role in [the higher] maternal death rates for 2020.

“Prior to this report, the NCHS released an e-report that there had been a rise in maternal mortality in 2020, but questions remained about the role of the pandemic in this rise that their report hadn’t addressed,” Dr. Thoma said in an interview “So we decided to look at the data further to assess whether the rise coincided with the pandemic and how this differed by race/ethnicity, whether there were changes in the causes of maternal death, and how often COVID-19 was listed as a contributory factor in those deaths.”

A total of 1,588 maternal deaths (18.8 per 100,000 live births) occurred before the pandemic versus 684 deaths (25.1 per 100,000 live births) during the 2020 phase of the pandemic, for a relative increase of 33.3%.

Direct obstetrical causes of death included diabetes, hypertensive and liver disorders, pregnancy-related infections, and obstetrical hemorrhage and embolism. Indirect causes comprised, among others, nonobstetrical infections and diseases of the circulatory and respiratory systems as well as mental and nervous disorders.

Relative increases in direct causes (27.7%) were mostly associated with diabetes (95.9%), hypertensive disorders (39.0%), and other specified pregnancy-related conditions (48.0%).

COVID-19 was commonly listed as a lethal condition along with other viral diseases (16 of 16 deaths and diseases of the respiratory system (11 of 19 deaths).

Late maternal mortality – defined as more than 42 days but less than 1 year after pregnancy – increased by 41%. “This was surprising as we might anticipate risk being higher during pregnancy given that pregnant women may be more susceptible, but we see that this rise was also found among people in the later postpartum period,” Dr. Thoma said.

Absolute and relative changes were highest for Hispanic women (8.9 per 100,000 live births and 74.2%, respectively) and non-Hispanic Black women (16.8 per 100,000 live births and 40.2%). In contrast, non-Hispanic White women saw increases of just 2.9 per 100,000 live births and 17.2%.

“Overall, we found the rise in maternal mortality in 2020 was concentrated after the start of pandemic, particularly for non-Hispanic Black and Hispanic women, and we saw a dramatic rise in respiratory-related conditions,” Dr. Thoma said.

In a comment, Steven Woolf, MD, MPH, director emeritus of the Center on Society and Health at Virginia Commonwealth University, Richmond, said the findings are very consistent with his and others research showing dramatic increases in overall death rates from many causes during the pandemic, with these ranging from COVID-19 leading conditions such as diabetes, cardiovascular and Alzheimer’s disease to less-studied causes such as drug overdoses and alcoholism caused by the stresses of the pandemic. Again, deaths were likely caused by both COVID-19 infections and disruptions in diagnosis and care.

“So a rise in maternal mortality would unfortunately also be expected, and these researchers have shown that,” he said in an interview. In addition, they have confirmed “the pattern of stark health disparities in the Hispanic and Black populations relative to the White. Our group has shown marked decreases in the life expectancies of the Black and Hispanic populations relative to the White population.”

While he might take issue with the study’s research methodology, Dr. Woolf said, “The work is useful partly because we need to work out the best research methods to do this kind of analysis because we really need to understand the effects on maternal mortality.”

He said sorting out the best way to do this type of research will be important for looking at excess deaths and maternal mortality following other events, for example, in the wake of the Supreme Court’s recent decision to reverse Roe v. Wade.

The authors acknowledged certain study limitations, including the large percentage of COVID-19 cases with a nonspecific underlying cause. According to Dr. Thoma and Dr. Declercq, that reflects a maternal death coding problem that needs to be addressed, as well as a partitioning of data. The latter resulted in small numbers for some categories, with rates suppressed for fewer than 16 deaths because of reduced reliability.

“We found that more specific information is often available on death certificates but is lost in the process of coding,” said Dr. Thoma. “We were able to reclassify many of these causes to a more specific cause that we attributed to be the primary cause of death.”

The authors said future studies of maternal death should examine the contribution of the pandemic to racial and ethnic disparities and should identify specific causes of maternal deaths overall and associated with COVID-19.

In earlier research, the authors previously warned of possible misclassifications of maternal deaths.

They found evidence of both underreporting and overreporting of deaths, with possible overreporting predominant, whereas accurate data are essential for measuring the effectiveness of maternal mortality reduction programs.

Dr. Thoma’s group will continue to monitor mortality trends with the release of 2021 data. “We hope we will see improvements in 2021 given greater access to vaccines, treatments, and fewer health care disruptions,” Dr. Thoma said. “It will be important to continue to stress the importance of COVID-19 vaccines for pregnant and postpartum people.”

This study had no external funding. The authors disclosed no competing interests. Dr. Woolf declared no conflicts of interest.

U.S. maternal deaths – those during pregnancy or within 42 days of pregnancy – increased substantially by 33.3% after March 2020 corresponding to the COVID-19 pandemic onset, according to new research published in JAMA Network Open.

Data from the National Center for Health Statistics (NCHS) revealed this rise in maternal deaths was higher than the 22% overall excess death estimate associated with the pandemic in 2020.

Increases were highest for Hispanic and non-Hispanic Black women, exacerbating already high rates of disparity in comparison with White women, wrote Marie E. Thoma, PhD, an associate professor at the University of Maryland, College Park, and Eugene R. Declercq, PhD, a professor at Boston University.

The authors noted that this spike in maternal deaths might be caused either by conditions directly related to COVID-19, such as respiratory or viral infections, or by conditions worsened by pandemic-associated health care disruptions including those for diabetes or cardiovascular disease.

The precise causes, however, could not be discerned from the data, the authors noted.

The NCHS reported an 18.4% increase in U.S. maternal mortality from 2019 to 2020. The relative increase was 44.4% among Hispanic, 25.7% among non-Hispanic Black, and 6.1% among non-Hispanic White women.

“The rise in maternal mortality among Hispanic women was unprecedented,” Dr. Thoma said in an interview. Given a 16.8% increase in overall U.S. mortality in 2020, largely attributed to the COVID-19 pandemic, the authors examined the pandemic’s role in [the higher] maternal death rates for 2020.

“Prior to this report, the NCHS released an e-report that there had been a rise in maternal mortality in 2020, but questions remained about the role of the pandemic in this rise that their report hadn’t addressed,” Dr. Thoma said in an interview “So we decided to look at the data further to assess whether the rise coincided with the pandemic and how this differed by race/ethnicity, whether there were changes in the causes of maternal death, and how often COVID-19 was listed as a contributory factor in those deaths.”

A total of 1,588 maternal deaths (18.8 per 100,000 live births) occurred before the pandemic versus 684 deaths (25.1 per 100,000 live births) during the 2020 phase of the pandemic, for a relative increase of 33.3%.

Direct obstetrical causes of death included diabetes, hypertensive and liver disorders, pregnancy-related infections, and obstetrical hemorrhage and embolism. Indirect causes comprised, among others, nonobstetrical infections and diseases of the circulatory and respiratory systems as well as mental and nervous disorders.

Relative increases in direct causes (27.7%) were mostly associated with diabetes (95.9%), hypertensive disorders (39.0%), and other specified pregnancy-related conditions (48.0%).

COVID-19 was commonly listed as a lethal condition along with other viral diseases (16 of 16 deaths and diseases of the respiratory system (11 of 19 deaths).

Late maternal mortality – defined as more than 42 days but less than 1 year after pregnancy – increased by 41%. “This was surprising as we might anticipate risk being higher during pregnancy given that pregnant women may be more susceptible, but we see that this rise was also found among people in the later postpartum period,” Dr. Thoma said.

Absolute and relative changes were highest for Hispanic women (8.9 per 100,000 live births and 74.2%, respectively) and non-Hispanic Black women (16.8 per 100,000 live births and 40.2%). In contrast, non-Hispanic White women saw increases of just 2.9 per 100,000 live births and 17.2%.

“Overall, we found the rise in maternal mortality in 2020 was concentrated after the start of pandemic, particularly for non-Hispanic Black and Hispanic women, and we saw a dramatic rise in respiratory-related conditions,” Dr. Thoma said.

In a comment, Steven Woolf, MD, MPH, director emeritus of the Center on Society and Health at Virginia Commonwealth University, Richmond, said the findings are very consistent with his and others research showing dramatic increases in overall death rates from many causes during the pandemic, with these ranging from COVID-19 leading conditions such as diabetes, cardiovascular and Alzheimer’s disease to less-studied causes such as drug overdoses and alcoholism caused by the stresses of the pandemic. Again, deaths were likely caused by both COVID-19 infections and disruptions in diagnosis and care.

“So a rise in maternal mortality would unfortunately also be expected, and these researchers have shown that,” he said in an interview. In addition, they have confirmed “the pattern of stark health disparities in the Hispanic and Black populations relative to the White. Our group has shown marked decreases in the life expectancies of the Black and Hispanic populations relative to the White population.”

While he might take issue with the study’s research methodology, Dr. Woolf said, “The work is useful partly because we need to work out the best research methods to do this kind of analysis because we really need to understand the effects on maternal mortality.”

He said sorting out the best way to do this type of research will be important for looking at excess deaths and maternal mortality following other events, for example, in the wake of the Supreme Court’s recent decision to reverse Roe v. Wade.

The authors acknowledged certain study limitations, including the large percentage of COVID-19 cases with a nonspecific underlying cause. According to Dr. Thoma and Dr. Declercq, that reflects a maternal death coding problem that needs to be addressed, as well as a partitioning of data. The latter resulted in small numbers for some categories, with rates suppressed for fewer than 16 deaths because of reduced reliability.

“We found that more specific information is often available on death certificates but is lost in the process of coding,” said Dr. Thoma. “We were able to reclassify many of these causes to a more specific cause that we attributed to be the primary cause of death.”

The authors said future studies of maternal death should examine the contribution of the pandemic to racial and ethnic disparities and should identify specific causes of maternal deaths overall and associated with COVID-19.

In earlier research, the authors previously warned of possible misclassifications of maternal deaths.

They found evidence of both underreporting and overreporting of deaths, with possible overreporting predominant, whereas accurate data are essential for measuring the effectiveness of maternal mortality reduction programs.

Dr. Thoma’s group will continue to monitor mortality trends with the release of 2021 data. “We hope we will see improvements in 2021 given greater access to vaccines, treatments, and fewer health care disruptions,” Dr. Thoma said. “It will be important to continue to stress the importance of COVID-19 vaccines for pregnant and postpartum people.”

This study had no external funding. The authors disclosed no competing interests. Dr. Woolf declared no conflicts of interest.

U.S. maternal deaths – those during pregnancy or within 42 days of pregnancy – increased substantially by 33.3% after March 2020 corresponding to the COVID-19 pandemic onset, according to new research published in JAMA Network Open.

Data from the National Center for Health Statistics (NCHS) revealed this rise in maternal deaths was higher than the 22% overall excess death estimate associated with the pandemic in 2020.

Increases were highest for Hispanic and non-Hispanic Black women, exacerbating already high rates of disparity in comparison with White women, wrote Marie E. Thoma, PhD, an associate professor at the University of Maryland, College Park, and Eugene R. Declercq, PhD, a professor at Boston University.

The authors noted that this spike in maternal deaths might be caused either by conditions directly related to COVID-19, such as respiratory or viral infections, or by conditions worsened by pandemic-associated health care disruptions including those for diabetes or cardiovascular disease.

The precise causes, however, could not be discerned from the data, the authors noted.

The NCHS reported an 18.4% increase in U.S. maternal mortality from 2019 to 2020. The relative increase was 44.4% among Hispanic, 25.7% among non-Hispanic Black, and 6.1% among non-Hispanic White women.

“The rise in maternal mortality among Hispanic women was unprecedented,” Dr. Thoma said in an interview. Given a 16.8% increase in overall U.S. mortality in 2020, largely attributed to the COVID-19 pandemic, the authors examined the pandemic’s role in [the higher] maternal death rates for 2020.

“Prior to this report, the NCHS released an e-report that there had been a rise in maternal mortality in 2020, but questions remained about the role of the pandemic in this rise that their report hadn’t addressed,” Dr. Thoma said in an interview “So we decided to look at the data further to assess whether the rise coincided with the pandemic and how this differed by race/ethnicity, whether there were changes in the causes of maternal death, and how often COVID-19 was listed as a contributory factor in those deaths.”

A total of 1,588 maternal deaths (18.8 per 100,000 live births) occurred before the pandemic versus 684 deaths (25.1 per 100,000 live births) during the 2020 phase of the pandemic, for a relative increase of 33.3%.

Direct obstetrical causes of death included diabetes, hypertensive and liver disorders, pregnancy-related infections, and obstetrical hemorrhage and embolism. Indirect causes comprised, among others, nonobstetrical infections and diseases of the circulatory and respiratory systems as well as mental and nervous disorders.

Relative increases in direct causes (27.7%) were mostly associated with diabetes (95.9%), hypertensive disorders (39.0%), and other specified pregnancy-related conditions (48.0%).

COVID-19 was commonly listed as a lethal condition along with other viral diseases (16 of 16 deaths and diseases of the respiratory system (11 of 19 deaths).

Late maternal mortality – defined as more than 42 days but less than 1 year after pregnancy – increased by 41%. “This was surprising as we might anticipate risk being higher during pregnancy given that pregnant women may be more susceptible, but we see that this rise was also found among people in the later postpartum period,” Dr. Thoma said.

Absolute and relative changes were highest for Hispanic women (8.9 per 100,000 live births and 74.2%, respectively) and non-Hispanic Black women (16.8 per 100,000 live births and 40.2%). In contrast, non-Hispanic White women saw increases of just 2.9 per 100,000 live births and 17.2%.

“Overall, we found the rise in maternal mortality in 2020 was concentrated after the start of pandemic, particularly for non-Hispanic Black and Hispanic women, and we saw a dramatic rise in respiratory-related conditions,” Dr. Thoma said.

In a comment, Steven Woolf, MD, MPH, director emeritus of the Center on Society and Health at Virginia Commonwealth University, Richmond, said the findings are very consistent with his and others research showing dramatic increases in overall death rates from many causes during the pandemic, with these ranging from COVID-19 leading conditions such as diabetes, cardiovascular and Alzheimer’s disease to less-studied causes such as drug overdoses and alcoholism caused by the stresses of the pandemic. Again, deaths were likely caused by both COVID-19 infections and disruptions in diagnosis and care.

“So a rise in maternal mortality would unfortunately also be expected, and these researchers have shown that,” he said in an interview. In addition, they have confirmed “the pattern of stark health disparities in the Hispanic and Black populations relative to the White. Our group has shown marked decreases in the life expectancies of the Black and Hispanic populations relative to the White population.”

While he might take issue with the study’s research methodology, Dr. Woolf said, “The work is useful partly because we need to work out the best research methods to do this kind of analysis because we really need to understand the effects on maternal mortality.”

He said sorting out the best way to do this type of research will be important for looking at excess deaths and maternal mortality following other events, for example, in the wake of the Supreme Court’s recent decision to reverse Roe v. Wade.

The authors acknowledged certain study limitations, including the large percentage of COVID-19 cases with a nonspecific underlying cause. According to Dr. Thoma and Dr. Declercq, that reflects a maternal death coding problem that needs to be addressed, as well as a partitioning of data. The latter resulted in small numbers for some categories, with rates suppressed for fewer than 16 deaths because of reduced reliability.

“We found that more specific information is often available on death certificates but is lost in the process of coding,” said Dr. Thoma. “We were able to reclassify many of these causes to a more specific cause that we attributed to be the primary cause of death.”

The authors said future studies of maternal death should examine the contribution of the pandemic to racial and ethnic disparities and should identify specific causes of maternal deaths overall and associated with COVID-19.

In earlier research, the authors previously warned of possible misclassifications of maternal deaths.

They found evidence of both underreporting and overreporting of deaths, with possible overreporting predominant, whereas accurate data are essential for measuring the effectiveness of maternal mortality reduction programs.

Dr. Thoma’s group will continue to monitor mortality trends with the release of 2021 data. “We hope we will see improvements in 2021 given greater access to vaccines, treatments, and fewer health care disruptions,” Dr. Thoma said. “It will be important to continue to stress the importance of COVID-19 vaccines for pregnant and postpartum people.”

This study had no external funding. The authors disclosed no competing interests. Dr. Woolf declared no conflicts of interest.

Acupuncture deep needling provides significant, long-term relief from chronic tension type headache (TTH), new research suggests. Result of a randomized trial showed that though the majority of participants reported some relief from TTH after 8 weeks of acupuncture treatment, those who received needling at a depth of 12.5-20.0 mm reported the greatest reduction in headache frequency and severity.

At this depth, acupuncture promotes deqi sensation, a feeling of numbness, soreness, heaviness, or irritating pain in the needling site that is considered key to successful acupuncture treatment in traditional Chinese acupuncture theory.

“Our study showed that deqi sensation could enhance the effect of acupuncture in the treatment of chronic TTH, and the effect of acupuncture lasted at least 6 months when the treatment was stopped,” said co-investigator Ying Li, MD, PhD, The Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, China.

The findings were published online in Neurology.
 

Deqi sensation key

TTH is the most common type of headache, with a lifetime prevalence of up to 78% in some studies. The pain is often described as throbbing or a vice-like tightness on both sides of the head. TTH is considered chronic when it occurs at least 15 days a month.

Previous studies have suggested that acupuncture can offer relief from headache pain, but specific information on TTH, especially chronic TTH, has been lacking.

To address the issue, researchers designed a parallel-design, patient-and-assessor blinded randomized controlled trial with 218 individuals with a history of chronic TTH. All were untreated with prophylactic treatment in the previous 3 months.

The treatment group (n = 110) received 20 sessions of true acupuncture (TA) over 8 weeks. This included three sessions per week in the first 4 weeks and two sessions per week in the last 4 weeks. The depth of needling at each point ranged from 12.5 to 20 mm, which is needed to achieve deqi sensation.

The control group (n = 108) received superficial acupuncture (SA) on the same schedule as the TA group and at traditional acupuncture points. However, this was done at a maximum depth of 2 mm, which is not deep enough for deqi sensation.

At week 16, 68.2% of the participants receiving TA reported a greater than 50% reduction in monthly headache days, compared with 48.1% of those receiving SA (odds ratio, 2.65; P < .001).

Mean monthly headache days decreased from 20.38 days at baseline to 7.48 days at week 32 in the TA group versus 22.6 days at baseline to 11.94 days in the SA group.

Headache intensity and severity decreased in both groups, although those who achieved deqi sensation reported the most improvement.

Only four patients reported adverse effects, all of which were mild and none requiring treatment.

Patients in both groups reported some pain relief, suggesting that those who are not comfortable with deqi sensation may still benefit from superficial acupuncture, although to a lesser extent, Dr. Li said.

“We assume that the point-specific effect and placebo effect were combined to give the patients relief of headaches,” Dr. Li added. “Further, the effect of deqi sensation added more treatment effect. This might be explained by gate-control theory or other unknown mechanisms.”
 

Deeper understanding?

Commenting on the research, Jennifer Bickel, MD, a senior member of neurology at Moffit Cancer Center and professor of oncologic sciences at University of South Florida, Tampa, said that the study provides a deeper understanding of acupuncture’s efficacy for chronic TTH, which could aid clinicians who are unfamiliar with the therapy or when and how to refer treatment.

“This study provides a more descriptive outline for what type of acupuncture treatment and duration can be effective for patients so doctors can prep patients on what to expect and so doctors can better assess if patients received appropriate acupuncture for their headaches,” said Dr. Bickel, who was not involved with the research.

However, she noted that the acupuncture sites and techniques did not vary during the trial. Although that makes sense for a controlled study, it may not reflect real-world clinical practice, she added.

“The downside is that the study didn’t fully reflect that most acupuncturists in clinical practice would alter treatments during the 20 sessions based on the patient’s response and accompanying symptoms or comorbidities,” Dr. Bickel said.

The study also lacked information on medication overuse headache or patients’ prior history of TTH treatments.

“This could be helpful to understand which patients in clinical practice are most likely to benefit from treatment,” Dr. Bickel said.

Study authors received funding from the Department of Science and Technology of Sichuan Province and the National Natural Science Foundation of China. Dr. Li, Dr. Bickel, and Dr. Vickers report no relevant financial relationships.

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

Acupuncture deep needling provides significant, long-term relief from chronic tension type headache (TTH), new research suggests. Result of a randomized trial showed that though the majority of participants reported some relief from TTH after 8 weeks of acupuncture treatment, those who received needling at a depth of 12.5-20.0 mm reported the greatest reduction in headache frequency and severity.

At this depth, acupuncture promotes deqi sensation, a feeling of numbness, soreness, heaviness, or irritating pain in the needling site that is considered key to successful acupuncture treatment in traditional Chinese acupuncture theory.

“Our study showed that deqi sensation could enhance the effect of acupuncture in the treatment of chronic TTH, and the effect of acupuncture lasted at least 6 months when the treatment was stopped,” said co-investigator Ying Li, MD, PhD, The Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, China.

The findings were published online in Neurology.
 

Deqi sensation key

TTH is the most common type of headache, with a lifetime prevalence of up to 78% in some studies. The pain is often described as throbbing or a vice-like tightness on both sides of the head. TTH is considered chronic when it occurs at least 15 days a month.

Previous studies have suggested that acupuncture can offer relief from headache pain, but specific information on TTH, especially chronic TTH, has been lacking.

To address the issue, researchers designed a parallel-design, patient-and-assessor blinded randomized controlled trial with 218 individuals with a history of chronic TTH. All were untreated with prophylactic treatment in the previous 3 months.

The treatment group (n = 110) received 20 sessions of true acupuncture (TA) over 8 weeks. This included three sessions per week in the first 4 weeks and two sessions per week in the last 4 weeks. The depth of needling at each point ranged from 12.5 to 20 mm, which is needed to achieve deqi sensation.

The control group (n = 108) received superficial acupuncture (SA) on the same schedule as the TA group and at traditional acupuncture points. However, this was done at a maximum depth of 2 mm, which is not deep enough for deqi sensation.

At week 16, 68.2% of the participants receiving TA reported a greater than 50% reduction in monthly headache days, compared with 48.1% of those receiving SA (odds ratio, 2.65; P < .001).

Mean monthly headache days decreased from 20.38 days at baseline to 7.48 days at week 32 in the TA group versus 22.6 days at baseline to 11.94 days in the SA group.

Headache intensity and severity decreased in both groups, although those who achieved deqi sensation reported the most improvement.

Only four patients reported adverse effects, all of which were mild and none requiring treatment.

Patients in both groups reported some pain relief, suggesting that those who are not comfortable with deqi sensation may still benefit from superficial acupuncture, although to a lesser extent, Dr. Li said.

“We assume that the point-specific effect and placebo effect were combined to give the patients relief of headaches,” Dr. Li added. “Further, the effect of deqi sensation added more treatment effect. This might be explained by gate-control theory or other unknown mechanisms.”
 

Deeper understanding?

Commenting on the research, Jennifer Bickel, MD, a senior member of neurology at Moffit Cancer Center and professor of oncologic sciences at University of South Florida, Tampa, said that the study provides a deeper understanding of acupuncture’s efficacy for chronic TTH, which could aid clinicians who are unfamiliar with the therapy or when and how to refer treatment.

“This study provides a more descriptive outline for what type of acupuncture treatment and duration can be effective for patients so doctors can prep patients on what to expect and so doctors can better assess if patients received appropriate acupuncture for their headaches,” said Dr. Bickel, who was not involved with the research.

However, she noted that the acupuncture sites and techniques did not vary during the trial. Although that makes sense for a controlled study, it may not reflect real-world clinical practice, she added.

“The downside is that the study didn’t fully reflect that most acupuncturists in clinical practice would alter treatments during the 20 sessions based on the patient’s response and accompanying symptoms or comorbidities,” Dr. Bickel said.

The study also lacked information on medication overuse headache or patients’ prior history of TTH treatments.

“This could be helpful to understand which patients in clinical practice are most likely to benefit from treatment,” Dr. Bickel said.

Study authors received funding from the Department of Science and Technology of Sichuan Province and the National Natural Science Foundation of China. Dr. Li, Dr. Bickel, and Dr. Vickers report no relevant financial relationships.

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

Acupuncture deep needling provides significant, long-term relief from chronic tension type headache (TTH), new research suggests. Result of a randomized trial showed that though the majority of participants reported some relief from TTH after 8 weeks of acupuncture treatment, those who received needling at a depth of 12.5-20.0 mm reported the greatest reduction in headache frequency and severity.

At this depth, acupuncture promotes deqi sensation, a feeling of numbness, soreness, heaviness, or irritating pain in the needling site that is considered key to successful acupuncture treatment in traditional Chinese acupuncture theory.

“Our study showed that deqi sensation could enhance the effect of acupuncture in the treatment of chronic TTH, and the effect of acupuncture lasted at least 6 months when the treatment was stopped,” said co-investigator Ying Li, MD, PhD, The Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, China.

The findings were published online in Neurology.
 

Deqi sensation key

TTH is the most common type of headache, with a lifetime prevalence of up to 78% in some studies. The pain is often described as throbbing or a vice-like tightness on both sides of the head. TTH is considered chronic when it occurs at least 15 days a month.

Previous studies have suggested that acupuncture can offer relief from headache pain, but specific information on TTH, especially chronic TTH, has been lacking.

To address the issue, researchers designed a parallel-design, patient-and-assessor blinded randomized controlled trial with 218 individuals with a history of chronic TTH. All were untreated with prophylactic treatment in the previous 3 months.

The treatment group (n = 110) received 20 sessions of true acupuncture (TA) over 8 weeks. This included three sessions per week in the first 4 weeks and two sessions per week in the last 4 weeks. The depth of needling at each point ranged from 12.5 to 20 mm, which is needed to achieve deqi sensation.

The control group (n = 108) received superficial acupuncture (SA) on the same schedule as the TA group and at traditional acupuncture points. However, this was done at a maximum depth of 2 mm, which is not deep enough for deqi sensation.

At week 16, 68.2% of the participants receiving TA reported a greater than 50% reduction in monthly headache days, compared with 48.1% of those receiving SA (odds ratio, 2.65; P < .001).

Mean monthly headache days decreased from 20.38 days at baseline to 7.48 days at week 32 in the TA group versus 22.6 days at baseline to 11.94 days in the SA group.

Headache intensity and severity decreased in both groups, although those who achieved deqi sensation reported the most improvement.

Only four patients reported adverse effects, all of which were mild and none requiring treatment.

Patients in both groups reported some pain relief, suggesting that those who are not comfortable with deqi sensation may still benefit from superficial acupuncture, although to a lesser extent, Dr. Li said.

“We assume that the point-specific effect and placebo effect were combined to give the patients relief of headaches,” Dr. Li added. “Further, the effect of deqi sensation added more treatment effect. This might be explained by gate-control theory or other unknown mechanisms.”
 

Deeper understanding?

Commenting on the research, Jennifer Bickel, MD, a senior member of neurology at Moffit Cancer Center and professor of oncologic sciences at University of South Florida, Tampa, said that the study provides a deeper understanding of acupuncture’s efficacy for chronic TTH, which could aid clinicians who are unfamiliar with the therapy or when and how to refer treatment.

“This study provides a more descriptive outline for what type of acupuncture treatment and duration can be effective for patients so doctors can prep patients on what to expect and so doctors can better assess if patients received appropriate acupuncture for their headaches,” said Dr. Bickel, who was not involved with the research.

However, she noted that the acupuncture sites and techniques did not vary during the trial. Although that makes sense for a controlled study, it may not reflect real-world clinical practice, she added.

“The downside is that the study didn’t fully reflect that most acupuncturists in clinical practice would alter treatments during the 20 sessions based on the patient’s response and accompanying symptoms or comorbidities,” Dr. Bickel said.

The study also lacked information on medication overuse headache or patients’ prior history of TTH treatments.

“This could be helpful to understand which patients in clinical practice are most likely to benefit from treatment,” Dr. Bickel said.

Study authors received funding from the Department of Science and Technology of Sichuan Province and the National Natural Science Foundation of China. Dr. Li, Dr. Bickel, and Dr. Vickers report no relevant financial relationships.

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

A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.

Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.

The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.

“As gastroenterologists, we are very excited,” she said.

The study was published online in Gastroenterology and was presented at the annual Digestive Disease^® Week.

Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.

“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”

The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).

The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
 

Randomized trial pits AI against standard procedure

To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.

The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.

The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.

The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.

“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.

The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.

The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
 

Next steps

This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”

The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.

“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.

The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.

“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.

That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.

In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.

“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”

He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.

He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.

The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.

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

A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.

Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.

The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.

“As gastroenterologists, we are very excited,” she said.

The study was published online in Gastroenterology and was presented at the annual Digestive Disease^® Week.

Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.

“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”

The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).

The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
 

Randomized trial pits AI against standard procedure

To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.

The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.

The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.

The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.

“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.

The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.

The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
 

Next steps

This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”

The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.

“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.

The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.

“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.

That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.

In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.

“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”

He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.

He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.

The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.

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

A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.

Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.

The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.

“As gastroenterologists, we are very excited,” she said.

The study was published online in Gastroenterology and was presented at the annual Digestive Disease^® Week.

Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.

“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”

The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).

The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
 

Randomized trial pits AI against standard procedure

To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.

The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.

The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.

The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.

“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.

The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.

The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
 

Next steps

This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”

The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.

“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.

The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.

“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.

That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.

In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.

“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”

He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.

He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.

The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.

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

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.