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FDA updates risks, cautions for clotting-bleeding disorder on Janssen COVID-19 vaccine
Updated Janssen/Johnson & Johnson COVID-19 vaccine fact sheets for health care professionals and the general public now include a contraindication to its use in persons with a history of thrombosis with thrombocytopenia after receiving it “or any other adenovirus-vectored COVID-19 vaccine,” the U.S. Food and Drug Administration has announced.
Thrombosis with thrombocytopenia syndrome (TTS) – thrombocytopenia and increased bleeding risk along with documented thrombosis – after administration of the Janssen Ad26.COV2.S vaccine remains rare. But over all age groups, about one in seven cases have been fatal, said the agency.
the provider fact sheet states.
Although TTS associated with the Janssen COVID-19 vaccine has been reported in men and women aged 18 and older, the highest reported rate has been for women aged 30-49, the agency states. The rate in that group has been about 1 case per 100,000 doses administered.
Symptoms of TTS may occur 1-2 weeks after administration of the Janssen COVID-19 vaccine, the FDA says, based on data from the Vaccine Adverse Events Reporting System (VAERS).
Its clinical course shares features with autoimmune heparin-induced thrombocytopenia. In individuals with suspected TTS following receipt of the Janssen COVID-19 vaccine, the agency cautions, the use of heparin “may be harmful and alternative treatments may be needed. Consultation with hematology specialists is strongly recommended.”
The apparent excess risk of TTS remains under investigation, but “the FDA continues to find that the known and potential benefits of the Janssen COVID-19 vaccine outweigh its known and potential risks in individuals 18 years of age and older,” the agency states.
A version of this article first appeared on Medscape.com.
Updated Janssen/Johnson & Johnson COVID-19 vaccine fact sheets for health care professionals and the general public now include a contraindication to its use in persons with a history of thrombosis with thrombocytopenia after receiving it “or any other adenovirus-vectored COVID-19 vaccine,” the U.S. Food and Drug Administration has announced.
Thrombosis with thrombocytopenia syndrome (TTS) – thrombocytopenia and increased bleeding risk along with documented thrombosis – after administration of the Janssen Ad26.COV2.S vaccine remains rare. But over all age groups, about one in seven cases have been fatal, said the agency.
the provider fact sheet states.
Although TTS associated with the Janssen COVID-19 vaccine has been reported in men and women aged 18 and older, the highest reported rate has been for women aged 30-49, the agency states. The rate in that group has been about 1 case per 100,000 doses administered.
Symptoms of TTS may occur 1-2 weeks after administration of the Janssen COVID-19 vaccine, the FDA says, based on data from the Vaccine Adverse Events Reporting System (VAERS).
Its clinical course shares features with autoimmune heparin-induced thrombocytopenia. In individuals with suspected TTS following receipt of the Janssen COVID-19 vaccine, the agency cautions, the use of heparin “may be harmful and alternative treatments may be needed. Consultation with hematology specialists is strongly recommended.”
The apparent excess risk of TTS remains under investigation, but “the FDA continues to find that the known and potential benefits of the Janssen COVID-19 vaccine outweigh its known and potential risks in individuals 18 years of age and older,” the agency states.
A version of this article first appeared on Medscape.com.
Updated Janssen/Johnson & Johnson COVID-19 vaccine fact sheets for health care professionals and the general public now include a contraindication to its use in persons with a history of thrombosis with thrombocytopenia after receiving it “or any other adenovirus-vectored COVID-19 vaccine,” the U.S. Food and Drug Administration has announced.
Thrombosis with thrombocytopenia syndrome (TTS) – thrombocytopenia and increased bleeding risk along with documented thrombosis – after administration of the Janssen Ad26.COV2.S vaccine remains rare. But over all age groups, about one in seven cases have been fatal, said the agency.
the provider fact sheet states.
Although TTS associated with the Janssen COVID-19 vaccine has been reported in men and women aged 18 and older, the highest reported rate has been for women aged 30-49, the agency states. The rate in that group has been about 1 case per 100,000 doses administered.
Symptoms of TTS may occur 1-2 weeks after administration of the Janssen COVID-19 vaccine, the FDA says, based on data from the Vaccine Adverse Events Reporting System (VAERS).
Its clinical course shares features with autoimmune heparin-induced thrombocytopenia. In individuals with suspected TTS following receipt of the Janssen COVID-19 vaccine, the agency cautions, the use of heparin “may be harmful and alternative treatments may be needed. Consultation with hematology specialists is strongly recommended.”
The apparent excess risk of TTS remains under investigation, but “the FDA continues to find that the known and potential benefits of the Janssen COVID-19 vaccine outweigh its known and potential risks in individuals 18 years of age and older,” the agency states.
A version of this article first appeared on Medscape.com.
Even COVID-19 can’t stop a true optimist
Squeezing a little lemonade out of COVID-19
We like to think of ourselves as optimists here at LOTME. A glass is half full, the sky is partly sunny, and our motto is “Always look on the bright side of insanity.” Then again, our motto before that was “LOTME: Where science meets stupid,” so what do we know?
Anyway, it’s that upbeat, can-do attitude that allows us to say something positive – two somethings, actually – about the insanity that is COVID-19.
Our journey to the bright side begins, oddly enough, in the courtroom. Seems that our old friend, the face mask, is something of a lie-detector aid for juries. The authors of a recent literature review of studies on deception “found that facial expressions and other forms of nonverbal behaviour are an unreliable indicator of deceit,” according to a statement from the University of Portsmouth, where the analysis was conducted.
The one study that directly examined the role of face coverings in court proceedings showed that, “by taking away the distraction of nonverbal behaviours, observers had to rely on speech content, which turned out to be better for detecting lies,” the university said.
The second stage of our positivity trek brings us to the National Trends in Disability Employment monthly update, where we see a fourth consecutive month of gains for people with disabilities despite the larger trend of declines among those without disabilities.
Here are some numbers from the Kessler Foundation and the University of New Hampshire’s Institute on Disability to tell the story: From October to November, the employment-to-population ratio increased 4.2% for working-age people with disabilities, compared with 0.4% for people without disabilities. At the same time, the labor force participation rate rose 2.4% for working-age people with disabilities and just 0.1% for working-age people without disabilities.
Both indicators surpassed their historic highs, Andrew Houtenville, PhD, director of the Institute on Disability, said in the update. “These gains suggest that the restructuring resulting from the pandemic may be benefiting people with disabilities. Ironically, it may have taken a pandemic to shake the labor market loose for people with disabilities.”
And that is how a world-class optimist turns one gigantic lemon into lemonade.
Cut the cheese for better sleep
So, we’ve already talked about the TikTok lettuce tea hack that’s supposed to help us sleep better. Well, there’s another food that could have the opposite effect.
According to an article from the BBC, cheese has something of a reputation. Ever since the 1960s, when a researcher noted that one patient’s nightmares stopped after he quit eating an ounce or two of cheddar each night, there’s been speculation that cheese gives you weird dreams. Another study in 2005 suggested certain types of cheese cause certain types of dreams. Blue cheese for vivid dreams and cheddar cheese for celebrity cameos.
But is there any truth to it at all?
Regardless of what we eat, going to bed hungry could cause vivid dreams, according to research by Tore Nielsen, director of the University of Montreal’s dream and nightmare lab. The 2015 study showed that high lactose could have an effect on dreams.
In that study, 17% of participants said their dreams were influenced by what they ate, but the kicker was that dairy products were the foods most reported as causing the weird dreams, the BBC noted.
“It’s likely an indirect effect in that lactose produces symptoms like gas, bloating and diarrhoea and influences dreams, as dreams draw on somatic sources like this. And if you have certain kinds of intolerances, you still may be likely to eat those foods sometimes,” Mr. Nielsen told the BBC.
There’s also the theory that it’s all in the timing of consumption. Are you the type of person to sneak a slice of cheese from the fridge late at night? (Nods.) Same.
“One reason cheese and nightmares come about is that eating later before bed is more likely to disrupt sleep, and cheese can be hard to digest,” said Charlotte Gupta, a research fellow at Central Queensland University in Australia and a coauthor of a 2020 review on how diet affects our sleep.
So as tempting as it is, maybe skip sprinkling Parmesan cheese shreds into your mouth at the open fridge before bed.
Teeing up against Parkinson’s
For the nearly 1 million people in the United States with Parkinson’s disease, tai chi is one of the best ways to alleviate the symptoms. The average Parkinson’s patient, however, is going to be on the older side and more likely to view the martial art as some sort of communist plot. And would you participate in a communist plot? We don’t think so.
One group of researchers saw that patients weren’t keeping up with their therapy and decided to try a different activity, something that older people would be more likely to stick with. Something a bit more stereotypical. No, not shuffleboard. They tried golf.
“Golf is popular – the most popular sport for people over the age of 55 – which might encourage people to try it and stick with it,” study author Anne-Marie A. Wills, MD, of Massachusetts General Hospital, Boston, said in a Study Finds report.
In a small study, the investigators had a group of patients with Parkinson’s regularly go to a driving range for 10 weeks to hit golf balls (all expenses paid too, and that’s a big deal for golf), while another group continued with their tai chi.
At the end of the study, the 8 patients who went to the driving range had significantly better results in a Parkinson’s mobility test than those of the 12 patients in the tai chi group. In addition, the golf-group participants said they were more likely to continue with their therapy than were those who did tai chi.
Despite the small size of the study, the research team said the results certainly warrant further research. After all, the best sort of therapy is the kind that actually gets done. And golf just gets in your head. The eternal quest to add distance, to straighten out that annoying slice, to stop thinning half your chips, to make those annoying 4-footers. ... Maybe that’s just us.
Squeezing a little lemonade out of COVID-19
We like to think of ourselves as optimists here at LOTME. A glass is half full, the sky is partly sunny, and our motto is “Always look on the bright side of insanity.” Then again, our motto before that was “LOTME: Where science meets stupid,” so what do we know?
Anyway, it’s that upbeat, can-do attitude that allows us to say something positive – two somethings, actually – about the insanity that is COVID-19.
Our journey to the bright side begins, oddly enough, in the courtroom. Seems that our old friend, the face mask, is something of a lie-detector aid for juries. The authors of a recent literature review of studies on deception “found that facial expressions and other forms of nonverbal behaviour are an unreliable indicator of deceit,” according to a statement from the University of Portsmouth, where the analysis was conducted.
The one study that directly examined the role of face coverings in court proceedings showed that, “by taking away the distraction of nonverbal behaviours, observers had to rely on speech content, which turned out to be better for detecting lies,” the university said.
The second stage of our positivity trek brings us to the National Trends in Disability Employment monthly update, where we see a fourth consecutive month of gains for people with disabilities despite the larger trend of declines among those without disabilities.
Here are some numbers from the Kessler Foundation and the University of New Hampshire’s Institute on Disability to tell the story: From October to November, the employment-to-population ratio increased 4.2% for working-age people with disabilities, compared with 0.4% for people without disabilities. At the same time, the labor force participation rate rose 2.4% for working-age people with disabilities and just 0.1% for working-age people without disabilities.
Both indicators surpassed their historic highs, Andrew Houtenville, PhD, director of the Institute on Disability, said in the update. “These gains suggest that the restructuring resulting from the pandemic may be benefiting people with disabilities. Ironically, it may have taken a pandemic to shake the labor market loose for people with disabilities.”
And that is how a world-class optimist turns one gigantic lemon into lemonade.
Cut the cheese for better sleep
So, we’ve already talked about the TikTok lettuce tea hack that’s supposed to help us sleep better. Well, there’s another food that could have the opposite effect.
According to an article from the BBC, cheese has something of a reputation. Ever since the 1960s, when a researcher noted that one patient’s nightmares stopped after he quit eating an ounce or two of cheddar each night, there’s been speculation that cheese gives you weird dreams. Another study in 2005 suggested certain types of cheese cause certain types of dreams. Blue cheese for vivid dreams and cheddar cheese for celebrity cameos.
But is there any truth to it at all?
Regardless of what we eat, going to bed hungry could cause vivid dreams, according to research by Tore Nielsen, director of the University of Montreal’s dream and nightmare lab. The 2015 study showed that high lactose could have an effect on dreams.
In that study, 17% of participants said their dreams were influenced by what they ate, but the kicker was that dairy products were the foods most reported as causing the weird dreams, the BBC noted.
“It’s likely an indirect effect in that lactose produces symptoms like gas, bloating and diarrhoea and influences dreams, as dreams draw on somatic sources like this. And if you have certain kinds of intolerances, you still may be likely to eat those foods sometimes,” Mr. Nielsen told the BBC.
There’s also the theory that it’s all in the timing of consumption. Are you the type of person to sneak a slice of cheese from the fridge late at night? (Nods.) Same.
“One reason cheese and nightmares come about is that eating later before bed is more likely to disrupt sleep, and cheese can be hard to digest,” said Charlotte Gupta, a research fellow at Central Queensland University in Australia and a coauthor of a 2020 review on how diet affects our sleep.
So as tempting as it is, maybe skip sprinkling Parmesan cheese shreds into your mouth at the open fridge before bed.
Teeing up against Parkinson’s
For the nearly 1 million people in the United States with Parkinson’s disease, tai chi is one of the best ways to alleviate the symptoms. The average Parkinson’s patient, however, is going to be on the older side and more likely to view the martial art as some sort of communist plot. And would you participate in a communist plot? We don’t think so.
One group of researchers saw that patients weren’t keeping up with their therapy and decided to try a different activity, something that older people would be more likely to stick with. Something a bit more stereotypical. No, not shuffleboard. They tried golf.
“Golf is popular – the most popular sport for people over the age of 55 – which might encourage people to try it and stick with it,” study author Anne-Marie A. Wills, MD, of Massachusetts General Hospital, Boston, said in a Study Finds report.
In a small study, the investigators had a group of patients with Parkinson’s regularly go to a driving range for 10 weeks to hit golf balls (all expenses paid too, and that’s a big deal for golf), while another group continued with their tai chi.
At the end of the study, the 8 patients who went to the driving range had significantly better results in a Parkinson’s mobility test than those of the 12 patients in the tai chi group. In addition, the golf-group participants said they were more likely to continue with their therapy than were those who did tai chi.
Despite the small size of the study, the research team said the results certainly warrant further research. After all, the best sort of therapy is the kind that actually gets done. And golf just gets in your head. The eternal quest to add distance, to straighten out that annoying slice, to stop thinning half your chips, to make those annoying 4-footers. ... Maybe that’s just us.
Squeezing a little lemonade out of COVID-19
We like to think of ourselves as optimists here at LOTME. A glass is half full, the sky is partly sunny, and our motto is “Always look on the bright side of insanity.” Then again, our motto before that was “LOTME: Where science meets stupid,” so what do we know?
Anyway, it’s that upbeat, can-do attitude that allows us to say something positive – two somethings, actually – about the insanity that is COVID-19.
Our journey to the bright side begins, oddly enough, in the courtroom. Seems that our old friend, the face mask, is something of a lie-detector aid for juries. The authors of a recent literature review of studies on deception “found that facial expressions and other forms of nonverbal behaviour are an unreliable indicator of deceit,” according to a statement from the University of Portsmouth, where the analysis was conducted.
The one study that directly examined the role of face coverings in court proceedings showed that, “by taking away the distraction of nonverbal behaviours, observers had to rely on speech content, which turned out to be better for detecting lies,” the university said.
The second stage of our positivity trek brings us to the National Trends in Disability Employment monthly update, where we see a fourth consecutive month of gains for people with disabilities despite the larger trend of declines among those without disabilities.
Here are some numbers from the Kessler Foundation and the University of New Hampshire’s Institute on Disability to tell the story: From October to November, the employment-to-population ratio increased 4.2% for working-age people with disabilities, compared with 0.4% for people without disabilities. At the same time, the labor force participation rate rose 2.4% for working-age people with disabilities and just 0.1% for working-age people without disabilities.
Both indicators surpassed their historic highs, Andrew Houtenville, PhD, director of the Institute on Disability, said in the update. “These gains suggest that the restructuring resulting from the pandemic may be benefiting people with disabilities. Ironically, it may have taken a pandemic to shake the labor market loose for people with disabilities.”
And that is how a world-class optimist turns one gigantic lemon into lemonade.
Cut the cheese for better sleep
So, we’ve already talked about the TikTok lettuce tea hack that’s supposed to help us sleep better. Well, there’s another food that could have the opposite effect.
According to an article from the BBC, cheese has something of a reputation. Ever since the 1960s, when a researcher noted that one patient’s nightmares stopped after he quit eating an ounce or two of cheddar each night, there’s been speculation that cheese gives you weird dreams. Another study in 2005 suggested certain types of cheese cause certain types of dreams. Blue cheese for vivid dreams and cheddar cheese for celebrity cameos.
But is there any truth to it at all?
Regardless of what we eat, going to bed hungry could cause vivid dreams, according to research by Tore Nielsen, director of the University of Montreal’s dream and nightmare lab. The 2015 study showed that high lactose could have an effect on dreams.
In that study, 17% of participants said their dreams were influenced by what they ate, but the kicker was that dairy products were the foods most reported as causing the weird dreams, the BBC noted.
“It’s likely an indirect effect in that lactose produces symptoms like gas, bloating and diarrhoea and influences dreams, as dreams draw on somatic sources like this. And if you have certain kinds of intolerances, you still may be likely to eat those foods sometimes,” Mr. Nielsen told the BBC.
There’s also the theory that it’s all in the timing of consumption. Are you the type of person to sneak a slice of cheese from the fridge late at night? (Nods.) Same.
“One reason cheese and nightmares come about is that eating later before bed is more likely to disrupt sleep, and cheese can be hard to digest,” said Charlotte Gupta, a research fellow at Central Queensland University in Australia and a coauthor of a 2020 review on how diet affects our sleep.
So as tempting as it is, maybe skip sprinkling Parmesan cheese shreds into your mouth at the open fridge before bed.
Teeing up against Parkinson’s
For the nearly 1 million people in the United States with Parkinson’s disease, tai chi is one of the best ways to alleviate the symptoms. The average Parkinson’s patient, however, is going to be on the older side and more likely to view the martial art as some sort of communist plot. And would you participate in a communist plot? We don’t think so.
One group of researchers saw that patients weren’t keeping up with their therapy and decided to try a different activity, something that older people would be more likely to stick with. Something a bit more stereotypical. No, not shuffleboard. They tried golf.
“Golf is popular – the most popular sport for people over the age of 55 – which might encourage people to try it and stick with it,” study author Anne-Marie A. Wills, MD, of Massachusetts General Hospital, Boston, said in a Study Finds report.
In a small study, the investigators had a group of patients with Parkinson’s regularly go to a driving range for 10 weeks to hit golf balls (all expenses paid too, and that’s a big deal for golf), while another group continued with their tai chi.
At the end of the study, the 8 patients who went to the driving range had significantly better results in a Parkinson’s mobility test than those of the 12 patients in the tai chi group. In addition, the golf-group participants said they were more likely to continue with their therapy than were those who did tai chi.
Despite the small size of the study, the research team said the results certainly warrant further research. After all, the best sort of therapy is the kind that actually gets done. And golf just gets in your head. The eternal quest to add distance, to straighten out that annoying slice, to stop thinning half your chips, to make those annoying 4-footers. ... Maybe that’s just us.
More Americans skipping medical care because of cost, survey says
That’s the highest reported number since the pandemic began and a tripling from March to October.
Even 20% of the country’s highest-income households – earning more than $120,000 per year – said they’ve also skipped care. That’s an increase of about seven times for higher-income families since March.
“Americans tend to think there is a group of lower-income people, and they have worse health care than the rest of us, and the rest of us, we’re okay,” Tim Lash, chief strategy officer for West Health, a nonprofit focused on lowering health care costs, told CBS News.
“What we are seeing now in this survey is this group of people who are identifying themselves as struggling with health care costs is growing,” he said.
As part of the 2021 Healthcare in America Report, researchers surveyed more than 6,000 people in September and October about their concerns and experiences with affording health care and treatment. About half of respondents said health care in America has gotten worse because of the pandemic, and more than half said they’re more worried about medical costs than before.
What’s more, many Americans put off routine doctor visits at the beginning of the pandemic, and now that they’re beginning to schedule appointments again, they’re facing major costs, the survey found. Some expenses have increased in the past year, including prescription medications.
The rising costs have led many people to skip care or treatment, which can have major consequences. About 1 in 20 adults said they know a friend or family member who died during the past year because they couldn’t afford medical care, the survey found. And about 20% of adults said they or someone in their household had a health issue that grew worse after postponing care because of price.
About 23% of survey respondents said that paying for health care represents a major financial burden, which increases to a third of respondents who earn less than $48,000 per year. Out-of-pocket costs such as deductibles and insurance premiums have increased, which have taken up larger portions of people’s budgets.
“We often overlook the side effect of costs, and it’s quite toxic – there is a financial toxicity that exists in health care,” Mr. Lash said. “We know when you skip treatment, that can have an impact on mortality.”
A version of this article first appeared on WebMD.com.
That’s the highest reported number since the pandemic began and a tripling from March to October.
Even 20% of the country’s highest-income households – earning more than $120,000 per year – said they’ve also skipped care. That’s an increase of about seven times for higher-income families since March.
“Americans tend to think there is a group of lower-income people, and they have worse health care than the rest of us, and the rest of us, we’re okay,” Tim Lash, chief strategy officer for West Health, a nonprofit focused on lowering health care costs, told CBS News.
“What we are seeing now in this survey is this group of people who are identifying themselves as struggling with health care costs is growing,” he said.
As part of the 2021 Healthcare in America Report, researchers surveyed more than 6,000 people in September and October about their concerns and experiences with affording health care and treatment. About half of respondents said health care in America has gotten worse because of the pandemic, and more than half said they’re more worried about medical costs than before.
What’s more, many Americans put off routine doctor visits at the beginning of the pandemic, and now that they’re beginning to schedule appointments again, they’re facing major costs, the survey found. Some expenses have increased in the past year, including prescription medications.
The rising costs have led many people to skip care or treatment, which can have major consequences. About 1 in 20 adults said they know a friend or family member who died during the past year because they couldn’t afford medical care, the survey found. And about 20% of adults said they or someone in their household had a health issue that grew worse after postponing care because of price.
About 23% of survey respondents said that paying for health care represents a major financial burden, which increases to a third of respondents who earn less than $48,000 per year. Out-of-pocket costs such as deductibles and insurance premiums have increased, which have taken up larger portions of people’s budgets.
“We often overlook the side effect of costs, and it’s quite toxic – there is a financial toxicity that exists in health care,” Mr. Lash said. “We know when you skip treatment, that can have an impact on mortality.”
A version of this article first appeared on WebMD.com.
That’s the highest reported number since the pandemic began and a tripling from March to October.
Even 20% of the country’s highest-income households – earning more than $120,000 per year – said they’ve also skipped care. That’s an increase of about seven times for higher-income families since March.
“Americans tend to think there is a group of lower-income people, and they have worse health care than the rest of us, and the rest of us, we’re okay,” Tim Lash, chief strategy officer for West Health, a nonprofit focused on lowering health care costs, told CBS News.
“What we are seeing now in this survey is this group of people who are identifying themselves as struggling with health care costs is growing,” he said.
As part of the 2021 Healthcare in America Report, researchers surveyed more than 6,000 people in September and October about their concerns and experiences with affording health care and treatment. About half of respondents said health care in America has gotten worse because of the pandemic, and more than half said they’re more worried about medical costs than before.
What’s more, many Americans put off routine doctor visits at the beginning of the pandemic, and now that they’re beginning to schedule appointments again, they’re facing major costs, the survey found. Some expenses have increased in the past year, including prescription medications.
The rising costs have led many people to skip care or treatment, which can have major consequences. About 1 in 20 adults said they know a friend or family member who died during the past year because they couldn’t afford medical care, the survey found. And about 20% of adults said they or someone in their household had a health issue that grew worse after postponing care because of price.
About 23% of survey respondents said that paying for health care represents a major financial burden, which increases to a third of respondents who earn less than $48,000 per year. Out-of-pocket costs such as deductibles and insurance premiums have increased, which have taken up larger portions of people’s budgets.
“We often overlook the side effect of costs, and it’s quite toxic – there is a financial toxicity that exists in health care,” Mr. Lash said. “We know when you skip treatment, that can have an impact on mortality.”
A version of this article first appeared on WebMD.com.
COVID-19 asymptomatic infection rate remains high
Based on data from a meta-analysis of 95 studies that included nearly 30,000,000 individuals, the pooled percentage of asymptomatic COVID-19 infections was 0.25% in the tested population and 40.5% among confirmed cases.
, wrote Qiuyue Ma, PhD, and colleagues of Peking University, Beijing.
In a study published in JAMA Network Open the researchers identified 44 cross-sectional studies, 41 cohort studies, seven case series, and three case series on transmission studies. A total of 74 studies were conducted in developed countries, including those in Europe, North America, and Asia. Approximately one-third (37) of the studies were conducted among health care workers or in-hospital patients, 17 among nursing home staff or residents, and 14 among community residents. In addition, 13 studies involved pregnant women, eight involved air or cruise ship travelers, and six involved close contacts of individuals with confirmed infections.
The meta-analysis included 29,776,306 tested individuals; 11,516 of them had asymptomatic infections.
Overall, the pooled percentage of asymptomatic infections among the tested population was 0.25%. In an analysis of different study populations, the percentage was higher in nursing home residents or staff (4.52%), air or cruise ship travelers (2.02%), and pregnant women (2.34%), compared against the pooled percentage.
The pooled percentage of asymptomatic infections among the confirmed population was 40.50%, and this percentage was higher in pregnant women (54.11%), air or cruise ship travelers (52.91%), and nursing home residents or staff (47.53%).
The pooled percentage in the tested population was higher than the overall percentage when the mean age of the study population was 60 years or older (3.69%). By contrast, in the confirmed population, the pooled percentage was higher than the overall percentage when the study population was younger than 20 years (60.2%) or aged 20 to 39 years (49.5%).
The researchers noted in their discussion that the varying percentage of asymptomatic individuals according to community prevalence might impact the heterogeneity of the included studies. They also noted the high number of studies conducted in nursing home populations, groups in which asymptomatic individuals were more likely to be tested.
The study findings were limited by several factors, including the potential for missed studies that were not published at the time of the meta-analysis, as well as the exclusion of studies written in Chinese, the researchers noted. Other limitations included lack of follow-up on presymptomatic and covert infections, and the focus on specific populations, factors that may limit the degree to which the results can be generalized.
However, the results highlight the need to screen for asymptomatic infections, especially in countries where COVID-19 has been better controlled, the researchers said. Management strategies for asymptomatic infections, when identified, should include isolation and contact tracing similar to strategies used with confirmed cases, they added.
More testing needed to catch cases early
“During the initial phase of [the] COVID-19 pandemic, testing was not widely available in the United States or the rest of the world,” Setu Patolia, MD, of Saint Louis University School of Medicine, Missouri, said in an interview. Much of the world still lacks access to COVID-19 testing, and early in the pandemic only severely symptomatic patients were tested, he said. “With new variants, particularly the Omicron variant, which may have mild or minimally symptomatic disease, asymptomatic carriers play an important role in propagation of the pandemic,” he explained. “It is important to know the asymptomatic carrier rate among the general population for the future control of [the] pandemic,” he added.
Dr. Patolia said he was surprised by the study finding that one in 400 people in the general population could be asymptomatic carriers of COVID-19.
“Also, nursing home patients are more at risk of complications of COVID, and I expected that they would have a higher rate of symptomatic disease as compared to [the] general population,” said Dr. Patolia. He was also surprised by the high rate of asymptomatic infections in travelers.
“Physicians should be more aware about the asymptomatic carrier rate, particularly in travelers and nursing home patients,” he noted. “Travelers carry high risk of transferring infection from one region to another region of the world, and physicians should advise them to get tested despite the absence of symptoms,” Dr. Patolia emphasized. “Similarly, once any nursing home patient has been diagnosed with COVID-19, physicians should be more careful with the rest of the nursing home patients and test them despite the absence of the symptoms,” he added.
Dr. Patolia also recommended that pregnant women wear masks to help prevent disease transmission when visiting a doctor’s office or labor unit.
Looking ahead, there is a need for cheaper at-home testing kits so that all vulnerable populations can be tested fast and frequently, Dr. Patolia said.
The study was supported by the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Patolia has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Based on data from a meta-analysis of 95 studies that included nearly 30,000,000 individuals, the pooled percentage of asymptomatic COVID-19 infections was 0.25% in the tested population and 40.5% among confirmed cases.
, wrote Qiuyue Ma, PhD, and colleagues of Peking University, Beijing.
In a study published in JAMA Network Open the researchers identified 44 cross-sectional studies, 41 cohort studies, seven case series, and three case series on transmission studies. A total of 74 studies were conducted in developed countries, including those in Europe, North America, and Asia. Approximately one-third (37) of the studies were conducted among health care workers or in-hospital patients, 17 among nursing home staff or residents, and 14 among community residents. In addition, 13 studies involved pregnant women, eight involved air or cruise ship travelers, and six involved close contacts of individuals with confirmed infections.
The meta-analysis included 29,776,306 tested individuals; 11,516 of them had asymptomatic infections.
Overall, the pooled percentage of asymptomatic infections among the tested population was 0.25%. In an analysis of different study populations, the percentage was higher in nursing home residents or staff (4.52%), air or cruise ship travelers (2.02%), and pregnant women (2.34%), compared against the pooled percentage.
The pooled percentage of asymptomatic infections among the confirmed population was 40.50%, and this percentage was higher in pregnant women (54.11%), air or cruise ship travelers (52.91%), and nursing home residents or staff (47.53%).
The pooled percentage in the tested population was higher than the overall percentage when the mean age of the study population was 60 years or older (3.69%). By contrast, in the confirmed population, the pooled percentage was higher than the overall percentage when the study population was younger than 20 years (60.2%) or aged 20 to 39 years (49.5%).
The researchers noted in their discussion that the varying percentage of asymptomatic individuals according to community prevalence might impact the heterogeneity of the included studies. They also noted the high number of studies conducted in nursing home populations, groups in which asymptomatic individuals were more likely to be tested.
The study findings were limited by several factors, including the potential for missed studies that were not published at the time of the meta-analysis, as well as the exclusion of studies written in Chinese, the researchers noted. Other limitations included lack of follow-up on presymptomatic and covert infections, and the focus on specific populations, factors that may limit the degree to which the results can be generalized.
However, the results highlight the need to screen for asymptomatic infections, especially in countries where COVID-19 has been better controlled, the researchers said. Management strategies for asymptomatic infections, when identified, should include isolation and contact tracing similar to strategies used with confirmed cases, they added.
More testing needed to catch cases early
“During the initial phase of [the] COVID-19 pandemic, testing was not widely available in the United States or the rest of the world,” Setu Patolia, MD, of Saint Louis University School of Medicine, Missouri, said in an interview. Much of the world still lacks access to COVID-19 testing, and early in the pandemic only severely symptomatic patients were tested, he said. “With new variants, particularly the Omicron variant, which may have mild or minimally symptomatic disease, asymptomatic carriers play an important role in propagation of the pandemic,” he explained. “It is important to know the asymptomatic carrier rate among the general population for the future control of [the] pandemic,” he added.
Dr. Patolia said he was surprised by the study finding that one in 400 people in the general population could be asymptomatic carriers of COVID-19.
“Also, nursing home patients are more at risk of complications of COVID, and I expected that they would have a higher rate of symptomatic disease as compared to [the] general population,” said Dr. Patolia. He was also surprised by the high rate of asymptomatic infections in travelers.
“Physicians should be more aware about the asymptomatic carrier rate, particularly in travelers and nursing home patients,” he noted. “Travelers carry high risk of transferring infection from one region to another region of the world, and physicians should advise them to get tested despite the absence of symptoms,” Dr. Patolia emphasized. “Similarly, once any nursing home patient has been diagnosed with COVID-19, physicians should be more careful with the rest of the nursing home patients and test them despite the absence of the symptoms,” he added.
Dr. Patolia also recommended that pregnant women wear masks to help prevent disease transmission when visiting a doctor’s office or labor unit.
Looking ahead, there is a need for cheaper at-home testing kits so that all vulnerable populations can be tested fast and frequently, Dr. Patolia said.
The study was supported by the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Patolia has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Based on data from a meta-analysis of 95 studies that included nearly 30,000,000 individuals, the pooled percentage of asymptomatic COVID-19 infections was 0.25% in the tested population and 40.5% among confirmed cases.
, wrote Qiuyue Ma, PhD, and colleagues of Peking University, Beijing.
In a study published in JAMA Network Open the researchers identified 44 cross-sectional studies, 41 cohort studies, seven case series, and three case series on transmission studies. A total of 74 studies were conducted in developed countries, including those in Europe, North America, and Asia. Approximately one-third (37) of the studies were conducted among health care workers or in-hospital patients, 17 among nursing home staff or residents, and 14 among community residents. In addition, 13 studies involved pregnant women, eight involved air or cruise ship travelers, and six involved close contacts of individuals with confirmed infections.
The meta-analysis included 29,776,306 tested individuals; 11,516 of them had asymptomatic infections.
Overall, the pooled percentage of asymptomatic infections among the tested population was 0.25%. In an analysis of different study populations, the percentage was higher in nursing home residents or staff (4.52%), air or cruise ship travelers (2.02%), and pregnant women (2.34%), compared against the pooled percentage.
The pooled percentage of asymptomatic infections among the confirmed population was 40.50%, and this percentage was higher in pregnant women (54.11%), air or cruise ship travelers (52.91%), and nursing home residents or staff (47.53%).
The pooled percentage in the tested population was higher than the overall percentage when the mean age of the study population was 60 years or older (3.69%). By contrast, in the confirmed population, the pooled percentage was higher than the overall percentage when the study population was younger than 20 years (60.2%) or aged 20 to 39 years (49.5%).
The researchers noted in their discussion that the varying percentage of asymptomatic individuals according to community prevalence might impact the heterogeneity of the included studies. They also noted the high number of studies conducted in nursing home populations, groups in which asymptomatic individuals were more likely to be tested.
The study findings were limited by several factors, including the potential for missed studies that were not published at the time of the meta-analysis, as well as the exclusion of studies written in Chinese, the researchers noted. Other limitations included lack of follow-up on presymptomatic and covert infections, and the focus on specific populations, factors that may limit the degree to which the results can be generalized.
However, the results highlight the need to screen for asymptomatic infections, especially in countries where COVID-19 has been better controlled, the researchers said. Management strategies for asymptomatic infections, when identified, should include isolation and contact tracing similar to strategies used with confirmed cases, they added.
More testing needed to catch cases early
“During the initial phase of [the] COVID-19 pandemic, testing was not widely available in the United States or the rest of the world,” Setu Patolia, MD, of Saint Louis University School of Medicine, Missouri, said in an interview. Much of the world still lacks access to COVID-19 testing, and early in the pandemic only severely symptomatic patients were tested, he said. “With new variants, particularly the Omicron variant, which may have mild or minimally symptomatic disease, asymptomatic carriers play an important role in propagation of the pandemic,” he explained. “It is important to know the asymptomatic carrier rate among the general population for the future control of [the] pandemic,” he added.
Dr. Patolia said he was surprised by the study finding that one in 400 people in the general population could be asymptomatic carriers of COVID-19.
“Also, nursing home patients are more at risk of complications of COVID, and I expected that they would have a higher rate of symptomatic disease as compared to [the] general population,” said Dr. Patolia. He was also surprised by the high rate of asymptomatic infections in travelers.
“Physicians should be more aware about the asymptomatic carrier rate, particularly in travelers and nursing home patients,” he noted. “Travelers carry high risk of transferring infection from one region to another region of the world, and physicians should advise them to get tested despite the absence of symptoms,” Dr. Patolia emphasized. “Similarly, once any nursing home patient has been diagnosed with COVID-19, physicians should be more careful with the rest of the nursing home patients and test them despite the absence of the symptoms,” he added.
Dr. Patolia also recommended that pregnant women wear masks to help prevent disease transmission when visiting a doctor’s office or labor unit.
Looking ahead, there is a need for cheaper at-home testing kits so that all vulnerable populations can be tested fast and frequently, Dr. Patolia said.
The study was supported by the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Patolia has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ASH studies look at racial disparities in ALL care, outcomes
Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.
When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.
However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.
Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.
Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.
However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.
“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.
Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.
Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.
Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.
Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.
Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.
When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.
However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.
Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.
Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.
However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.
“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.
Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.
Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.
Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.
Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.
Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.
When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.
However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.
Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.
Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.
However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.
“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.
Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.
Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.
Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.
Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.
FROM ASH 2021
NHL: As a second-line treatment in phase 3 trial, tisa-cel disappoints
according to results of a randomized, phase 3 trial.
The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.
Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.
Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.
“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.
Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.
The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.
About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.
The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.
“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”
Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.
The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.
While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.
In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.
Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.
“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.
There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.
“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.
In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.
Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m2 and 90 mg/m2, respectively.
Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.
Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.
according to results of a randomized, phase 3 trial.
The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.
Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.
Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.
“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.
Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.
The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.
About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.
The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.
“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”
Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.
The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.
While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.
In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.
Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.
“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.
There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.
“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.
In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.
Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m2 and 90 mg/m2, respectively.
Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.
Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.
according to results of a randomized, phase 3 trial.
The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.
Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.
Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.
“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.
Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.
The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.
About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.
The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.
“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”
Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.
The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.
While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.
In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.
Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.
“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.
There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.
“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.
In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.
Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m2 and 90 mg/m2, respectively.
Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.
Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.
FROM ASH 2021
TKI/BiTE combo extends survival of older patients with Ph+ALL
ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.
Now, results from an ongoing study suggest that the combination of the
The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).
Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.
At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.
“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.
“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
Early promise
A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.
“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.
“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.
“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.
Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.
“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
Study results
The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.
Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.
Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.
Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.
Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.
Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.
Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.
In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.
These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.
The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.
Now, results from an ongoing study suggest that the combination of the
The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).
Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.
At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.
“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.
“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
Early promise
A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.
“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.
“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.
“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.
Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.
“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
Study results
The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.
Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.
Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.
Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.
Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.
Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.
Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.
In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.
These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.
The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.
Now, results from an ongoing study suggest that the combination of the
The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).
Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.
At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.
“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.
“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
Early promise
A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.
“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.
“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.
“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.
Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.
“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
Study results
The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.
Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.
Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.
Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.
Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.
Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.
Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.
In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.
These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.
The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASH 2021
Meeting the unmet need in multiple myeloma
In multiple myeloma, survival has been very significantly improved by immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies. Despite these advances, multiple myeloma, which is characterized by malignant proliferation of clonal plasma cells in bone marrow, remains an incurable plasma cell disorder with near-certain relapse after successful treatment. Prognosis for patients who develop triple-class refractory disease is poor, with less than 1-year survival. The substantial unmet therapeutic need extends further to other poor survival multiple myeloma populations that include newly diagnosed patients with high cytogenic risk profiles and those with early relapse after first-line therapy. For all of these, interest in drugs with novel mechanisms of action is naturally high.
More specific, less toxic
Post allogeneic hematopoietic stem-cell transplantation and donor lymphocyte infusion sustained remissions reflect a graft-versus-myeloma effect mediated by donor T cells.1 The substantial morbidity and mortality associated with graft-versus-host disease and opportunistic infections, however, have spurred searches for alternative, more specific, and less toxic T-cell therapies with stronger antitumor activity.
Chimeric antigen receptors (CARs)
In CAR T-cell therapies for multiple myeloma, autologous T cells are harvested from the patient and reprogrammed to target multiple myeloma cells through the introduction of genes that encode CARs, which are fusion proteins coupling an antigen-recognition moiety and a transmembrane-spanning element to a T-cell activation domain (typically CD3 zeta [CD247]). The T cells are then expanded and reinfused to the patient following a lymphodepletion regimen. Five strategies using autologous CAR T cells are currently approved for diffuse large B-cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies. Notably, in patients with heavily pretreated multiple myeloma, CAR T cells have demonstrated impressive activity.
BCMA-targeting CAR T cells
The B-cell maturation antigen (BCMA; TNFRSF17), which plays an important role in the survival of long-lived plasma cells in bone marrow, is an attractive target for CAR T-cell therapy because it is expressed on normal and malignant plasma cell surfaces and by mature B cells. When ligands (TNFSF 13B/TNFSF13) bind to BCMA expressed on multiple myeloma cell surfaces, survival and proliferation pathways and drug resistance are activated.
High-quality responses have been demonstrated in several trials of anti-BCMA CAR T cells, which kill multiple myeloma cell lines and primary multiple myeloma cells through degranulation of T cells and lysis of tumor cells, even those with low BCMA expression. Based on efficacy in triple-class exposed multiple myeloma that compared favorably to conventional care with improved health-related quality of life, the U.S. Food and Drug Administration gave breakthrough designation to ciltacabtagene autoleucel in December 2019 and approval for idecabtagene vicleucel in March 2021.
Idecabtagene vicleucel
Idecabtagene vicleucel expresses a murine BCMA-targeting single-chain variable fragment with a 4-1BB costimulatory motif. The phase 2 KarMMa study2 evaluated idecabtagene vicleucel (target dose of 450 × 106 CAR T cells; range 150 × 106 to 450 × 106) activity in 128 patients with triple-class exposed multiple myeloma. Partial responses or better were observed in 94 of 128 patients (73%) (95% confidence interval, 66-81); 42 (33%) had a complete response or better (95% CI, 25-41), with a median progression-free survival of 8.8 months (95% CI, 5.6-11.6). Outcomes were improved in the highest fixed-dose group, with partial response or better in 81% (44 of 55), complete response or better in 39% (21), and median overall survival of 12.1 months (95% CI, 8.8-12.3). Patients with high-risk cytogenetic profiles, extramedullary disease, and high tumor burden also had deep and durable responses. Outcomes were less favorable in patients with revised International Staging System stage 3 disease.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel, a 4-1BB–based CAR T-cell therapy with two BCMA-targeting domains, confers high-avidity binding. In the phase 1b/2 CARTITUDE-1 study, conducted in the United States and Europe, preliminary results in 97 patients showed a 97% response rate with ciltacabtagene autoleucel (target dose 0.75 × 106 CAR T cells per kg), and in 65 patients, a complete response (67%). Progression-free survival at 12 months was 77% (95% CI, 66-84) and overall survival was 89% (95% CI, 80-94).3
In the phase 1 LEGEND-2 study4 that was conducted at four sites in China among less heavily pretreated multiple myeloma patients, while all used the same CAR construct, sites used variable conditioning regimens (split versus single). In the site using cyclophosphamide as the lymphodepletion therapy and three split CAR T-cell infusions, partial response or better was achieved in 50 patients (88%) with a median of three prior therapy lines. The complete response rate was high (74%) and minimal residual disease negativity was reached in 39 patients (68%). Median progression-free survival was 19.9 months (95% CI, 9.6-31.0), but 28.2 months among those with complete responses (95% CI, 19.9-not estimable). Median overall survival was also favorable at 36.1 months (95% CI, 26.4-not estimable); it was 35.0 months-not estimable among patients with complete responses. Results from the other three sites were comparable.
Noteworthy among other BCMA-targeting CAR T-cell products in earlier stages of clinical development is orvacabtagene autoleucel, which has a fully human BCMA-specific binding domain. At higher doses (300 × 106 to 600 × 106 CAR T cells) among 62 patients with triple-class–exposed multiple myeloma in the EVOLVE trial, 92% had a partial or better response, with complete responses or better in 36%, all with an encouraging safety profile.
BCMA-targeting CAR T cell toxicity
While van de Donk, Usmani, and Yong, in their review1 note a lack of evidence of off-target toxicity with BCMA-targeting CAR T-cell therapy in clinical studies so far, they do point to several clinical syndromes (cytokine release syndrome, infections, respiratory failure, neurotoxicity, pulmonary aspergillosis, gastrointestinal hemorrhage) caused by cytokines produced during CAR T-cell expansion and to cytopenias and infections arising from prior treatment, bridging therapy, and lymphodepleting conditioning. Deaths attributed to treatment in the above-mentioned trials underscore the need for careful monitoring and early intervention.
Cytokine release syndrome
In the BCMA-targeting CAR T-cell therapy studies, the frequency of cytokine release syndrome varies widely from 17% to 95% but is generally attributed to CAR T-cell activation and is associated with increased serum ferritin concentrations, high c-reactive proteins, and proinflammatory cytokines. High tumor load, in multiple myeloma patients receiving CD19-targeting CAR T cells, was associated with a higher incidence of severe cytokine release syndrome. In a small number of patients, macrophage activation syndrome and hemophagocytic lymphohistiocytosis, the most aggressive variants of cytokine release syndrome, are caused by severe immune activation and lead to multiorgan dysfunction.
Neurotoxicity
Immune effector cell–-associated neurotoxicity syndrome (ICANS) symptoms, in multiple myeloma patients treated with BCMA-targeting CAR T cells, may include delirium, transient confusion, aphasia, lethargy, tremor, dysgraphia, seizures, cerebral edema, and rarely, posterior reversible encephalopathy syndrome.1 While the pathophysiology of CAR T cell–related neurotoxicity is not well understood, high tumor load, higher peak concentrations of CAR T cells, and more severe cytokine release syndrome are more common in patients with severe neurotoxicity. “The frequency of neurotoxicities,” Dr. Yong noted in an interview, “has been reduced by steps taken to mitigate these risk factors.”
High interest in phase I study
A phase I study presented in Blood has attracted interest because the novel BCMA-targeting CAR agent (CT103A) being tested is fully human.4 In an accompanying editorial, Lee and Yong note that doubt for any real potential for durable CAR T therapy responses in multiple myeloma is raised by the poor persistence of multiple myeloma CAR T cells in multiple myeloma patients.3
In the earliest trials of BCMA CARs, while reported rates of objective antimyeloma responses were in the approximately 33%-88% range among patients with relapsed/refractory multiple myeloma (RRMM), persistence was typically 6 months or less. Lee and Yong point out, however, that while correlation between persistence and duration of response (DOR) has been variable, median persistence was 308 days in the phase I study. Wang and colleagues, the phase I study authors, state that levels of CAR T-cell proliferation and duration of cellular persistence may be determinants of DOR in CAR T therapy for multiple myeloma. They observe that the multiple mechanisms potentially responsible for the inability of some CAR T cells to survive in vivo, may include antigen escape, T-cell intrinsic mechanisms, tumor microenvironment–mediated suppression, and host anti-CAR immunity. CARs with humanized or fully human single-chain variable fragments (scFvs), prior studies suggest, may retain antitumor activity through bypassing potential host anti-CAR immunogenicity.
In the study, CT103A, a fully human scFv, was tested in an open-label, single-arm design for safety and preliminary efficacy in 18 patients (8 female; median age 53.5 years) with RRMM (at least three lines of prior therapies including a proteasome inhibitor and an immunomodulatory agent) who had undergone leukapheresis and had received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Four patients (22.2%) had been treated previously with murine anti-BCMA CAR T cells. Safety and tolerability (including dose-limiting toxicity) were the primary endpoints, with efficacy and pharmacokinetics secondary.
Rapid responses
Two weeks after infusion, the overall response rate (ORR) was 77.8% (14 of 18) and by 1 month it was 88.9% (16 of 18). Eventually, all responded and 72.2% (13 of 18) achieved a complete response (CR) or stringent complete response (sCR). All 17 patients evaluated for minimum residual disease (MRD) in bone marrow were MRD-negative at 10-4 nucleated cells by flow cytometry within 1 month. Median DOR was 325 days (range, 7-573 days) for all patients and 412 days (range, 213-573 days) for the 13 with CR/sCR. CAR transgenes were detectable at the cutoff date in 77.8% of patients, with a median CAR transgene persistence of 307.5 days.
During follow-up, four deaths were reported, including one patient with persistent sCR (sudden severe infection). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 58.3% and 75%, respectively. Extramedullary myeloma was associated with a shortened PFS (79.1% versus 20.0%, P = .015), but not OS (79.1% versus 60.0%, P = .328) at 1 year.
All patients experienced grade 3 or higher adverse events, most of which were expected hematologic effects of lymphodepleting chemotherapy and CT103A infusions. Grade 1 and 2 cytokine release syndromes occurred in 70.6% patients (17 of 18), with 1 grade 4 event (5.9%). The patients receiving a dose of up to 3.0 × 106 CAR+ T cells/kg required less treatment of cytokine release syndrome than the patients who received a dose of 6.0 × 106 CAR+ T cells/kg. No immune effector cell–associated neurotoxicity syndrome was observed. Antidrug antibody positivity occurred in only 1 patient.
Two characteristics of CT103A may contribute to its long persistence, stated study senior author Jianfeng Zhou, MD, PhD, chairman and professor of the department of hematology, Tongji Hospital in Wuhan, China. “One is the reduced immunogenicity achieved by the fully human construct; another is the relatively low binding affinity of the CAR binder. Notably, four patients who previously received murine BCMA CAR were included and still benefit from CT103A. It demonstrates the possibility of retreatment with a different CAR.” Dr. Zhou also emphasized that the lack of ICANS in the entire cohort reflects the excellent safety profile of CT103A.
The editorial commentary in Blood by Lydia Sarah Hui Lee, MD, and Kwee L. Yong, PhD, underscored impressive responses to CT103A, specifically to the median time to response of 15 days, the 100% ORR, and the not reached median progression-free survival at 394 days).5 The best results in other published nonhuman BCMA CAR T-cell trials, they note, were about 1 month (time to response), approximately 33%-88% (ORR), and median progression-free survival of 7-15 months.
Immune responses, Dr. Yong said in an interview, can guide subsequent treatment. “For example, if a patient previously exposed to BCMA CAR T cells in which the construct is either chimeric or humanized, but retains some murine elements, and had detectable antimurine antibodies, we may aim for a fully human one if we are considering treating with a different BCMA CAR T-cell product.” She added, “On the other hand, a similar patient whose serum did not contain such antibodies may be a candidate for a humanized product that retained some murine elements.”
Wang and colleagues concluded, “Altogether, CT103A is safe and highly active in patients with relapsed/refractory multiple myeloma and can be developed as a promising therapy for relapsed/refractory multiple myeloma.”4 An ongoing multicenter phase II trial with single-arm design is recruiting 100 patients. The infusion dosage, suggested by the phase I trial, is 1 × 106 cells/kg. Endpoints include efficacy and safety.
Improving CAR T
Optimizing CAR design and adapting manufacturing processes to generate cell products enriched for T-cell subsets, such as early memory cells, are among strategies being explored to improve CAR T effectiveness.1 Also, dual-antigen targeting to interdict antigen escape and rational combination treatments to enhance persistence are under investigation, along with efforts to improve CAR T-cell therapy safety (for example, incorporation of a suicide gene safety system). They note further that several groups are researching use of induced pluripotent stem cells to generate large quantities of off-the-shelf CAR T-cell immunotherapies that would circumvent the complex, costly, and time-consuming process of manufacturing patient-specific autologous CAR T cells.
References
1. van de Donk N et al. Lancet Haematol. 2021 June;8(6):e446-61.
2. Munshi NC et al. N Engl J Med 2021; 384:705-716.
3. Berdeja JG et al. The Lancet. 2021 July; 398:314-24.
4. Wang D et al. Blood. 2021 May;137(21):2890-901.
5. Lee L and Yong K. Blood. 2021 May;137(21):2859-60.
In multiple myeloma, survival has been very significantly improved by immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies. Despite these advances, multiple myeloma, which is characterized by malignant proliferation of clonal plasma cells in bone marrow, remains an incurable plasma cell disorder with near-certain relapse after successful treatment. Prognosis for patients who develop triple-class refractory disease is poor, with less than 1-year survival. The substantial unmet therapeutic need extends further to other poor survival multiple myeloma populations that include newly diagnosed patients with high cytogenic risk profiles and those with early relapse after first-line therapy. For all of these, interest in drugs with novel mechanisms of action is naturally high.
More specific, less toxic
Post allogeneic hematopoietic stem-cell transplantation and donor lymphocyte infusion sustained remissions reflect a graft-versus-myeloma effect mediated by donor T cells.1 The substantial morbidity and mortality associated with graft-versus-host disease and opportunistic infections, however, have spurred searches for alternative, more specific, and less toxic T-cell therapies with stronger antitumor activity.
Chimeric antigen receptors (CARs)
In CAR T-cell therapies for multiple myeloma, autologous T cells are harvested from the patient and reprogrammed to target multiple myeloma cells through the introduction of genes that encode CARs, which are fusion proteins coupling an antigen-recognition moiety and a transmembrane-spanning element to a T-cell activation domain (typically CD3 zeta [CD247]). The T cells are then expanded and reinfused to the patient following a lymphodepletion regimen. Five strategies using autologous CAR T cells are currently approved for diffuse large B-cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies. Notably, in patients with heavily pretreated multiple myeloma, CAR T cells have demonstrated impressive activity.
BCMA-targeting CAR T cells
The B-cell maturation antigen (BCMA; TNFRSF17), which plays an important role in the survival of long-lived plasma cells in bone marrow, is an attractive target for CAR T-cell therapy because it is expressed on normal and malignant plasma cell surfaces and by mature B cells. When ligands (TNFSF 13B/TNFSF13) bind to BCMA expressed on multiple myeloma cell surfaces, survival and proliferation pathways and drug resistance are activated.
High-quality responses have been demonstrated in several trials of anti-BCMA CAR T cells, which kill multiple myeloma cell lines and primary multiple myeloma cells through degranulation of T cells and lysis of tumor cells, even those with low BCMA expression. Based on efficacy in triple-class exposed multiple myeloma that compared favorably to conventional care with improved health-related quality of life, the U.S. Food and Drug Administration gave breakthrough designation to ciltacabtagene autoleucel in December 2019 and approval for idecabtagene vicleucel in March 2021.
Idecabtagene vicleucel
Idecabtagene vicleucel expresses a murine BCMA-targeting single-chain variable fragment with a 4-1BB costimulatory motif. The phase 2 KarMMa study2 evaluated idecabtagene vicleucel (target dose of 450 × 106 CAR T cells; range 150 × 106 to 450 × 106) activity in 128 patients with triple-class exposed multiple myeloma. Partial responses or better were observed in 94 of 128 patients (73%) (95% confidence interval, 66-81); 42 (33%) had a complete response or better (95% CI, 25-41), with a median progression-free survival of 8.8 months (95% CI, 5.6-11.6). Outcomes were improved in the highest fixed-dose group, with partial response or better in 81% (44 of 55), complete response or better in 39% (21), and median overall survival of 12.1 months (95% CI, 8.8-12.3). Patients with high-risk cytogenetic profiles, extramedullary disease, and high tumor burden also had deep and durable responses. Outcomes were less favorable in patients with revised International Staging System stage 3 disease.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel, a 4-1BB–based CAR T-cell therapy with two BCMA-targeting domains, confers high-avidity binding. In the phase 1b/2 CARTITUDE-1 study, conducted in the United States and Europe, preliminary results in 97 patients showed a 97% response rate with ciltacabtagene autoleucel (target dose 0.75 × 106 CAR T cells per kg), and in 65 patients, a complete response (67%). Progression-free survival at 12 months was 77% (95% CI, 66-84) and overall survival was 89% (95% CI, 80-94).3
In the phase 1 LEGEND-2 study4 that was conducted at four sites in China among less heavily pretreated multiple myeloma patients, while all used the same CAR construct, sites used variable conditioning regimens (split versus single). In the site using cyclophosphamide as the lymphodepletion therapy and three split CAR T-cell infusions, partial response or better was achieved in 50 patients (88%) with a median of three prior therapy lines. The complete response rate was high (74%) and minimal residual disease negativity was reached in 39 patients (68%). Median progression-free survival was 19.9 months (95% CI, 9.6-31.0), but 28.2 months among those with complete responses (95% CI, 19.9-not estimable). Median overall survival was also favorable at 36.1 months (95% CI, 26.4-not estimable); it was 35.0 months-not estimable among patients with complete responses. Results from the other three sites were comparable.
Noteworthy among other BCMA-targeting CAR T-cell products in earlier stages of clinical development is orvacabtagene autoleucel, which has a fully human BCMA-specific binding domain. At higher doses (300 × 106 to 600 × 106 CAR T cells) among 62 patients with triple-class–exposed multiple myeloma in the EVOLVE trial, 92% had a partial or better response, with complete responses or better in 36%, all with an encouraging safety profile.
BCMA-targeting CAR T cell toxicity
While van de Donk, Usmani, and Yong, in their review1 note a lack of evidence of off-target toxicity with BCMA-targeting CAR T-cell therapy in clinical studies so far, they do point to several clinical syndromes (cytokine release syndrome, infections, respiratory failure, neurotoxicity, pulmonary aspergillosis, gastrointestinal hemorrhage) caused by cytokines produced during CAR T-cell expansion and to cytopenias and infections arising from prior treatment, bridging therapy, and lymphodepleting conditioning. Deaths attributed to treatment in the above-mentioned trials underscore the need for careful monitoring and early intervention.
Cytokine release syndrome
In the BCMA-targeting CAR T-cell therapy studies, the frequency of cytokine release syndrome varies widely from 17% to 95% but is generally attributed to CAR T-cell activation and is associated with increased serum ferritin concentrations, high c-reactive proteins, and proinflammatory cytokines. High tumor load, in multiple myeloma patients receiving CD19-targeting CAR T cells, was associated with a higher incidence of severe cytokine release syndrome. In a small number of patients, macrophage activation syndrome and hemophagocytic lymphohistiocytosis, the most aggressive variants of cytokine release syndrome, are caused by severe immune activation and lead to multiorgan dysfunction.
Neurotoxicity
Immune effector cell–-associated neurotoxicity syndrome (ICANS) symptoms, in multiple myeloma patients treated with BCMA-targeting CAR T cells, may include delirium, transient confusion, aphasia, lethargy, tremor, dysgraphia, seizures, cerebral edema, and rarely, posterior reversible encephalopathy syndrome.1 While the pathophysiology of CAR T cell–related neurotoxicity is not well understood, high tumor load, higher peak concentrations of CAR T cells, and more severe cytokine release syndrome are more common in patients with severe neurotoxicity. “The frequency of neurotoxicities,” Dr. Yong noted in an interview, “has been reduced by steps taken to mitigate these risk factors.”
High interest in phase I study
A phase I study presented in Blood has attracted interest because the novel BCMA-targeting CAR agent (CT103A) being tested is fully human.4 In an accompanying editorial, Lee and Yong note that doubt for any real potential for durable CAR T therapy responses in multiple myeloma is raised by the poor persistence of multiple myeloma CAR T cells in multiple myeloma patients.3
In the earliest trials of BCMA CARs, while reported rates of objective antimyeloma responses were in the approximately 33%-88% range among patients with relapsed/refractory multiple myeloma (RRMM), persistence was typically 6 months or less. Lee and Yong point out, however, that while correlation between persistence and duration of response (DOR) has been variable, median persistence was 308 days in the phase I study. Wang and colleagues, the phase I study authors, state that levels of CAR T-cell proliferation and duration of cellular persistence may be determinants of DOR in CAR T therapy for multiple myeloma. They observe that the multiple mechanisms potentially responsible for the inability of some CAR T cells to survive in vivo, may include antigen escape, T-cell intrinsic mechanisms, tumor microenvironment–mediated suppression, and host anti-CAR immunity. CARs with humanized or fully human single-chain variable fragments (scFvs), prior studies suggest, may retain antitumor activity through bypassing potential host anti-CAR immunogenicity.
In the study, CT103A, a fully human scFv, was tested in an open-label, single-arm design for safety and preliminary efficacy in 18 patients (8 female; median age 53.5 years) with RRMM (at least three lines of prior therapies including a proteasome inhibitor and an immunomodulatory agent) who had undergone leukapheresis and had received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Four patients (22.2%) had been treated previously with murine anti-BCMA CAR T cells. Safety and tolerability (including dose-limiting toxicity) were the primary endpoints, with efficacy and pharmacokinetics secondary.
Rapid responses
Two weeks after infusion, the overall response rate (ORR) was 77.8% (14 of 18) and by 1 month it was 88.9% (16 of 18). Eventually, all responded and 72.2% (13 of 18) achieved a complete response (CR) or stringent complete response (sCR). All 17 patients evaluated for minimum residual disease (MRD) in bone marrow were MRD-negative at 10-4 nucleated cells by flow cytometry within 1 month. Median DOR was 325 days (range, 7-573 days) for all patients and 412 days (range, 213-573 days) for the 13 with CR/sCR. CAR transgenes were detectable at the cutoff date in 77.8% of patients, with a median CAR transgene persistence of 307.5 days.
During follow-up, four deaths were reported, including one patient with persistent sCR (sudden severe infection). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 58.3% and 75%, respectively. Extramedullary myeloma was associated with a shortened PFS (79.1% versus 20.0%, P = .015), but not OS (79.1% versus 60.0%, P = .328) at 1 year.
All patients experienced grade 3 or higher adverse events, most of which were expected hematologic effects of lymphodepleting chemotherapy and CT103A infusions. Grade 1 and 2 cytokine release syndromes occurred in 70.6% patients (17 of 18), with 1 grade 4 event (5.9%). The patients receiving a dose of up to 3.0 × 106 CAR+ T cells/kg required less treatment of cytokine release syndrome than the patients who received a dose of 6.0 × 106 CAR+ T cells/kg. No immune effector cell–associated neurotoxicity syndrome was observed. Antidrug antibody positivity occurred in only 1 patient.
Two characteristics of CT103A may contribute to its long persistence, stated study senior author Jianfeng Zhou, MD, PhD, chairman and professor of the department of hematology, Tongji Hospital in Wuhan, China. “One is the reduced immunogenicity achieved by the fully human construct; another is the relatively low binding affinity of the CAR binder. Notably, four patients who previously received murine BCMA CAR were included and still benefit from CT103A. It demonstrates the possibility of retreatment with a different CAR.” Dr. Zhou also emphasized that the lack of ICANS in the entire cohort reflects the excellent safety profile of CT103A.
The editorial commentary in Blood by Lydia Sarah Hui Lee, MD, and Kwee L. Yong, PhD, underscored impressive responses to CT103A, specifically to the median time to response of 15 days, the 100% ORR, and the not reached median progression-free survival at 394 days).5 The best results in other published nonhuman BCMA CAR T-cell trials, they note, were about 1 month (time to response), approximately 33%-88% (ORR), and median progression-free survival of 7-15 months.
Immune responses, Dr. Yong said in an interview, can guide subsequent treatment. “For example, if a patient previously exposed to BCMA CAR T cells in which the construct is either chimeric or humanized, but retains some murine elements, and had detectable antimurine antibodies, we may aim for a fully human one if we are considering treating with a different BCMA CAR T-cell product.” She added, “On the other hand, a similar patient whose serum did not contain such antibodies may be a candidate for a humanized product that retained some murine elements.”
Wang and colleagues concluded, “Altogether, CT103A is safe and highly active in patients with relapsed/refractory multiple myeloma and can be developed as a promising therapy for relapsed/refractory multiple myeloma.”4 An ongoing multicenter phase II trial with single-arm design is recruiting 100 patients. The infusion dosage, suggested by the phase I trial, is 1 × 106 cells/kg. Endpoints include efficacy and safety.
Improving CAR T
Optimizing CAR design and adapting manufacturing processes to generate cell products enriched for T-cell subsets, such as early memory cells, are among strategies being explored to improve CAR T effectiveness.1 Also, dual-antigen targeting to interdict antigen escape and rational combination treatments to enhance persistence are under investigation, along with efforts to improve CAR T-cell therapy safety (for example, incorporation of a suicide gene safety system). They note further that several groups are researching use of induced pluripotent stem cells to generate large quantities of off-the-shelf CAR T-cell immunotherapies that would circumvent the complex, costly, and time-consuming process of manufacturing patient-specific autologous CAR T cells.
References
1. van de Donk N et al. Lancet Haematol. 2021 June;8(6):e446-61.
2. Munshi NC et al. N Engl J Med 2021; 384:705-716.
3. Berdeja JG et al. The Lancet. 2021 July; 398:314-24.
4. Wang D et al. Blood. 2021 May;137(21):2890-901.
5. Lee L and Yong K. Blood. 2021 May;137(21):2859-60.
In multiple myeloma, survival has been very significantly improved by immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies. Despite these advances, multiple myeloma, which is characterized by malignant proliferation of clonal plasma cells in bone marrow, remains an incurable plasma cell disorder with near-certain relapse after successful treatment. Prognosis for patients who develop triple-class refractory disease is poor, with less than 1-year survival. The substantial unmet therapeutic need extends further to other poor survival multiple myeloma populations that include newly diagnosed patients with high cytogenic risk profiles and those with early relapse after first-line therapy. For all of these, interest in drugs with novel mechanisms of action is naturally high.
More specific, less toxic
Post allogeneic hematopoietic stem-cell transplantation and donor lymphocyte infusion sustained remissions reflect a graft-versus-myeloma effect mediated by donor T cells.1 The substantial morbidity and mortality associated with graft-versus-host disease and opportunistic infections, however, have spurred searches for alternative, more specific, and less toxic T-cell therapies with stronger antitumor activity.
Chimeric antigen receptors (CARs)
In CAR T-cell therapies for multiple myeloma, autologous T cells are harvested from the patient and reprogrammed to target multiple myeloma cells through the introduction of genes that encode CARs, which are fusion proteins coupling an antigen-recognition moiety and a transmembrane-spanning element to a T-cell activation domain (typically CD3 zeta [CD247]). The T cells are then expanded and reinfused to the patient following a lymphodepletion regimen. Five strategies using autologous CAR T cells are currently approved for diffuse large B-cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies. Notably, in patients with heavily pretreated multiple myeloma, CAR T cells have demonstrated impressive activity.
BCMA-targeting CAR T cells
The B-cell maturation antigen (BCMA; TNFRSF17), which plays an important role in the survival of long-lived plasma cells in bone marrow, is an attractive target for CAR T-cell therapy because it is expressed on normal and malignant plasma cell surfaces and by mature B cells. When ligands (TNFSF 13B/TNFSF13) bind to BCMA expressed on multiple myeloma cell surfaces, survival and proliferation pathways and drug resistance are activated.
High-quality responses have been demonstrated in several trials of anti-BCMA CAR T cells, which kill multiple myeloma cell lines and primary multiple myeloma cells through degranulation of T cells and lysis of tumor cells, even those with low BCMA expression. Based on efficacy in triple-class exposed multiple myeloma that compared favorably to conventional care with improved health-related quality of life, the U.S. Food and Drug Administration gave breakthrough designation to ciltacabtagene autoleucel in December 2019 and approval for idecabtagene vicleucel in March 2021.
Idecabtagene vicleucel
Idecabtagene vicleucel expresses a murine BCMA-targeting single-chain variable fragment with a 4-1BB costimulatory motif. The phase 2 KarMMa study2 evaluated idecabtagene vicleucel (target dose of 450 × 106 CAR T cells; range 150 × 106 to 450 × 106) activity in 128 patients with triple-class exposed multiple myeloma. Partial responses or better were observed in 94 of 128 patients (73%) (95% confidence interval, 66-81); 42 (33%) had a complete response or better (95% CI, 25-41), with a median progression-free survival of 8.8 months (95% CI, 5.6-11.6). Outcomes were improved in the highest fixed-dose group, with partial response or better in 81% (44 of 55), complete response or better in 39% (21), and median overall survival of 12.1 months (95% CI, 8.8-12.3). Patients with high-risk cytogenetic profiles, extramedullary disease, and high tumor burden also had deep and durable responses. Outcomes were less favorable in patients with revised International Staging System stage 3 disease.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel, a 4-1BB–based CAR T-cell therapy with two BCMA-targeting domains, confers high-avidity binding. In the phase 1b/2 CARTITUDE-1 study, conducted in the United States and Europe, preliminary results in 97 patients showed a 97% response rate with ciltacabtagene autoleucel (target dose 0.75 × 106 CAR T cells per kg), and in 65 patients, a complete response (67%). Progression-free survival at 12 months was 77% (95% CI, 66-84) and overall survival was 89% (95% CI, 80-94).3
In the phase 1 LEGEND-2 study4 that was conducted at four sites in China among less heavily pretreated multiple myeloma patients, while all used the same CAR construct, sites used variable conditioning regimens (split versus single). In the site using cyclophosphamide as the lymphodepletion therapy and three split CAR T-cell infusions, partial response or better was achieved in 50 patients (88%) with a median of three prior therapy lines. The complete response rate was high (74%) and minimal residual disease negativity was reached in 39 patients (68%). Median progression-free survival was 19.9 months (95% CI, 9.6-31.0), but 28.2 months among those with complete responses (95% CI, 19.9-not estimable). Median overall survival was also favorable at 36.1 months (95% CI, 26.4-not estimable); it was 35.0 months-not estimable among patients with complete responses. Results from the other three sites were comparable.
Noteworthy among other BCMA-targeting CAR T-cell products in earlier stages of clinical development is orvacabtagene autoleucel, which has a fully human BCMA-specific binding domain. At higher doses (300 × 106 to 600 × 106 CAR T cells) among 62 patients with triple-class–exposed multiple myeloma in the EVOLVE trial, 92% had a partial or better response, with complete responses or better in 36%, all with an encouraging safety profile.
BCMA-targeting CAR T cell toxicity
While van de Donk, Usmani, and Yong, in their review1 note a lack of evidence of off-target toxicity with BCMA-targeting CAR T-cell therapy in clinical studies so far, they do point to several clinical syndromes (cytokine release syndrome, infections, respiratory failure, neurotoxicity, pulmonary aspergillosis, gastrointestinal hemorrhage) caused by cytokines produced during CAR T-cell expansion and to cytopenias and infections arising from prior treatment, bridging therapy, and lymphodepleting conditioning. Deaths attributed to treatment in the above-mentioned trials underscore the need for careful monitoring and early intervention.
Cytokine release syndrome
In the BCMA-targeting CAR T-cell therapy studies, the frequency of cytokine release syndrome varies widely from 17% to 95% but is generally attributed to CAR T-cell activation and is associated with increased serum ferritin concentrations, high c-reactive proteins, and proinflammatory cytokines. High tumor load, in multiple myeloma patients receiving CD19-targeting CAR T cells, was associated with a higher incidence of severe cytokine release syndrome. In a small number of patients, macrophage activation syndrome and hemophagocytic lymphohistiocytosis, the most aggressive variants of cytokine release syndrome, are caused by severe immune activation and lead to multiorgan dysfunction.
Neurotoxicity
Immune effector cell–-associated neurotoxicity syndrome (ICANS) symptoms, in multiple myeloma patients treated with BCMA-targeting CAR T cells, may include delirium, transient confusion, aphasia, lethargy, tremor, dysgraphia, seizures, cerebral edema, and rarely, posterior reversible encephalopathy syndrome.1 While the pathophysiology of CAR T cell–related neurotoxicity is not well understood, high tumor load, higher peak concentrations of CAR T cells, and more severe cytokine release syndrome are more common in patients with severe neurotoxicity. “The frequency of neurotoxicities,” Dr. Yong noted in an interview, “has been reduced by steps taken to mitigate these risk factors.”
High interest in phase I study
A phase I study presented in Blood has attracted interest because the novel BCMA-targeting CAR agent (CT103A) being tested is fully human.4 In an accompanying editorial, Lee and Yong note that doubt for any real potential for durable CAR T therapy responses in multiple myeloma is raised by the poor persistence of multiple myeloma CAR T cells in multiple myeloma patients.3
In the earliest trials of BCMA CARs, while reported rates of objective antimyeloma responses were in the approximately 33%-88% range among patients with relapsed/refractory multiple myeloma (RRMM), persistence was typically 6 months or less. Lee and Yong point out, however, that while correlation between persistence and duration of response (DOR) has been variable, median persistence was 308 days in the phase I study. Wang and colleagues, the phase I study authors, state that levels of CAR T-cell proliferation and duration of cellular persistence may be determinants of DOR in CAR T therapy for multiple myeloma. They observe that the multiple mechanisms potentially responsible for the inability of some CAR T cells to survive in vivo, may include antigen escape, T-cell intrinsic mechanisms, tumor microenvironment–mediated suppression, and host anti-CAR immunity. CARs with humanized or fully human single-chain variable fragments (scFvs), prior studies suggest, may retain antitumor activity through bypassing potential host anti-CAR immunogenicity.
In the study, CT103A, a fully human scFv, was tested in an open-label, single-arm design for safety and preliminary efficacy in 18 patients (8 female; median age 53.5 years) with RRMM (at least three lines of prior therapies including a proteasome inhibitor and an immunomodulatory agent) who had undergone leukapheresis and had received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Four patients (22.2%) had been treated previously with murine anti-BCMA CAR T cells. Safety and tolerability (including dose-limiting toxicity) were the primary endpoints, with efficacy and pharmacokinetics secondary.
Rapid responses
Two weeks after infusion, the overall response rate (ORR) was 77.8% (14 of 18) and by 1 month it was 88.9% (16 of 18). Eventually, all responded and 72.2% (13 of 18) achieved a complete response (CR) or stringent complete response (sCR). All 17 patients evaluated for minimum residual disease (MRD) in bone marrow were MRD-negative at 10-4 nucleated cells by flow cytometry within 1 month. Median DOR was 325 days (range, 7-573 days) for all patients and 412 days (range, 213-573 days) for the 13 with CR/sCR. CAR transgenes were detectable at the cutoff date in 77.8% of patients, with a median CAR transgene persistence of 307.5 days.
During follow-up, four deaths were reported, including one patient with persistent sCR (sudden severe infection). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 58.3% and 75%, respectively. Extramedullary myeloma was associated with a shortened PFS (79.1% versus 20.0%, P = .015), but not OS (79.1% versus 60.0%, P = .328) at 1 year.
All patients experienced grade 3 or higher adverse events, most of which were expected hematologic effects of lymphodepleting chemotherapy and CT103A infusions. Grade 1 and 2 cytokine release syndromes occurred in 70.6% patients (17 of 18), with 1 grade 4 event (5.9%). The patients receiving a dose of up to 3.0 × 106 CAR+ T cells/kg required less treatment of cytokine release syndrome than the patients who received a dose of 6.0 × 106 CAR+ T cells/kg. No immune effector cell–associated neurotoxicity syndrome was observed. Antidrug antibody positivity occurred in only 1 patient.
Two characteristics of CT103A may contribute to its long persistence, stated study senior author Jianfeng Zhou, MD, PhD, chairman and professor of the department of hematology, Tongji Hospital in Wuhan, China. “One is the reduced immunogenicity achieved by the fully human construct; another is the relatively low binding affinity of the CAR binder. Notably, four patients who previously received murine BCMA CAR were included and still benefit from CT103A. It demonstrates the possibility of retreatment with a different CAR.” Dr. Zhou also emphasized that the lack of ICANS in the entire cohort reflects the excellent safety profile of CT103A.
The editorial commentary in Blood by Lydia Sarah Hui Lee, MD, and Kwee L. Yong, PhD, underscored impressive responses to CT103A, specifically to the median time to response of 15 days, the 100% ORR, and the not reached median progression-free survival at 394 days).5 The best results in other published nonhuman BCMA CAR T-cell trials, they note, were about 1 month (time to response), approximately 33%-88% (ORR), and median progression-free survival of 7-15 months.
Immune responses, Dr. Yong said in an interview, can guide subsequent treatment. “For example, if a patient previously exposed to BCMA CAR T cells in which the construct is either chimeric or humanized, but retains some murine elements, and had detectable antimurine antibodies, we may aim for a fully human one if we are considering treating with a different BCMA CAR T-cell product.” She added, “On the other hand, a similar patient whose serum did not contain such antibodies may be a candidate for a humanized product that retained some murine elements.”
Wang and colleagues concluded, “Altogether, CT103A is safe and highly active in patients with relapsed/refractory multiple myeloma and can be developed as a promising therapy for relapsed/refractory multiple myeloma.”4 An ongoing multicenter phase II trial with single-arm design is recruiting 100 patients. The infusion dosage, suggested by the phase I trial, is 1 × 106 cells/kg. Endpoints include efficacy and safety.
Improving CAR T
Optimizing CAR design and adapting manufacturing processes to generate cell products enriched for T-cell subsets, such as early memory cells, are among strategies being explored to improve CAR T effectiveness.1 Also, dual-antigen targeting to interdict antigen escape and rational combination treatments to enhance persistence are under investigation, along with efforts to improve CAR T-cell therapy safety (for example, incorporation of a suicide gene safety system). They note further that several groups are researching use of induced pluripotent stem cells to generate large quantities of off-the-shelf CAR T-cell immunotherapies that would circumvent the complex, costly, and time-consuming process of manufacturing patient-specific autologous CAR T cells.
References
1. van de Donk N et al. Lancet Haematol. 2021 June;8(6):e446-61.
2. Munshi NC et al. N Engl J Med 2021; 384:705-716.
3. Berdeja JG et al. The Lancet. 2021 July; 398:314-24.
4. Wang D et al. Blood. 2021 May;137(21):2890-901.
5. Lee L and Yong K. Blood. 2021 May;137(21):2859-60.
Physician gender pay gap isn’t news; health inequity is rampant
A recent study examined projected career earnings between the genders in a largely community-based physician population, finding a difference of about $2 million in career earnings. That a gender pay gap exists in medicine is not news – but the manner in which this study was done, the investigators’ ability to control for a number of confounding variables, and the size of the study group (over 80,000) are newsworthy.
Some of the key findings include that gender pay gaps start with your first job, and you never close the gap, even as you gain experience and efficiency. Also, the more highly remunerated your specialty, the larger the gap. The gender pay gap joins a growing list of inequities within health care. Although physician compensation is not the most important, given that nearly all physicians are well-paid, and we have much more significant inequities that lead to direct patient harm, the reasons for this discrepancy warrant further consideration.
When I was first being educated about social inequity as part of work in social determinants of health, I made the error of using “inequality” and “inequity” interchangeably. The subtle yet important difference between the two terms was quickly described to me. Inequality is a gastroenterologist getting paid more money to do a colonoscopy than a family physician. Inequity is a female gastroenterologist getting paid less than a male gastroenterologist. Global Health Europe boldly identifies that “inequity is the result of failure.” In looking at the inequity inherent in the gender pay gap, I consider what failed and why.
I’m currently making a major career change, leaving an executive leadership position to return to full-time clinical practice. There is a significant pay decrease that will accompany this change because I am in a primary care specialty. Beyond that, I am considering two employment contracts from different systems to do a similar clinical role.
One of the questions my husband asked was which will pay more over the long run. This is difficult to discern because the compensation formula each health system uses is different, even though they are based on standard national benchmarking data. It is possible that women, in general, are like I am and look for factors other than compensation to make a job decision – assuming, like I do, that it will be close enough to not matter or is generally fair. In fact, while compensation is most certainly a consideration for me, once I determined that it was likely to be in the same ballpark, I stopped comparing. Even as the sole breadwinner in our family, I take this (probably faulty) approach.
It’s time to reconsider how we pay physicians
Women may be more likely to gloss over compensation details that men evaluate and negotiate carefully. To change this, women must first take responsibility for being an active, informed, and engaged part of compensation negotiations. In addition, employers who value gender pay equity must negotiate in good faith, keeping in mind the well-described vulnerabilities in discussions about pay. Finally, male and female mentors and leaders should actively coach female physicians on how to approach these conversations with confidence and skill.
In primary care, female physicians spend, on average, about 15% more time with their patients during a visit. Despite spending as much time in clinic seeing patients per week, they see fewer patients, thereby generating less revenue. For compensation plans that are based on productivity, the extra time spent costs money. In this case, it costs the female physicians lost compensation.
The way in which women are more likely to practice medicine, which includes the amount of time they spend with patients, may affect clinical outcomes without directly increasing productivity. A 2017 study demonstrated that elderly patients had lower rates of mortality and readmission when cared for by a female rather than a male physician. These findings require health systems to critically evaluate what compensation plans value and to promote an appropriate balance between quality of care, quantity of care, and style of care.
Although I’ve seen gender pay inequity as blatant as two different salaries for physicians doing the same work – one male and one female – I think this is uncommon. Like many forms of inequity, the outputs are often related to a failed system rather than solely a series of individual failures. Making compensation formulas gender-blind is an important step – but it is only the first step, not the last. Recognizing that the structure of a compensation formula may be biased toward a style of medical practice more likely to be espoused by one gender is necessary as well.
The data, including the findings of this recent study, clearly identify the gender pay gap that exists in medicine, as it does in many other fields, and that it is not explainable solely by differences in specialties, work hours, family status, or title.
To address the inequity, it is imperative that women engage with employers and leaders to both understand and develop skills around effective and appropriate compensation negotiation. Recognizing that compensation plans, especially those built on productivity models, may fail to place adequate value on gender-specific practice styles.
Jennifer Frank is a family physician, physician leader, wife, and mother in Northeast Wisconsin.
A version of this article first appeared on Medscape.com.
A recent study examined projected career earnings between the genders in a largely community-based physician population, finding a difference of about $2 million in career earnings. That a gender pay gap exists in medicine is not news – but the manner in which this study was done, the investigators’ ability to control for a number of confounding variables, and the size of the study group (over 80,000) are newsworthy.
Some of the key findings include that gender pay gaps start with your first job, and you never close the gap, even as you gain experience and efficiency. Also, the more highly remunerated your specialty, the larger the gap. The gender pay gap joins a growing list of inequities within health care. Although physician compensation is not the most important, given that nearly all physicians are well-paid, and we have much more significant inequities that lead to direct patient harm, the reasons for this discrepancy warrant further consideration.
When I was first being educated about social inequity as part of work in social determinants of health, I made the error of using “inequality” and “inequity” interchangeably. The subtle yet important difference between the two terms was quickly described to me. Inequality is a gastroenterologist getting paid more money to do a colonoscopy than a family physician. Inequity is a female gastroenterologist getting paid less than a male gastroenterologist. Global Health Europe boldly identifies that “inequity is the result of failure.” In looking at the inequity inherent in the gender pay gap, I consider what failed and why.
I’m currently making a major career change, leaving an executive leadership position to return to full-time clinical practice. There is a significant pay decrease that will accompany this change because I am in a primary care specialty. Beyond that, I am considering two employment contracts from different systems to do a similar clinical role.
One of the questions my husband asked was which will pay more over the long run. This is difficult to discern because the compensation formula each health system uses is different, even though they are based on standard national benchmarking data. It is possible that women, in general, are like I am and look for factors other than compensation to make a job decision – assuming, like I do, that it will be close enough to not matter or is generally fair. In fact, while compensation is most certainly a consideration for me, once I determined that it was likely to be in the same ballpark, I stopped comparing. Even as the sole breadwinner in our family, I take this (probably faulty) approach.
It’s time to reconsider how we pay physicians
Women may be more likely to gloss over compensation details that men evaluate and negotiate carefully. To change this, women must first take responsibility for being an active, informed, and engaged part of compensation negotiations. In addition, employers who value gender pay equity must negotiate in good faith, keeping in mind the well-described vulnerabilities in discussions about pay. Finally, male and female mentors and leaders should actively coach female physicians on how to approach these conversations with confidence and skill.
In primary care, female physicians spend, on average, about 15% more time with their patients during a visit. Despite spending as much time in clinic seeing patients per week, they see fewer patients, thereby generating less revenue. For compensation plans that are based on productivity, the extra time spent costs money. In this case, it costs the female physicians lost compensation.
The way in which women are more likely to practice medicine, which includes the amount of time they spend with patients, may affect clinical outcomes without directly increasing productivity. A 2017 study demonstrated that elderly patients had lower rates of mortality and readmission when cared for by a female rather than a male physician. These findings require health systems to critically evaluate what compensation plans value and to promote an appropriate balance between quality of care, quantity of care, and style of care.
Although I’ve seen gender pay inequity as blatant as two different salaries for physicians doing the same work – one male and one female – I think this is uncommon. Like many forms of inequity, the outputs are often related to a failed system rather than solely a series of individual failures. Making compensation formulas gender-blind is an important step – but it is only the first step, not the last. Recognizing that the structure of a compensation formula may be biased toward a style of medical practice more likely to be espoused by one gender is necessary as well.
The data, including the findings of this recent study, clearly identify the gender pay gap that exists in medicine, as it does in many other fields, and that it is not explainable solely by differences in specialties, work hours, family status, or title.
To address the inequity, it is imperative that women engage with employers and leaders to both understand and develop skills around effective and appropriate compensation negotiation. Recognizing that compensation plans, especially those built on productivity models, may fail to place adequate value on gender-specific practice styles.
Jennifer Frank is a family physician, physician leader, wife, and mother in Northeast Wisconsin.
A version of this article first appeared on Medscape.com.
A recent study examined projected career earnings between the genders in a largely community-based physician population, finding a difference of about $2 million in career earnings. That a gender pay gap exists in medicine is not news – but the manner in which this study was done, the investigators’ ability to control for a number of confounding variables, and the size of the study group (over 80,000) are newsworthy.
Some of the key findings include that gender pay gaps start with your first job, and you never close the gap, even as you gain experience and efficiency. Also, the more highly remunerated your specialty, the larger the gap. The gender pay gap joins a growing list of inequities within health care. Although physician compensation is not the most important, given that nearly all physicians are well-paid, and we have much more significant inequities that lead to direct patient harm, the reasons for this discrepancy warrant further consideration.
When I was first being educated about social inequity as part of work in social determinants of health, I made the error of using “inequality” and “inequity” interchangeably. The subtle yet important difference between the two terms was quickly described to me. Inequality is a gastroenterologist getting paid more money to do a colonoscopy than a family physician. Inequity is a female gastroenterologist getting paid less than a male gastroenterologist. Global Health Europe boldly identifies that “inequity is the result of failure.” In looking at the inequity inherent in the gender pay gap, I consider what failed and why.
I’m currently making a major career change, leaving an executive leadership position to return to full-time clinical practice. There is a significant pay decrease that will accompany this change because I am in a primary care specialty. Beyond that, I am considering two employment contracts from different systems to do a similar clinical role.
One of the questions my husband asked was which will pay more over the long run. This is difficult to discern because the compensation formula each health system uses is different, even though they are based on standard national benchmarking data. It is possible that women, in general, are like I am and look for factors other than compensation to make a job decision – assuming, like I do, that it will be close enough to not matter or is generally fair. In fact, while compensation is most certainly a consideration for me, once I determined that it was likely to be in the same ballpark, I stopped comparing. Even as the sole breadwinner in our family, I take this (probably faulty) approach.
It’s time to reconsider how we pay physicians
Women may be more likely to gloss over compensation details that men evaluate and negotiate carefully. To change this, women must first take responsibility for being an active, informed, and engaged part of compensation negotiations. In addition, employers who value gender pay equity must negotiate in good faith, keeping in mind the well-described vulnerabilities in discussions about pay. Finally, male and female mentors and leaders should actively coach female physicians on how to approach these conversations with confidence and skill.
In primary care, female physicians spend, on average, about 15% more time with their patients during a visit. Despite spending as much time in clinic seeing patients per week, they see fewer patients, thereby generating less revenue. For compensation plans that are based on productivity, the extra time spent costs money. In this case, it costs the female physicians lost compensation.
The way in which women are more likely to practice medicine, which includes the amount of time they spend with patients, may affect clinical outcomes without directly increasing productivity. A 2017 study demonstrated that elderly patients had lower rates of mortality and readmission when cared for by a female rather than a male physician. These findings require health systems to critically evaluate what compensation plans value and to promote an appropriate balance between quality of care, quantity of care, and style of care.
Although I’ve seen gender pay inequity as blatant as two different salaries for physicians doing the same work – one male and one female – I think this is uncommon. Like many forms of inequity, the outputs are often related to a failed system rather than solely a series of individual failures. Making compensation formulas gender-blind is an important step – but it is only the first step, not the last. Recognizing that the structure of a compensation formula may be biased toward a style of medical practice more likely to be espoused by one gender is necessary as well.
The data, including the findings of this recent study, clearly identify the gender pay gap that exists in medicine, as it does in many other fields, and that it is not explainable solely by differences in specialties, work hours, family status, or title.
To address the inequity, it is imperative that women engage with employers and leaders to both understand and develop skills around effective and appropriate compensation negotiation. Recognizing that compensation plans, especially those built on productivity models, may fail to place adequate value on gender-specific practice styles.
Jennifer Frank is a family physician, physician leader, wife, and mother in Northeast Wisconsin.
A version of this article first appeared on Medscape.com.
AGILE: ‘Exciting’ survival results for IDH1-mutated AML
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
AT ASH 2021