Gene Therapy

On any given day, oncologist Mark Lewis, MD, feels like he’s seesawing between two eras of technology. 

One minute, he’s working on sequencing a tumor genome. The next, he’s sifting through pages of disorganized data from a device that has been around for decades: the fax machine. 

“If two doctors’ offices aren’t on the same electronic medical record, one of the main ways to transfer records is still by fax,” said Dr. Lewis, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah. “I can go from cutting-edge innovation to relying on, at best, 1980s information technology. It just boggles my mind.”

Dr. Lewis, who has posted about his frustration with fax machines, is far from alone. Oncologists are among the many specialists across the country at the mercy of telecopiers. 

According to a 2021 report by the Office of the National Coordinator for Health Information Technology, fax and mail continue to be the most common methods for hospitals and health systems to exchange care record summaries. In 2019, nearly 8 in 10 hospitals used mail or fax to send and receive health information, the report found. 

Fax machines are still commonplace across the healthcare spectrum, said Robert Havasy, MS, senior director for informatics strategy at the Healthcare Information and Management Systems Society (HIMSS). Inertia, cost, and more pressing priorities for hospitals and medical institutions contribute to the technology sticking around, he explained. 

“Post-COVID, my guess is we’re still at over 50% of healthcare practices using fax for some reason, on a daily basis,” Mr. Havasy said in an interview. “A lot of hospitals just don’t have the time, the money, or the staff to fix that problem because there’s always something a little higher up the priority chain they need to focus on.” 

If, for instance, “you’re going to do a process redesign to reduce hospital total acquired infections, your fax machine replacement might be 10th or 12th on the list. It just never gets up to 1 or 2 because it’s ‘not that much of a problem,’ ” he added.

Or is it?

Administrators may not view fax machines as a top concern, but clinicians who deal with the machines daily see it differently. 

“What worries me is we’re taking records out of an electronic storehouse [and] converting them to a paper medium,” Dr. Lewis said. “And then we are scanning into another electronic storehouse. The more steps, the more can be lost.”

And when information is lost, patient care can be compromised. 

Slower Workflows, Care Concerns

Although there are no published data on fax machine use in oncology specifically, this outdated technology does come into play in a variety of ways along the cancer care continuum. 

Radiation oncologist David R. Penberthy, MD, said patients often seek his cancer center’s expertise for second opinions, and that requires collecting patient records from many different practices. 

“Ideally, it would come electronically, but sometimes it does come by fax,” said Dr. Penberthy, program director of radiation oncology at the University of Virginia School of Medicine in Charlottesville. “The quality of the fax is not always the best. Sometimes it’s literally a fax of a fax. You’re reading something that’s very difficult to read.” 

Orders for new tests are also typically sent and received via fax temporarily while IT teams work to integrate them into the electronic health record (EHR), Dr. Penberthy said. 

Insurers and third-party laboratories often send test results back by fax as well.

“Even if I haven’t actually sent my patient out of our institution, this crucial result may only be entered back into the record as a scanned document from a fax, which is not great because it can get lost in the other results that are reported electronically,” Dr. Lewis said. The risk here is that an ordering physician won’t see these results, which can lead to delayed or overlooked care for patients, he explained.

“To me, it’s like a blind spot,” Dr. Lewis said. “Every time we use a fax, I see it actually as an opportunity for oversight and missed opportunity to collect data.”

Dr. Penberthy said faxing can slow things down at his practice, particularly if he faxes a document to another office but receives no confirmation and has to track down what happened. 

As for cybersecurity, data that are in transit during faxing are generally considered secure and compliant with the Health Insurance Portability and Accountability Act (HIPAA), said Mr. Havasy of HIMSS. However, the Privacy Rule also requires that data remain secure while at rest, which isn’t always possible, he added. 

“That’s where faxes fall down, because generally fax machines are in public, if you will, or open areas in a hospital,” he said. “They just sit on a desk. I don’t know that the next nurse who comes up and looks through that stack was the nurse who was treating the patient.” 

Important decisions or results can also be missed when sent by fax, creating headaches for physicians and care problems for patients. 

Dr. Lewis recently experienced an insurance-related fax mishap over Memorial Day weekend. He believed his patient had access to the antinausea medication he had prescribed. When Dr. Lewis happened to check the fax machine over the weekend, he found a coverage denial for the medication from the insurer but, at that point, had no recourse to appeal because it was a long holiday weekend. 

“Had the denial been sent by an electronic means that was quicker and more readily available, it would have been possible to appeal before the holiday weekend,” he said. 

Hematologist Aaron Goodman, MD, encountered a similar problem after an insurer denied coverage of an expensive cancer drug for a patient and faxed over its reason for the denial. Dr. Goodman was not directly notified that the information arrived and didn’t learn about the denial for a week, he said. 

“There’s no ‘ding’ in my inbox if something is faxed over and scanned,” said Dr. Goodman, associate professor of medicine at UC San Diego Health. “Once I realized it was denied, I was able to rectify it, but it wasted a week of a patient not getting a drug that I felt would be beneficial for them.”

Broader Health Policy Impacts

The use of outdated technology, such as fax machines, also creates ripple effects that burden the health system, health policy experts say. 

Duplicate testing and unnecessary care are top impacts, said Julia Adler-Milstein, PhD, professor of medicine and chief of the division of clinical informatics and digital transformation at the University of California, San Francisco.

Studies show that 20%-30% of the $65 billion spent annually on lab tests is used on unnecessary duplicate tests, and another estimated $30 billion is spent each year on unnecessary duplicate medical imaging. These duplicate tests may be mitigated if hospitals adopt certified EHR technology, research shows.

Still, without EHR interoperability between institutions, new providers may be unaware that tests or past labs for patients exist, leading to repeat tests, said Dr. Adler-Milstein, who researches health IT policy with a focus on EHRs. Patients can sometimes fill in the gaps, but not always. 

“Fax machines only help close information gaps if the clinician is aware of where to seek out the information and there is someone at the other organization to locate and transmit the information in a timely manner,” Dr. Adler-Milstein said. 

Old technology and poor interoperability also greatly affect data collection for disease surveillance and monitoring, said Janet Hamilton, MPH, executive director for the Council of State and Territorial Epidemiologists. This issue was keenly demonstrated during the pandemic, Ms. Hamilton said. 

“It was tragic, quite honestly,” she said. “There was such an immense amount of data that needed to be moved quickly, and that’s when computers are at their best.”

But, she said, “we didn’t have the level of systems in place to do it well.”

Specifically, the lack of electronic case reporting in place during the pandemic — where diagnoses are documented in the record and then immediately sent to the public health system — led to reports that were delayed, not made, or had missing or incomplete information, such as patients’ race and ethnicity or other health conditions, Ms. Hamilton said. 

Incomplete or missing data hampered the ability of public health officials and researchers to understand how the virus might affect different patients.

“If you had a chronic condition like cancer, you were less likely to have a positive outcome with COVID,” Ms. Hamilton said. “But because electronic case reporting was not in place, we didn’t get some of those additional pieces of information. We didn’t have people’s underlying oncology status to then say, ‘Here are individuals with these types of characteristics, and these are the things that happen if they also have a cancer.’” 

Slow, but Steady, Improvements

Efforts at the state and federal levels have targeted improved health information exchange, but progress takes time, Dr. Adler-Milstein said.

Most states have some form of health information exchange, such as statewide exchanges, regional health information organizations, or clinical data registries. Maryland is often held up as a notable example for its health information exchange, Dr. Adler-Milstein noted.

According to Maryland law, all hospitals under the jurisdiction of the Maryland Health Care Commission are required to electronically connect to the state-designated health information exchange. In 2012, Maryland became the first state to connect all its 46 acute care hospitals in the sharing of real-time data. 

The Health Information Technology for Economic and Clinical Health (HITECH) Act provided federal-enhanced Medicaid matching funds to states through 2021 to support efforts to advance electronic exchange. Nearly all states used these funds, and most have identified other sources to sustain the efforts, according to a recent US Government Accountability Office (GAO) report. However, GAO found that small and rural providers are less likely to have the financial and technological resources to participate in or maintain electronic exchange capabilities.

Nationally, several recent initiatives have targeted health data interoperability, including for cancer care. The Centers for Disease Control and Prevention’s Data Modernization Initiative is a multiyear, multi–billion-dollar effort to improve data sharing across the federal and state public health landscape. 

Meanwhile, in March 2024, the Biden-Harris administration launched United States Core Data for Interoperability Plus Cancer. The program will define a recommended minimum set of cancer-related data to be included in a patient’s EHR to enhance data exchange for research and clinical care. 

EHR vendors are also key to improving the landscape, said Dr. Adler-Milstein. Vendors such as Epic have developed strong sharing capabilities for transmitting health information from site to site, but of course, that only helps if providers have Epic, she said. 

“That’s where these national frameworks should help, because we don’t want it to break down by what EHR vendor you have,” she said. “It’s a patchwork. You can go to some places and hear success stories because they have Epic or a state health information exchange, but it’s very heterogeneous. In some places, they have nothing and are using a fax machine.”

Mr. Havasy believes fax machines will ultimately go extinct, particularly as a younger, more digitally savvy generation enters the healthcare workforce. He also foresees that the growing use of artificial intelligence will help eradicate the outdated technology. 

But, Ms. Hamilton noted, “unless we have consistent, ongoing, sustained funding, it is very hard to move off [an older] technology that can work. That’s one of the biggest barriers.” 

“Public health is about protecting the lives of every single person everywhere,” Ms. Hamilton said, “but when we don’t have the data that comes into the system, we can’t achieve our mission.”
 

A version of this article appeared on Medscape.com.

On any given day, oncologist Mark Lewis, MD, feels like he’s seesawing between two eras of technology. 

One minute, he’s working on sequencing a tumor genome. The next, he’s sifting through pages of disorganized data from a device that has been around for decades: the fax machine. 

“If two doctors’ offices aren’t on the same electronic medical record, one of the main ways to transfer records is still by fax,” said Dr. Lewis, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah. “I can go from cutting-edge innovation to relying on, at best, 1980s information technology. It just boggles my mind.”

Dr. Lewis, who has posted about his frustration with fax machines, is far from alone. Oncologists are among the many specialists across the country at the mercy of telecopiers. 

According to a 2021 report by the Office of the National Coordinator for Health Information Technology, fax and mail continue to be the most common methods for hospitals and health systems to exchange care record summaries. In 2019, nearly 8 in 10 hospitals used mail or fax to send and receive health information, the report found. 

Fax machines are still commonplace across the healthcare spectrum, said Robert Havasy, MS, senior director for informatics strategy at the Healthcare Information and Management Systems Society (HIMSS). Inertia, cost, and more pressing priorities for hospitals and medical institutions contribute to the technology sticking around, he explained. 

“Post-COVID, my guess is we’re still at over 50% of healthcare practices using fax for some reason, on a daily basis,” Mr. Havasy said in an interview. “A lot of hospitals just don’t have the time, the money, or the staff to fix that problem because there’s always something a little higher up the priority chain they need to focus on.” 

If, for instance, “you’re going to do a process redesign to reduce hospital total acquired infections, your fax machine replacement might be 10th or 12th on the list. It just never gets up to 1 or 2 because it’s ‘not that much of a problem,’ ” he added.

Or is it?

Administrators may not view fax machines as a top concern, but clinicians who deal with the machines daily see it differently. 

“What worries me is we’re taking records out of an electronic storehouse [and] converting them to a paper medium,” Dr. Lewis said. “And then we are scanning into another electronic storehouse. The more steps, the more can be lost.”

And when information is lost, patient care can be compromised. 

Slower Workflows, Care Concerns

Although there are no published data on fax machine use in oncology specifically, this outdated technology does come into play in a variety of ways along the cancer care continuum. 

Radiation oncologist David R. Penberthy, MD, said patients often seek his cancer center’s expertise for second opinions, and that requires collecting patient records from many different practices. 

“Ideally, it would come electronically, but sometimes it does come by fax,” said Dr. Penberthy, program director of radiation oncology at the University of Virginia School of Medicine in Charlottesville. “The quality of the fax is not always the best. Sometimes it’s literally a fax of a fax. You’re reading something that’s very difficult to read.” 

Orders for new tests are also typically sent and received via fax temporarily while IT teams work to integrate them into the electronic health record (EHR), Dr. Penberthy said. 

Insurers and third-party laboratories often send test results back by fax as well.

“Even if I haven’t actually sent my patient out of our institution, this crucial result may only be entered back into the record as a scanned document from a fax, which is not great because it can get lost in the other results that are reported electronically,” Dr. Lewis said. The risk here is that an ordering physician won’t see these results, which can lead to delayed or overlooked care for patients, he explained.

“To me, it’s like a blind spot,” Dr. Lewis said. “Every time we use a fax, I see it actually as an opportunity for oversight and missed opportunity to collect data.”

Dr. Penberthy said faxing can slow things down at his practice, particularly if he faxes a document to another office but receives no confirmation and has to track down what happened. 

As for cybersecurity, data that are in transit during faxing are generally considered secure and compliant with the Health Insurance Portability and Accountability Act (HIPAA), said Mr. Havasy of HIMSS. However, the Privacy Rule also requires that data remain secure while at rest, which isn’t always possible, he added. 

“That’s where faxes fall down, because generally fax machines are in public, if you will, or open areas in a hospital,” he said. “They just sit on a desk. I don’t know that the next nurse who comes up and looks through that stack was the nurse who was treating the patient.” 

Important decisions or results can also be missed when sent by fax, creating headaches for physicians and care problems for patients. 

Dr. Lewis recently experienced an insurance-related fax mishap over Memorial Day weekend. He believed his patient had access to the antinausea medication he had prescribed. When Dr. Lewis happened to check the fax machine over the weekend, he found a coverage denial for the medication from the insurer but, at that point, had no recourse to appeal because it was a long holiday weekend. 

“Had the denial been sent by an electronic means that was quicker and more readily available, it would have been possible to appeal before the holiday weekend,” he said. 

Hematologist Aaron Goodman, MD, encountered a similar problem after an insurer denied coverage of an expensive cancer drug for a patient and faxed over its reason for the denial. Dr. Goodman was not directly notified that the information arrived and didn’t learn about the denial for a week, he said. 

“There’s no ‘ding’ in my inbox if something is faxed over and scanned,” said Dr. Goodman, associate professor of medicine at UC San Diego Health. “Once I realized it was denied, I was able to rectify it, but it wasted a week of a patient not getting a drug that I felt would be beneficial for them.”

Broader Health Policy Impacts

The use of outdated technology, such as fax machines, also creates ripple effects that burden the health system, health policy experts say. 

Duplicate testing and unnecessary care are top impacts, said Julia Adler-Milstein, PhD, professor of medicine and chief of the division of clinical informatics and digital transformation at the University of California, San Francisco.

Studies show that 20%-30% of the $65 billion spent annually on lab tests is used on unnecessary duplicate tests, and another estimated $30 billion is spent each year on unnecessary duplicate medical imaging. These duplicate tests may be mitigated if hospitals adopt certified EHR technology, research shows.

Still, without EHR interoperability between institutions, new providers may be unaware that tests or past labs for patients exist, leading to repeat tests, said Dr. Adler-Milstein, who researches health IT policy with a focus on EHRs. Patients can sometimes fill in the gaps, but not always. 

“Fax machines only help close information gaps if the clinician is aware of where to seek out the information and there is someone at the other organization to locate and transmit the information in a timely manner,” Dr. Adler-Milstein said. 

Old technology and poor interoperability also greatly affect data collection for disease surveillance and monitoring, said Janet Hamilton, MPH, executive director for the Council of State and Territorial Epidemiologists. This issue was keenly demonstrated during the pandemic, Ms. Hamilton said. 

“It was tragic, quite honestly,” she said. “There was such an immense amount of data that needed to be moved quickly, and that’s when computers are at their best.”

But, she said, “we didn’t have the level of systems in place to do it well.”

Specifically, the lack of electronic case reporting in place during the pandemic — where diagnoses are documented in the record and then immediately sent to the public health system — led to reports that were delayed, not made, or had missing or incomplete information, such as patients’ race and ethnicity or other health conditions, Ms. Hamilton said. 

Incomplete or missing data hampered the ability of public health officials and researchers to understand how the virus might affect different patients.

“If you had a chronic condition like cancer, you were less likely to have a positive outcome with COVID,” Ms. Hamilton said. “But because electronic case reporting was not in place, we didn’t get some of those additional pieces of information. We didn’t have people’s underlying oncology status to then say, ‘Here are individuals with these types of characteristics, and these are the things that happen if they also have a cancer.’” 

Slow, but Steady, Improvements

Efforts at the state and federal levels have targeted improved health information exchange, but progress takes time, Dr. Adler-Milstein said.

Most states have some form of health information exchange, such as statewide exchanges, regional health information organizations, or clinical data registries. Maryland is often held up as a notable example for its health information exchange, Dr. Adler-Milstein noted.

According to Maryland law, all hospitals under the jurisdiction of the Maryland Health Care Commission are required to electronically connect to the state-designated health information exchange. In 2012, Maryland became the first state to connect all its 46 acute care hospitals in the sharing of real-time data. 

The Health Information Technology for Economic and Clinical Health (HITECH) Act provided federal-enhanced Medicaid matching funds to states through 2021 to support efforts to advance electronic exchange. Nearly all states used these funds, and most have identified other sources to sustain the efforts, according to a recent US Government Accountability Office (GAO) report. However, GAO found that small and rural providers are less likely to have the financial and technological resources to participate in or maintain electronic exchange capabilities.

Nationally, several recent initiatives have targeted health data interoperability, including for cancer care. The Centers for Disease Control and Prevention’s Data Modernization Initiative is a multiyear, multi–billion-dollar effort to improve data sharing across the federal and state public health landscape. 

Meanwhile, in March 2024, the Biden-Harris administration launched United States Core Data for Interoperability Plus Cancer. The program will define a recommended minimum set of cancer-related data to be included in a patient’s EHR to enhance data exchange for research and clinical care. 

EHR vendors are also key to improving the landscape, said Dr. Adler-Milstein. Vendors such as Epic have developed strong sharing capabilities for transmitting health information from site to site, but of course, that only helps if providers have Epic, she said. 

“That’s where these national frameworks should help, because we don’t want it to break down by what EHR vendor you have,” she said. “It’s a patchwork. You can go to some places and hear success stories because they have Epic or a state health information exchange, but it’s very heterogeneous. In some places, they have nothing and are using a fax machine.”

Mr. Havasy believes fax machines will ultimately go extinct, particularly as a younger, more digitally savvy generation enters the healthcare workforce. He also foresees that the growing use of artificial intelligence will help eradicate the outdated technology. 

But, Ms. Hamilton noted, “unless we have consistent, ongoing, sustained funding, it is very hard to move off [an older] technology that can work. That’s one of the biggest barriers.” 

“Public health is about protecting the lives of every single person everywhere,” Ms. Hamilton said, “but when we don’t have the data that comes into the system, we can’t achieve our mission.”
 

A version of this article appeared on Medscape.com.

On any given day, oncologist Mark Lewis, MD, feels like he’s seesawing between two eras of technology. 

One minute, he’s working on sequencing a tumor genome. The next, he’s sifting through pages of disorganized data from a device that has been around for decades: the fax machine. 

“If two doctors’ offices aren’t on the same electronic medical record, one of the main ways to transfer records is still by fax,” said Dr. Lewis, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah. “I can go from cutting-edge innovation to relying on, at best, 1980s information technology. It just boggles my mind.”

Dr. Lewis, who has posted about his frustration with fax machines, is far from alone. Oncologists are among the many specialists across the country at the mercy of telecopiers. 

According to a 2021 report by the Office of the National Coordinator for Health Information Technology, fax and mail continue to be the most common methods for hospitals and health systems to exchange care record summaries. In 2019, nearly 8 in 10 hospitals used mail or fax to send and receive health information, the report found. 

Fax machines are still commonplace across the healthcare spectrum, said Robert Havasy, MS, senior director for informatics strategy at the Healthcare Information and Management Systems Society (HIMSS). Inertia, cost, and more pressing priorities for hospitals and medical institutions contribute to the technology sticking around, he explained. 

“Post-COVID, my guess is we’re still at over 50% of healthcare practices using fax for some reason, on a daily basis,” Mr. Havasy said in an interview. “A lot of hospitals just don’t have the time, the money, or the staff to fix that problem because there’s always something a little higher up the priority chain they need to focus on.” 

If, for instance, “you’re going to do a process redesign to reduce hospital total acquired infections, your fax machine replacement might be 10th or 12th on the list. It just never gets up to 1 or 2 because it’s ‘not that much of a problem,’ ” he added.

Or is it?

Administrators may not view fax machines as a top concern, but clinicians who deal with the machines daily see it differently. 

“What worries me is we’re taking records out of an electronic storehouse [and] converting them to a paper medium,” Dr. Lewis said. “And then we are scanning into another electronic storehouse. The more steps, the more can be lost.”

And when information is lost, patient care can be compromised. 

Slower Workflows, Care Concerns

Although there are no published data on fax machine use in oncology specifically, this outdated technology does come into play in a variety of ways along the cancer care continuum. 

Radiation oncologist David R. Penberthy, MD, said patients often seek his cancer center’s expertise for second opinions, and that requires collecting patient records from many different practices. 

“Ideally, it would come electronically, but sometimes it does come by fax,” said Dr. Penberthy, program director of radiation oncology at the University of Virginia School of Medicine in Charlottesville. “The quality of the fax is not always the best. Sometimes it’s literally a fax of a fax. You’re reading something that’s very difficult to read.” 

Orders for new tests are also typically sent and received via fax temporarily while IT teams work to integrate them into the electronic health record (EHR), Dr. Penberthy said. 

Insurers and third-party laboratories often send test results back by fax as well.

“Even if I haven’t actually sent my patient out of our institution, this crucial result may only be entered back into the record as a scanned document from a fax, which is not great because it can get lost in the other results that are reported electronically,” Dr. Lewis said. The risk here is that an ordering physician won’t see these results, which can lead to delayed or overlooked care for patients, he explained.

“To me, it’s like a blind spot,” Dr. Lewis said. “Every time we use a fax, I see it actually as an opportunity for oversight and missed opportunity to collect data.”

Dr. Penberthy said faxing can slow things down at his practice, particularly if he faxes a document to another office but receives no confirmation and has to track down what happened. 

As for cybersecurity, data that are in transit during faxing are generally considered secure and compliant with the Health Insurance Portability and Accountability Act (HIPAA), said Mr. Havasy of HIMSS. However, the Privacy Rule also requires that data remain secure while at rest, which isn’t always possible, he added. 

“That’s where faxes fall down, because generally fax machines are in public, if you will, or open areas in a hospital,” he said. “They just sit on a desk. I don’t know that the next nurse who comes up and looks through that stack was the nurse who was treating the patient.” 

Important decisions or results can also be missed when sent by fax, creating headaches for physicians and care problems for patients. 

Dr. Lewis recently experienced an insurance-related fax mishap over Memorial Day weekend. He believed his patient had access to the antinausea medication he had prescribed. When Dr. Lewis happened to check the fax machine over the weekend, he found a coverage denial for the medication from the insurer but, at that point, had no recourse to appeal because it was a long holiday weekend. 

“Had the denial been sent by an electronic means that was quicker and more readily available, it would have been possible to appeal before the holiday weekend,” he said. 

Hematologist Aaron Goodman, MD, encountered a similar problem after an insurer denied coverage of an expensive cancer drug for a patient and faxed over its reason for the denial. Dr. Goodman was not directly notified that the information arrived and didn’t learn about the denial for a week, he said. 

“There’s no ‘ding’ in my inbox if something is faxed over and scanned,” said Dr. Goodman, associate professor of medicine at UC San Diego Health. “Once I realized it was denied, I was able to rectify it, but it wasted a week of a patient not getting a drug that I felt would be beneficial for them.”

Broader Health Policy Impacts

The use of outdated technology, such as fax machines, also creates ripple effects that burden the health system, health policy experts say. 

Duplicate testing and unnecessary care are top impacts, said Julia Adler-Milstein, PhD, professor of medicine and chief of the division of clinical informatics and digital transformation at the University of California, San Francisco.

Studies show that 20%-30% of the $65 billion spent annually on lab tests is used on unnecessary duplicate tests, and another estimated $30 billion is spent each year on unnecessary duplicate medical imaging. These duplicate tests may be mitigated if hospitals adopt certified EHR technology, research shows.

Still, without EHR interoperability between institutions, new providers may be unaware that tests or past labs for patients exist, leading to repeat tests, said Dr. Adler-Milstein, who researches health IT policy with a focus on EHRs. Patients can sometimes fill in the gaps, but not always. 

“Fax machines only help close information gaps if the clinician is aware of where to seek out the information and there is someone at the other organization to locate and transmit the information in a timely manner,” Dr. Adler-Milstein said. 

Old technology and poor interoperability also greatly affect data collection for disease surveillance and monitoring, said Janet Hamilton, MPH, executive director for the Council of State and Territorial Epidemiologists. This issue was keenly demonstrated during the pandemic, Ms. Hamilton said. 

“It was tragic, quite honestly,” she said. “There was such an immense amount of data that needed to be moved quickly, and that’s when computers are at their best.”

But, she said, “we didn’t have the level of systems in place to do it well.”

Specifically, the lack of electronic case reporting in place during the pandemic — where diagnoses are documented in the record and then immediately sent to the public health system — led to reports that were delayed, not made, or had missing or incomplete information, such as patients’ race and ethnicity or other health conditions, Ms. Hamilton said. 

Incomplete or missing data hampered the ability of public health officials and researchers to understand how the virus might affect different patients.

“If you had a chronic condition like cancer, you were less likely to have a positive outcome with COVID,” Ms. Hamilton said. “But because electronic case reporting was not in place, we didn’t get some of those additional pieces of information. We didn’t have people’s underlying oncology status to then say, ‘Here are individuals with these types of characteristics, and these are the things that happen if they also have a cancer.’” 

Slow, but Steady, Improvements

Efforts at the state and federal levels have targeted improved health information exchange, but progress takes time, Dr. Adler-Milstein said.

Most states have some form of health information exchange, such as statewide exchanges, regional health information organizations, or clinical data registries. Maryland is often held up as a notable example for its health information exchange, Dr. Adler-Milstein noted.

According to Maryland law, all hospitals under the jurisdiction of the Maryland Health Care Commission are required to electronically connect to the state-designated health information exchange. In 2012, Maryland became the first state to connect all its 46 acute care hospitals in the sharing of real-time data. 

The Health Information Technology for Economic and Clinical Health (HITECH) Act provided federal-enhanced Medicaid matching funds to states through 2021 to support efforts to advance electronic exchange. Nearly all states used these funds, and most have identified other sources to sustain the efforts, according to a recent US Government Accountability Office (GAO) report. However, GAO found that small and rural providers are less likely to have the financial and technological resources to participate in or maintain electronic exchange capabilities.

Nationally, several recent initiatives have targeted health data interoperability, including for cancer care. The Centers for Disease Control and Prevention’s Data Modernization Initiative is a multiyear, multi–billion-dollar effort to improve data sharing across the federal and state public health landscape. 

Meanwhile, in March 2024, the Biden-Harris administration launched United States Core Data for Interoperability Plus Cancer. The program will define a recommended minimum set of cancer-related data to be included in a patient’s EHR to enhance data exchange for research and clinical care. 

EHR vendors are also key to improving the landscape, said Dr. Adler-Milstein. Vendors such as Epic have developed strong sharing capabilities for transmitting health information from site to site, but of course, that only helps if providers have Epic, she said. 

“That’s where these national frameworks should help, because we don’t want it to break down by what EHR vendor you have,” she said. “It’s a patchwork. You can go to some places and hear success stories because they have Epic or a state health information exchange, but it’s very heterogeneous. In some places, they have nothing and are using a fax machine.”

Mr. Havasy believes fax machines will ultimately go extinct, particularly as a younger, more digitally savvy generation enters the healthcare workforce. He also foresees that the growing use of artificial intelligence will help eradicate the outdated technology. 

But, Ms. Hamilton noted, “unless we have consistent, ongoing, sustained funding, it is very hard to move off [an older] technology that can work. That’s one of the biggest barriers.” 

“Public health is about protecting the lives of every single person everywhere,” Ms. Hamilton said, “but when we don’t have the data that comes into the system, we can’t achieve our mission.”
 

A version of this article appeared on Medscape.com.

Nearly one in three physicians endorsing drugs and devices on the social media platform X did not disclose that they received payments from the manufacturers, according to a new study published in JAMA.

Lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told this news organization that he and his colleagues undertook the study in part to see whether physicians were adhering to professional and industry guidelines regarding marketing communications.

The team reviewed posts by physicians on X during 2022, looking for key words that might indicate that the posts were intended as endorsements of a product. The researchers then delved into the Centers for Medicare and Medicaid Services Open Payments database to see how many of those identified as having endorsed a product were paid by the manufacturers.

What Dr. Mitchell found concerned him, he said.

Overall, the researchers identified 28 physician endorsers who received a total of $1.4 million from sponsors in 2022. Among these, 26 physicians (93%) received payments from the product’s manufacturer, totaling $713,976, and 24 physicians (86%) accepted payments related to the endorsed drug or device, totaling $492,098.

While most did disclose that the posts were sponsored — by adding the word “sponsored” or using #sponsored — nine physicians did not.

Although 28 physician endorsers represent a “small fraction” of the overall number of physicians who use X, each endorsement was ultimately posted dozens, if not hundreds of times, said Dr. Mitchell. In fact, he said he saw the same particular endorsement post every time he opened his X app for months.

Overall, Dr. Mitchell noted that it’s less about the fact that the endorsements are occurring on social media and more that there are these paid endorsements taking place at all.

Among the physician specialties promoting a product, urologists and oncologists dominated. Almost one third were urologists, and 57% were oncologists — six medical oncologists, six radiation oncologists, and four gynecologic oncologists. Of the remaining three physicians, two were internists and one was a pulmonary and critical care medicine specialist.

The authors tracked posts from physicians and industry accounts. Many of the posts on industry accounts were physician testimonials, usually videos. Almost half — 8 of 17 — of those testimonials did not disclose that the doctor was being paid by the manufacturer. In another case, a physician did not disclose that they were paid to endorse a white paper.

Fifteen promotional posts were for a Boston Scientific product, followed by six for GlaxoSmithKline, two for Eisai, two for Exelixis, and one each for AstraZeneca, Novartis, and Pfizer.

In general, Dr. Mitchell said, industry guidelines suggest that manufacturer-paid speakers or consultants should have well-regarded expertise in the area they are being asked to weigh in on, but most physician endorsers in the study were not key opinion leaders or experts.

The authors examined the paid endorsers’ H-index — a measure of academic productivity provided by Scopus. Overall, 19 of the 28 physicians had an H-index below 20, which is considered less accomplished, and 14 had no published research related to the endorsed product.

Ten received payments from manufacturers for research purposes, and only one received research payments related to the endorsed product ($224,577).

“Physicians’ participation in industry marketing raises questions regarding professionalism and their responsibilities as patient advocates,” the JAMA authors wrote.

The study was supported by grants from the National Cancer Institute. Dr. Mitchell reported no relevant financial relationships. Coauthors Samer Al Hadidi, MD, reported receiving personal fees from Pfizer, Sanofi, and Janssen during the conduct of the study, and Timothy S. Anderson, MD, reported receiving grants from the National Institute on Aging, the American Heart Association, and the American College of Cardiology, and receiving consulting fees from the American Medical Student Association. Dr. Anderson is also an associate editor of JAMA Internal Medicine.

A version of this article appeared on Medscape.com.

Nearly one in three physicians endorsing drugs and devices on the social media platform X did not disclose that they received payments from the manufacturers, according to a new study published in JAMA.

Lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told this news organization that he and his colleagues undertook the study in part to see whether physicians were adhering to professional and industry guidelines regarding marketing communications.

The team reviewed posts by physicians on X during 2022, looking for key words that might indicate that the posts were intended as endorsements of a product. The researchers then delved into the Centers for Medicare and Medicaid Services Open Payments database to see how many of those identified as having endorsed a product were paid by the manufacturers.

What Dr. Mitchell found concerned him, he said.

Overall, the researchers identified 28 physician endorsers who received a total of $1.4 million from sponsors in 2022. Among these, 26 physicians (93%) received payments from the product’s manufacturer, totaling $713,976, and 24 physicians (86%) accepted payments related to the endorsed drug or device, totaling $492,098.

While most did disclose that the posts were sponsored — by adding the word “sponsored” or using #sponsored — nine physicians did not.

Although 28 physician endorsers represent a “small fraction” of the overall number of physicians who use X, each endorsement was ultimately posted dozens, if not hundreds of times, said Dr. Mitchell. In fact, he said he saw the same particular endorsement post every time he opened his X app for months.

Overall, Dr. Mitchell noted that it’s less about the fact that the endorsements are occurring on social media and more that there are these paid endorsements taking place at all.

Among the physician specialties promoting a product, urologists and oncologists dominated. Almost one third were urologists, and 57% were oncologists — six medical oncologists, six radiation oncologists, and four gynecologic oncologists. Of the remaining three physicians, two were internists and one was a pulmonary and critical care medicine specialist.

The authors tracked posts from physicians and industry accounts. Many of the posts on industry accounts were physician testimonials, usually videos. Almost half — 8 of 17 — of those testimonials did not disclose that the doctor was being paid by the manufacturer. In another case, a physician did not disclose that they were paid to endorse a white paper.

Fifteen promotional posts were for a Boston Scientific product, followed by six for GlaxoSmithKline, two for Eisai, two for Exelixis, and one each for AstraZeneca, Novartis, and Pfizer.

In general, Dr. Mitchell said, industry guidelines suggest that manufacturer-paid speakers or consultants should have well-regarded expertise in the area they are being asked to weigh in on, but most physician endorsers in the study were not key opinion leaders or experts.

The authors examined the paid endorsers’ H-index — a measure of academic productivity provided by Scopus. Overall, 19 of the 28 physicians had an H-index below 20, which is considered less accomplished, and 14 had no published research related to the endorsed product.

Ten received payments from manufacturers for research purposes, and only one received research payments related to the endorsed product ($224,577).

“Physicians’ participation in industry marketing raises questions regarding professionalism and their responsibilities as patient advocates,” the JAMA authors wrote.

The study was supported by grants from the National Cancer Institute. Dr. Mitchell reported no relevant financial relationships. Coauthors Samer Al Hadidi, MD, reported receiving personal fees from Pfizer, Sanofi, and Janssen during the conduct of the study, and Timothy S. Anderson, MD, reported receiving grants from the National Institute on Aging, the American Heart Association, and the American College of Cardiology, and receiving consulting fees from the American Medical Student Association. Dr. Anderson is also an associate editor of JAMA Internal Medicine.

A version of this article appeared on Medscape.com.

Nearly one in three physicians endorsing drugs and devices on the social media platform X did not disclose that they received payments from the manufacturers, according to a new study published in JAMA.

Lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told this news organization that he and his colleagues undertook the study in part to see whether physicians were adhering to professional and industry guidelines regarding marketing communications.

The team reviewed posts by physicians on X during 2022, looking for key words that might indicate that the posts were intended as endorsements of a product. The researchers then delved into the Centers for Medicare and Medicaid Services Open Payments database to see how many of those identified as having endorsed a product were paid by the manufacturers.

What Dr. Mitchell found concerned him, he said.

Overall, the researchers identified 28 physician endorsers who received a total of $1.4 million from sponsors in 2022. Among these, 26 physicians (93%) received payments from the product’s manufacturer, totaling $713,976, and 24 physicians (86%) accepted payments related to the endorsed drug or device, totaling $492,098.

While most did disclose that the posts were sponsored — by adding the word “sponsored” or using #sponsored — nine physicians did not.

Although 28 physician endorsers represent a “small fraction” of the overall number of physicians who use X, each endorsement was ultimately posted dozens, if not hundreds of times, said Dr. Mitchell. In fact, he said he saw the same particular endorsement post every time he opened his X app for months.

Overall, Dr. Mitchell noted that it’s less about the fact that the endorsements are occurring on social media and more that there are these paid endorsements taking place at all.

Among the physician specialties promoting a product, urologists and oncologists dominated. Almost one third were urologists, and 57% were oncologists — six medical oncologists, six radiation oncologists, and four gynecologic oncologists. Of the remaining three physicians, two were internists and one was a pulmonary and critical care medicine specialist.

The authors tracked posts from physicians and industry accounts. Many of the posts on industry accounts were physician testimonials, usually videos. Almost half — 8 of 17 — of those testimonials did not disclose that the doctor was being paid by the manufacturer. In another case, a physician did not disclose that they were paid to endorse a white paper.

Fifteen promotional posts were for a Boston Scientific product, followed by six for GlaxoSmithKline, two for Eisai, two for Exelixis, and one each for AstraZeneca, Novartis, and Pfizer.

In general, Dr. Mitchell said, industry guidelines suggest that manufacturer-paid speakers or consultants should have well-regarded expertise in the area they are being asked to weigh in on, but most physician endorsers in the study were not key opinion leaders or experts.

The authors examined the paid endorsers’ H-index — a measure of academic productivity provided by Scopus. Overall, 19 of the 28 physicians had an H-index below 20, which is considered less accomplished, and 14 had no published research related to the endorsed product.

Ten received payments from manufacturers for research purposes, and only one received research payments related to the endorsed product ($224,577).

“Physicians’ participation in industry marketing raises questions regarding professionalism and their responsibilities as patient advocates,” the JAMA authors wrote.

The study was supported by grants from the National Cancer Institute. Dr. Mitchell reported no relevant financial relationships. Coauthors Samer Al Hadidi, MD, reported receiving personal fees from Pfizer, Sanofi, and Janssen during the conduct of the study, and Timothy S. Anderson, MD, reported receiving grants from the National Institute on Aging, the American Heart Association, and the American College of Cardiology, and receiving consulting fees from the American Medical Student Association. Dr. Anderson is also an associate editor of JAMA Internal Medicine.

A version of this article appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

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

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

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

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

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

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

Earlier this month, the U.S. Food and Drug Administration (FDA) approved two gene-editing therapies for patients aged 12 years or older with severe sickle cell disease.

One therapy — exagamglogene autotemcel or exa-cel (Casgevy) — is the first to use CRISPR gene-editing technology, and could “provide a one-time functional cure to patients with sickle cell disease,” said Haydar Frangoul, MD, of The Children’s Hospital at TriStar Centennial, Nashville, Tennessee.

Dr. Frangoul, who presented a recent interim analysis on the therapy at the American Society of Hematology (ASH) annual meeting earlier this month, reported that one infusion of exa-cel prompted rapid increases in total hemoglobin levels and almost completely eliminated a common and painful complication of sickle cell disease that can lead to irreversible organ damage, known as vaso-occlusive crisis.

Overall, the gene therapy led to “a rapid, robust, and durable increase in total hemoglobin to normal or near normal levels,” Dr. Frangoul said.

Exa-cel, from Vertex Pharmaceuticals and CRISPR Therapeutics, is a single-dose infusion containing a patient’s modified cells. First, a patient’s stem cells are harvested and then genetically modified to produce fetal hemoglobin. 

The development of exa-cel was “grounded in human genetics, which show that fetal hemoglobin can substitute for sickle hemoglobin,” Dr. Frangoul explained. Patients receive these edited cells, which then help restore normal hemoglobin production.

The analysis showed that a one-time infusion of exa-cel following myeloablative conditioning prevented vaso-occlusive crisis in all but one patient with severe sickle cell disease. The therapy also prevented inpatient hospitalizations for vaso-occlusive crisis in all patients and led to sustained improvements in quality of life.

The results are “really striking,” said Sarah H. O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, who was not involved in the research. “The majority of our admissions on the hematology service are our patients with sickle cell. They’re uncomfortable, they’re in pain, they’re missing school, and they’re missing their activities,” which makes these interim findings quite “impactful.”

To examine the impact of exa-cel on vaso-occlusive crisis, the phase 3 trial included individuals aged 12 to 35 years with severe sickle cell disease and a history of at least two vaso-occlusive crises per year over the past 2 years.

Participants underwent cell CD34+ stem cell collection. These cells then underwent gene editing using CRISPR technology, explained Dr. Frangoul.

At the transplant center, patients received myeloablative conditioning chemotherapy with busulfan for 4 days before receiving an exa-cel infusion.

At the data cutoff in June 2023, 44 patients had been enrolled, of whom 30 were available for efficacy analysis. The mean age at screening was 22.1 years, and almost half (46.7%) were female. Prior to study recruitment, patients had a mean of 3.9 vaso-occlusive crises per year and a mean of 2.7 inpatient hospitalizations per year for severe vaso-occlusive crisis.

All but one patient (96.7%) met the primary endpoint of freedom from severe vaso-occlusive crisis for at least 12 consecutive months. The mean duration of freedom from vaso-occlusive crisis was 22.4 months, ranging from 14.8 months to 45.5 months. Moreover, 28 of the 29 patients who remained crisis-free at 12 months did not have a further vaso-occlusive crisis throughout the rest of the follow-up period.

Dr. Frangoul noted that results were similar for both adults and adolescents.

Exa-cel also led to a significant increase in freedom from inpatient hospitalizations, with 100% of patients achieving that goal, as well as early and sustained increases in both total and fetal hemoglobin levels, suggesting a “long-term meaningful benefit” from the therapy.

All 44 patients experienced adverse events related to myeloablative conditioning with busulfan, but only 29.5% had events linked to exa-cel. The most common adverse events overall were nausea (70.5%), stomatitis (63.6%), vomiting (56.8%), and febrile neutropenia (54.5%).

In a separate poster presented at ASH, Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, Dr. Frangoul, and colleagues reported that exa-cel also led to better health-related quality of life. 

Patients showed “substantial improvements” in measures of quality of life, which included physical, emotional, social, and functional well-being as well as pain at a 6-month follow-up through year 2.

Typical outcomes studied in most trials are “emergency room visits and hospitalizations but what people may not appreciate as much is how much these patients are dealing with pain and discomfort at home,” Dr. O’Brien said. These recently reported quality-of-life metrics “are so key and really help us understand the impact” of this new therapy.

Dr. O’Brien noted, however, that “patients may be reluctant to undergo” this therapy because of the impact myeloablative conditioning has on fertility. That is why ongoing research on how stem cell transplants can be delivered “without impacting fertility is very important.”

It is “hard to know,” Dr. O’Brien explained, whether exa-cel will be a one-time treatment in practice, as many of the patients “already have end-organ damage from their disease.” 

To that end, Dr. Frangoul noted that patients who complete the current trial can enroll in one that will include 13 years of additional follow-up.

Finally, Dr. O’Brien cautioned, gene therapies such as exa-cel “are only going to apply to a small segment of the population” — patients with the most severe form of the disease. That’s why “it’s important that we still prioritize hydroxyurea [and] multidisciplinary care for patients with sickle cell disease,” she said.

The study was sponsored by Vertex Pharmaceuticals in collaboration with CRISPR Therapeutics. Dr. Frangoul declared relationships with Editas Medicine, Rocket Pharmaceuticals, Jazz Pharmaceuticals, Vertex Pharmaceuticals, CRISPR Therapeutics, Bluebird Bio, and others. Dr. Sharma declared relationships with Vertex Pharmaceuticals, CRISPR Therapeutics, and others. Other authors declare numerous financial relationships.

A version of this article appeared on Medscape.com.

Earlier this month, the U.S. Food and Drug Administration (FDA) approved two gene-editing therapies for patients aged 12 years or older with severe sickle cell disease.

One therapy — exagamglogene autotemcel or exa-cel (Casgevy) — is the first to use CRISPR gene-editing technology, and could “provide a one-time functional cure to patients with sickle cell disease,” said Haydar Frangoul, MD, of The Children’s Hospital at TriStar Centennial, Nashville, Tennessee.

Dr. Frangoul, who presented a recent interim analysis on the therapy at the American Society of Hematology (ASH) annual meeting earlier this month, reported that one infusion of exa-cel prompted rapid increases in total hemoglobin levels and almost completely eliminated a common and painful complication of sickle cell disease that can lead to irreversible organ damage, known as vaso-occlusive crisis.

Overall, the gene therapy led to “a rapid, robust, and durable increase in total hemoglobin to normal or near normal levels,” Dr. Frangoul said.

Exa-cel, from Vertex Pharmaceuticals and CRISPR Therapeutics, is a single-dose infusion containing a patient’s modified cells. First, a patient’s stem cells are harvested and then genetically modified to produce fetal hemoglobin. 

The development of exa-cel was “grounded in human genetics, which show that fetal hemoglobin can substitute for sickle hemoglobin,” Dr. Frangoul explained. Patients receive these edited cells, which then help restore normal hemoglobin production.

The analysis showed that a one-time infusion of exa-cel following myeloablative conditioning prevented vaso-occlusive crisis in all but one patient with severe sickle cell disease. The therapy also prevented inpatient hospitalizations for vaso-occlusive crisis in all patients and led to sustained improvements in quality of life.

The results are “really striking,” said Sarah H. O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, who was not involved in the research. “The majority of our admissions on the hematology service are our patients with sickle cell. They’re uncomfortable, they’re in pain, they’re missing school, and they’re missing their activities,” which makes these interim findings quite “impactful.”

To examine the impact of exa-cel on vaso-occlusive crisis, the phase 3 trial included individuals aged 12 to 35 years with severe sickle cell disease and a history of at least two vaso-occlusive crises per year over the past 2 years.

Participants underwent cell CD34+ stem cell collection. These cells then underwent gene editing using CRISPR technology, explained Dr. Frangoul.

At the transplant center, patients received myeloablative conditioning chemotherapy with busulfan for 4 days before receiving an exa-cel infusion.

At the data cutoff in June 2023, 44 patients had been enrolled, of whom 30 were available for efficacy analysis. The mean age at screening was 22.1 years, and almost half (46.7%) were female. Prior to study recruitment, patients had a mean of 3.9 vaso-occlusive crises per year and a mean of 2.7 inpatient hospitalizations per year for severe vaso-occlusive crisis.

All but one patient (96.7%) met the primary endpoint of freedom from severe vaso-occlusive crisis for at least 12 consecutive months. The mean duration of freedom from vaso-occlusive crisis was 22.4 months, ranging from 14.8 months to 45.5 months. Moreover, 28 of the 29 patients who remained crisis-free at 12 months did not have a further vaso-occlusive crisis throughout the rest of the follow-up period.

Dr. Frangoul noted that results were similar for both adults and adolescents.

Exa-cel also led to a significant increase in freedom from inpatient hospitalizations, with 100% of patients achieving that goal, as well as early and sustained increases in both total and fetal hemoglobin levels, suggesting a “long-term meaningful benefit” from the therapy.

All 44 patients experienced adverse events related to myeloablative conditioning with busulfan, but only 29.5% had events linked to exa-cel. The most common adverse events overall were nausea (70.5%), stomatitis (63.6%), vomiting (56.8%), and febrile neutropenia (54.5%).

In a separate poster presented at ASH, Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, Dr. Frangoul, and colleagues reported that exa-cel also led to better health-related quality of life. 

Patients showed “substantial improvements” in measures of quality of life, which included physical, emotional, social, and functional well-being as well as pain at a 6-month follow-up through year 2.

Typical outcomes studied in most trials are “emergency room visits and hospitalizations but what people may not appreciate as much is how much these patients are dealing with pain and discomfort at home,” Dr. O’Brien said. These recently reported quality-of-life metrics “are so key and really help us understand the impact” of this new therapy.

Dr. O’Brien noted, however, that “patients may be reluctant to undergo” this therapy because of the impact myeloablative conditioning has on fertility. That is why ongoing research on how stem cell transplants can be delivered “without impacting fertility is very important.”

It is “hard to know,” Dr. O’Brien explained, whether exa-cel will be a one-time treatment in practice, as many of the patients “already have end-organ damage from their disease.” 

To that end, Dr. Frangoul noted that patients who complete the current trial can enroll in one that will include 13 years of additional follow-up.

Finally, Dr. O’Brien cautioned, gene therapies such as exa-cel “are only going to apply to a small segment of the population” — patients with the most severe form of the disease. That’s why “it’s important that we still prioritize hydroxyurea [and] multidisciplinary care for patients with sickle cell disease,” she said.

The study was sponsored by Vertex Pharmaceuticals in collaboration with CRISPR Therapeutics. Dr. Frangoul declared relationships with Editas Medicine, Rocket Pharmaceuticals, Jazz Pharmaceuticals, Vertex Pharmaceuticals, CRISPR Therapeutics, Bluebird Bio, and others. Dr. Sharma declared relationships with Vertex Pharmaceuticals, CRISPR Therapeutics, and others. Other authors declare numerous financial relationships.

A version of this article appeared on Medscape.com.

Earlier this month, the U.S. Food and Drug Administration (FDA) approved two gene-editing therapies for patients aged 12 years or older with severe sickle cell disease.

One therapy — exagamglogene autotemcel or exa-cel (Casgevy) — is the first to use CRISPR gene-editing technology, and could “provide a one-time functional cure to patients with sickle cell disease,” said Haydar Frangoul, MD, of The Children’s Hospital at TriStar Centennial, Nashville, Tennessee.

Dr. Frangoul, who presented a recent interim analysis on the therapy at the American Society of Hematology (ASH) annual meeting earlier this month, reported that one infusion of exa-cel prompted rapid increases in total hemoglobin levels and almost completely eliminated a common and painful complication of sickle cell disease that can lead to irreversible organ damage, known as vaso-occlusive crisis.

Overall, the gene therapy led to “a rapid, robust, and durable increase in total hemoglobin to normal or near normal levels,” Dr. Frangoul said.

Exa-cel, from Vertex Pharmaceuticals and CRISPR Therapeutics, is a single-dose infusion containing a patient’s modified cells. First, a patient’s stem cells are harvested and then genetically modified to produce fetal hemoglobin. 

The development of exa-cel was “grounded in human genetics, which show that fetal hemoglobin can substitute for sickle hemoglobin,” Dr. Frangoul explained. Patients receive these edited cells, which then help restore normal hemoglobin production.

The analysis showed that a one-time infusion of exa-cel following myeloablative conditioning prevented vaso-occlusive crisis in all but one patient with severe sickle cell disease. The therapy also prevented inpatient hospitalizations for vaso-occlusive crisis in all patients and led to sustained improvements in quality of life.

The results are “really striking,” said Sarah H. O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, who was not involved in the research. “The majority of our admissions on the hematology service are our patients with sickle cell. They’re uncomfortable, they’re in pain, they’re missing school, and they’re missing their activities,” which makes these interim findings quite “impactful.”

To examine the impact of exa-cel on vaso-occlusive crisis, the phase 3 trial included individuals aged 12 to 35 years with severe sickle cell disease and a history of at least two vaso-occlusive crises per year over the past 2 years.

Participants underwent cell CD34+ stem cell collection. These cells then underwent gene editing using CRISPR technology, explained Dr. Frangoul.

At the transplant center, patients received myeloablative conditioning chemotherapy with busulfan for 4 days before receiving an exa-cel infusion.

At the data cutoff in June 2023, 44 patients had been enrolled, of whom 30 were available for efficacy analysis. The mean age at screening was 22.1 years, and almost half (46.7%) were female. Prior to study recruitment, patients had a mean of 3.9 vaso-occlusive crises per year and a mean of 2.7 inpatient hospitalizations per year for severe vaso-occlusive crisis.

All but one patient (96.7%) met the primary endpoint of freedom from severe vaso-occlusive crisis for at least 12 consecutive months. The mean duration of freedom from vaso-occlusive crisis was 22.4 months, ranging from 14.8 months to 45.5 months. Moreover, 28 of the 29 patients who remained crisis-free at 12 months did not have a further vaso-occlusive crisis throughout the rest of the follow-up period.

Dr. Frangoul noted that results were similar for both adults and adolescents.

Exa-cel also led to a significant increase in freedom from inpatient hospitalizations, with 100% of patients achieving that goal, as well as early and sustained increases in both total and fetal hemoglobin levels, suggesting a “long-term meaningful benefit” from the therapy.

All 44 patients experienced adverse events related to myeloablative conditioning with busulfan, but only 29.5% had events linked to exa-cel. The most common adverse events overall were nausea (70.5%), stomatitis (63.6%), vomiting (56.8%), and febrile neutropenia (54.5%).

In a separate poster presented at ASH, Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, Dr. Frangoul, and colleagues reported that exa-cel also led to better health-related quality of life. 

Patients showed “substantial improvements” in measures of quality of life, which included physical, emotional, social, and functional well-being as well as pain at a 6-month follow-up through year 2.

Typical outcomes studied in most trials are “emergency room visits and hospitalizations but what people may not appreciate as much is how much these patients are dealing with pain and discomfort at home,” Dr. O’Brien said. These recently reported quality-of-life metrics “are so key and really help us understand the impact” of this new therapy.

Dr. O’Brien noted, however, that “patients may be reluctant to undergo” this therapy because of the impact myeloablative conditioning has on fertility. That is why ongoing research on how stem cell transplants can be delivered “without impacting fertility is very important.”

It is “hard to know,” Dr. O’Brien explained, whether exa-cel will be a one-time treatment in practice, as many of the patients “already have end-organ damage from their disease.” 

To that end, Dr. Frangoul noted that patients who complete the current trial can enroll in one that will include 13 years of additional follow-up.

Finally, Dr. O’Brien cautioned, gene therapies such as exa-cel “are only going to apply to a small segment of the population” — patients with the most severe form of the disease. That’s why “it’s important that we still prioritize hydroxyurea [and] multidisciplinary care for patients with sickle cell disease,” she said.

The study was sponsored by Vertex Pharmaceuticals in collaboration with CRISPR Therapeutics. Dr. Frangoul declared relationships with Editas Medicine, Rocket Pharmaceuticals, Jazz Pharmaceuticals, Vertex Pharmaceuticals, CRISPR Therapeutics, Bluebird Bio, and others. Dr. Sharma declared relationships with Vertex Pharmaceuticals, CRISPR Therapeutics, and others. Other authors declare numerous financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO — A newly approved gene therapy product for sickle cell disease, lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia), led to durable disease remissions for up to 5 years and almost complete elimination of dangerous and debilitating vaso-occlusive events, according to results of a long-term follow-up study.

More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.

“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added. 

For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
 

One and Done

Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US. 

People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events. 

On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.

Both are one-time, single-dose cell-based gene therapies.

With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.

Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel. 

All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months. 

Most patients achieved a durable globin response through their final follow-up visit.

Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events. 

In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.

Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.

Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke. 

One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.

To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.

However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”

The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio. 

A version of this article appeared on Medscape.com.

SAN DIEGO — A newly approved gene therapy product for sickle cell disease, lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia), led to durable disease remissions for up to 5 years and almost complete elimination of dangerous and debilitating vaso-occlusive events, according to results of a long-term follow-up study.

More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.

“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added. 

For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
 

One and Done

Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US. 

People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events. 

On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.

Both are one-time, single-dose cell-based gene therapies.

With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.

Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel. 

All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months. 

Most patients achieved a durable globin response through their final follow-up visit.

Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events. 

In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.

Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.

Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke. 

One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.

To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.

However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”

The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio. 

A version of this article appeared on Medscape.com.

SAN DIEGO — A newly approved gene therapy product for sickle cell disease, lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia), led to durable disease remissions for up to 5 years and almost complete elimination of dangerous and debilitating vaso-occlusive events, according to results of a long-term follow-up study.

More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.

“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added. 

For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
 

One and Done

Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US. 

People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events. 

On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.

Both are one-time, single-dose cell-based gene therapies.

With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.

Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel. 

All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months. 

Most patients achieved a durable globin response through their final follow-up visit.

Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events. 

In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.

Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.

Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke. 

One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.

To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.

However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”

The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio. 

A version of this article appeared on Medscape.com.

SAN DIEGO — A polygenic score can link outcomes in Black pediatric patients with acute myeloid leukemia (AML) to genetic traits that arise more frequently in this population, new data reveal. 

The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.

In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide. 

The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine. 

The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.

This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH. 

The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday. 

Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity. 

In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML. 

The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine. 

Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.

Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%). 

Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24). 

However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away. 

Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).

“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.

In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.

No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable.. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — A polygenic score can link outcomes in Black pediatric patients with acute myeloid leukemia (AML) to genetic traits that arise more frequently in this population, new data reveal. 

The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.

In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide. 

The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine. 

The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.

This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH. 

The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday. 

Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity. 

In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML. 

The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine. 

Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.

Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%). 

Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24). 

However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away. 

Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).

“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.

In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.

No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable.. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — A polygenic score can link outcomes in Black pediatric patients with acute myeloid leukemia (AML) to genetic traits that arise more frequently in this population, new data reveal. 

The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.

In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide. 

The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine. 

The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.

This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH. 

The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday. 

Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity. 

In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML. 

The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine. 

Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.

Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%). 

Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24). 

However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away. 

Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).

“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.

In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.

No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable.. 
 

A version of this article appeared on Medscape.com.