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The majority of patients with migraine do not get the recommended amount of weekly exercise, but those who do gain benefits that extend to fewer migraine days and reduced rates of triggers including stress, depression, and sleep problems, new research shows.

“This study adds to an ever-growing body of research that points to exercise as an effective way to promote general well-being and reduce monthly migraine days,” said study investigator Mason Dyess, DO, from the University of Washington, Seattle. “This study also highlights that exercise is an underutilized resource in migraine sufferers.”

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology..
 

An accessible prophylactic

Dr. Dyess said that the COVID-19 pandemic prompted him and his colleagues to investigate how many patients with migraine in their headache clinic were utilizing “one of the most accessible prevention tools for migraine – exercise.”

“The pandemic has restricted physical and financial access to care for patients in our community and across the country, so understanding how exercise is being used by our patients and its effect on monthly migraine days has never been more important,” Dr. Dyess said.

The study involved 4,647 people diagnosed with migraine. About three-fourths had chronic migraine (at least 15 migraine days a month) and about one-quarter had episodic migraine (up to 14 monthly migraine days).

The patients provided information via a questionnaire about their migraine characteristics, sleep, depression, stress, anxiety, and the amount of moderate to vigorous exercise they got each week.

Only 27% of patients reported getting at least 150 minutes of moderate to vigorous exercise each week, the minimum amount recommended by the World Health Organization.

Patients with migraine who did not achieve the minimum 2.5 hours of moderate to vigorous exercise recommended per week had increased rates of depression, anxiety, and sleep problems.
 

A word of caution

Depression was reported by 47% of patients who reported no exercise, compared with 25% of people who reported the recommended amount of weekly exercise.

Anxiety was reported by 39% of people who did not exercise, compared with 28% of those who got the recommended 150-plus minutes of exercise. Sleep problems were reported by 77% of the nonexercisers versus 61% of those who achieved the recommended exercise amount.

Exercise also appeared to reduce the risk for migraine attacks.

Among patients who did not exercise, 48% had high headache frequency (25-plus headache days per month), while only 5% had low headache frequency (0-4 headache days per month).

In contrast, of people who got the recommended 150-plus minutes of exercise per week, 28% had high headache frequency and 10% had low headache frequency.

“Exercise should be part of the discussion while counseling patients with migraines. This is a resource available across the socioeconomic spectrum that is easily integrated into the plan of care for many patients,” said Dr. Dyess. 

However, he cautioned that there is a subgroup of migraine patients for whom moderate to vigorous exercise is simply not tolerable. “In these patients, research points to the promotion of a healthy diet and lifestyle with gentle movement exercises like yoga rather than aggressively pursuing moderate or vigorous exercise regimens,” Dr. Dyess said.
 

A ‘puzzling’ relationship

Reached for comment, Shaheen Lakhan, MD, PhD, a neurologist in Newton, Mass., and executive director of Global Neuroscience Initiative Foundation, said the interaction of exercise and migraine is “puzzling.”

“First, it is well known that strenuous physical exercise may aggravate or even trigger migraine attacks. These are found even in the migraine diagnostic criteria,” said Dr. Lakhan. “Interestingly, there is a body of evidence that demonstrates a basic level of exercise as prophylactic treatment for migraine.”

Dr. Lakhan said that exercise is “definitely underutilized in clinical practice for migraine for these reasons: Migraineurs have fear avoidance behavior given the strenuous physical exercise as a potential trigger.”

Also weighing in on the study, Noah Rosen, MD, director of Northwell Health’s Headache Center in Great Neck, N.Y., said it’s a “useful reminder of the benefits that can be achieved without medication, but we need more information to give better guidance. I wish this study had given us more information as to what type of exercise was best for people with migraine, whether active group sports, running, swimming, or others.”

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

The majority of patients with migraine do not get the recommended amount of weekly exercise, but those who do gain benefits that extend to fewer migraine days and reduced rates of triggers including stress, depression, and sleep problems, new research shows.

“This study adds to an ever-growing body of research that points to exercise as an effective way to promote general well-being and reduce monthly migraine days,” said study investigator Mason Dyess, DO, from the University of Washington, Seattle. “This study also highlights that exercise is an underutilized resource in migraine sufferers.”

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology..
 

An accessible prophylactic

Dr. Dyess said that the COVID-19 pandemic prompted him and his colleagues to investigate how many patients with migraine in their headache clinic were utilizing “one of the most accessible prevention tools for migraine – exercise.”

“The pandemic has restricted physical and financial access to care for patients in our community and across the country, so understanding how exercise is being used by our patients and its effect on monthly migraine days has never been more important,” Dr. Dyess said.

The study involved 4,647 people diagnosed with migraine. About three-fourths had chronic migraine (at least 15 migraine days a month) and about one-quarter had episodic migraine (up to 14 monthly migraine days).

The patients provided information via a questionnaire about their migraine characteristics, sleep, depression, stress, anxiety, and the amount of moderate to vigorous exercise they got each week.

Only 27% of patients reported getting at least 150 minutes of moderate to vigorous exercise each week, the minimum amount recommended by the World Health Organization.

Patients with migraine who did not achieve the minimum 2.5 hours of moderate to vigorous exercise recommended per week had increased rates of depression, anxiety, and sleep problems.
 

A word of caution

Depression was reported by 47% of patients who reported no exercise, compared with 25% of people who reported the recommended amount of weekly exercise.

Anxiety was reported by 39% of people who did not exercise, compared with 28% of those who got the recommended 150-plus minutes of exercise. Sleep problems were reported by 77% of the nonexercisers versus 61% of those who achieved the recommended exercise amount.

Exercise also appeared to reduce the risk for migraine attacks.

Among patients who did not exercise, 48% had high headache frequency (25-plus headache days per month), while only 5% had low headache frequency (0-4 headache days per month).

In contrast, of people who got the recommended 150-plus minutes of exercise per week, 28% had high headache frequency and 10% had low headache frequency.

“Exercise should be part of the discussion while counseling patients with migraines. This is a resource available across the socioeconomic spectrum that is easily integrated into the plan of care for many patients,” said Dr. Dyess. 

However, he cautioned that there is a subgroup of migraine patients for whom moderate to vigorous exercise is simply not tolerable. “In these patients, research points to the promotion of a healthy diet and lifestyle with gentle movement exercises like yoga rather than aggressively pursuing moderate or vigorous exercise regimens,” Dr. Dyess said.
 

A ‘puzzling’ relationship

Reached for comment, Shaheen Lakhan, MD, PhD, a neurologist in Newton, Mass., and executive director of Global Neuroscience Initiative Foundation, said the interaction of exercise and migraine is “puzzling.”

“First, it is well known that strenuous physical exercise may aggravate or even trigger migraine attacks. These are found even in the migraine diagnostic criteria,” said Dr. Lakhan. “Interestingly, there is a body of evidence that demonstrates a basic level of exercise as prophylactic treatment for migraine.”

Dr. Lakhan said that exercise is “definitely underutilized in clinical practice for migraine for these reasons: Migraineurs have fear avoidance behavior given the strenuous physical exercise as a potential trigger.”

Also weighing in on the study, Noah Rosen, MD, director of Northwell Health’s Headache Center in Great Neck, N.Y., said it’s a “useful reminder of the benefits that can be achieved without medication, but we need more information to give better guidance. I wish this study had given us more information as to what type of exercise was best for people with migraine, whether active group sports, running, swimming, or others.”

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

The majority of patients with migraine do not get the recommended amount of weekly exercise, but those who do gain benefits that extend to fewer migraine days and reduced rates of triggers including stress, depression, and sleep problems, new research shows.

“This study adds to an ever-growing body of research that points to exercise as an effective way to promote general well-being and reduce monthly migraine days,” said study investigator Mason Dyess, DO, from the University of Washington, Seattle. “This study also highlights that exercise is an underutilized resource in migraine sufferers.”

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology..
 

An accessible prophylactic

Dr. Dyess said that the COVID-19 pandemic prompted him and his colleagues to investigate how many patients with migraine in their headache clinic were utilizing “one of the most accessible prevention tools for migraine – exercise.”

“The pandemic has restricted physical and financial access to care for patients in our community and across the country, so understanding how exercise is being used by our patients and its effect on monthly migraine days has never been more important,” Dr. Dyess said.

The study involved 4,647 people diagnosed with migraine. About three-fourths had chronic migraine (at least 15 migraine days a month) and about one-quarter had episodic migraine (up to 14 monthly migraine days).

The patients provided information via a questionnaire about their migraine characteristics, sleep, depression, stress, anxiety, and the amount of moderate to vigorous exercise they got each week.

Only 27% of patients reported getting at least 150 minutes of moderate to vigorous exercise each week, the minimum amount recommended by the World Health Organization.

Patients with migraine who did not achieve the minimum 2.5 hours of moderate to vigorous exercise recommended per week had increased rates of depression, anxiety, and sleep problems.
 

A word of caution

Depression was reported by 47% of patients who reported no exercise, compared with 25% of people who reported the recommended amount of weekly exercise.

Anxiety was reported by 39% of people who did not exercise, compared with 28% of those who got the recommended 150-plus minutes of exercise. Sleep problems were reported by 77% of the nonexercisers versus 61% of those who achieved the recommended exercise amount.

Exercise also appeared to reduce the risk for migraine attacks.

Among patients who did not exercise, 48% had high headache frequency (25-plus headache days per month), while only 5% had low headache frequency (0-4 headache days per month).

In contrast, of people who got the recommended 150-plus minutes of exercise per week, 28% had high headache frequency and 10% had low headache frequency.

“Exercise should be part of the discussion while counseling patients with migraines. This is a resource available across the socioeconomic spectrum that is easily integrated into the plan of care for many patients,” said Dr. Dyess. 

However, he cautioned that there is a subgroup of migraine patients for whom moderate to vigorous exercise is simply not tolerable. “In these patients, research points to the promotion of a healthy diet and lifestyle with gentle movement exercises like yoga rather than aggressively pursuing moderate or vigorous exercise regimens,” Dr. Dyess said.
 

A ‘puzzling’ relationship

Reached for comment, Shaheen Lakhan, MD, PhD, a neurologist in Newton, Mass., and executive director of Global Neuroscience Initiative Foundation, said the interaction of exercise and migraine is “puzzling.”

“First, it is well known that strenuous physical exercise may aggravate or even trigger migraine attacks. These are found even in the migraine diagnostic criteria,” said Dr. Lakhan. “Interestingly, there is a body of evidence that demonstrates a basic level of exercise as prophylactic treatment for migraine.”

Dr. Lakhan said that exercise is “definitely underutilized in clinical practice for migraine for these reasons: Migraineurs have fear avoidance behavior given the strenuous physical exercise as a potential trigger.”

Also weighing in on the study, Noah Rosen, MD, director of Northwell Health’s Headache Center in Great Neck, N.Y., said it’s a “useful reminder of the benefits that can be achieved without medication, but we need more information to give better guidance. I wish this study had given us more information as to what type of exercise was best for people with migraine, whether active group sports, running, swimming, or others.”

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

Exposure to antibiotics 30 days before or after starting treatment with an immune checkpoint inhibitor (ICI) was associated with a benefit in progression-free survival (PFS) among patients with hepatocellular carcinoma (HCC) in an international study.

Response rates and overall survival (OS), on the other hand, did not seem to be affected by antibiotic administration, according to investigator Petros Fessas, MD, of Imperial College London.

Dr. Fessas and colleagues presented these findings in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 485).

Dr. Fessas noted that, in other cancers, antibiotics have been shown to reduce both response and survival rates after ICI.

To assess the impact of early antibiotic exposure on ICI efficacy in HCC, Dr. Fessas and colleagues examined data from 449 patients treated at 12 centers in the United States, Europe, and Asia.

The patients’ median age was 65 years, and 79.1% were men. Nearly three-quarters (73.3%) were cirrhotic (60.4% because of viral hepatitis), 79.9% were Child-Pugh class A, 72.4% were Barcelona Clinic Liver Cancer stage C, and 79% had an Eastern Cooperative Oncology Group performance status of 0-1.
 

Response and survival results

The investigators compared outcomes between patients with and without antibiotic exposure in the early immunotherapy period (EIOP) 30 days before and after ICI initiation.

In all, 170 patients (37.9%) received antibiotics in the EIOP. There were no differences in response rates, disease control rates, or median OS between patients who received antibiotics and those who did not.

The objective response rate was 20.2% in patients who received antibiotics in the EIOP and 16.1% in patients who did not (P = .2808). Disease control rates were 63.1% and 55.4%, respectively (P = .1144). The median OS was 15.3 months and 15.4 months, respectively (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21; P = .6275).

The median PFS, however, was significantly longer in patients who received antibiotics than in patients who did not – 6.1 months and 3.7 months, respectively (HR, 0.74; 95% CI, 0.60-0.93; P = .0135).

To overcome possible bias introduced by misclassification of patients who received antibiotics but discontinued immunotherapy within 30 days of initiation, the investigators conducted a landmark selection analysis among only those patients with a median follow-up for PFS of 30 days or longer (n = 402). This analysis confirmed the prior findings.

“Antibiotic exposure in the 30 days before or after immune checkpoint initiation in hepatocellular carcinoma is associated with prolonged progression-free survival,” Dr. Fessas concluded.

He added that a key question for future research is to discover the immune-microbiologic determinants of response to initiation of ICIs.
 

Positive effect surprising

“My group has shown that antibiotic therapy is normally detrimental in patients with cancer,” investigator David J. Pinato, MD, PhD, of Imperial College London, said in an interview. “So we were very surprised to see a positive effect on PFS.”

He added that the new findings should be interpreted with caution.

“My feeling is that, unlike with many other malignancies, the gut microbiome is heavily involved in the progression of the cirrhosis that pre-dates HCC onset,” he said.

That would suggest the relationship between antibiotics and perturbation of the gut microbiome is dictated by something more than changes in antitumor immune tolerance, he added.

“Overall, I think the interplay is more complex in HCC: cirrhosis/cancer/microbiome, not just microbiome/cancer as in many other tumors,” Dr. Pinato said. “So we are looking at microbial determinants of response in HCC patients undergoing ICI therapy, and we are hopeful to see some more mechanistic evidence behind this association.”

Dr. Pinato disclosed relationships with ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Mina Therapeutics, Eisai, Roche, and AstraZeneca. Dr. Fessas reported having no conflicts of interest. No funding source for the study was disclosed.

Exposure to antibiotics 30 days before or after starting treatment with an immune checkpoint inhibitor (ICI) was associated with a benefit in progression-free survival (PFS) among patients with hepatocellular carcinoma (HCC) in an international study.

Response rates and overall survival (OS), on the other hand, did not seem to be affected by antibiotic administration, according to investigator Petros Fessas, MD, of Imperial College London.

Dr. Fessas and colleagues presented these findings in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 485).

Dr. Fessas noted that, in other cancers, antibiotics have been shown to reduce both response and survival rates after ICI.

To assess the impact of early antibiotic exposure on ICI efficacy in HCC, Dr. Fessas and colleagues examined data from 449 patients treated at 12 centers in the United States, Europe, and Asia.

The patients’ median age was 65 years, and 79.1% were men. Nearly three-quarters (73.3%) were cirrhotic (60.4% because of viral hepatitis), 79.9% were Child-Pugh class A, 72.4% were Barcelona Clinic Liver Cancer stage C, and 79% had an Eastern Cooperative Oncology Group performance status of 0-1.
 

Response and survival results

The investigators compared outcomes between patients with and without antibiotic exposure in the early immunotherapy period (EIOP) 30 days before and after ICI initiation.

In all, 170 patients (37.9%) received antibiotics in the EIOP. There were no differences in response rates, disease control rates, or median OS between patients who received antibiotics and those who did not.

The objective response rate was 20.2% in patients who received antibiotics in the EIOP and 16.1% in patients who did not (P = .2808). Disease control rates were 63.1% and 55.4%, respectively (P = .1144). The median OS was 15.3 months and 15.4 months, respectively (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21; P = .6275).

The median PFS, however, was significantly longer in patients who received antibiotics than in patients who did not – 6.1 months and 3.7 months, respectively (HR, 0.74; 95% CI, 0.60-0.93; P = .0135).

To overcome possible bias introduced by misclassification of patients who received antibiotics but discontinued immunotherapy within 30 days of initiation, the investigators conducted a landmark selection analysis among only those patients with a median follow-up for PFS of 30 days or longer (n = 402). This analysis confirmed the prior findings.

“Antibiotic exposure in the 30 days before or after immune checkpoint initiation in hepatocellular carcinoma is associated with prolonged progression-free survival,” Dr. Fessas concluded.

He added that a key question for future research is to discover the immune-microbiologic determinants of response to initiation of ICIs.
 

Positive effect surprising

“My group has shown that antibiotic therapy is normally detrimental in patients with cancer,” investigator David J. Pinato, MD, PhD, of Imperial College London, said in an interview. “So we were very surprised to see a positive effect on PFS.”

He added that the new findings should be interpreted with caution.

“My feeling is that, unlike with many other malignancies, the gut microbiome is heavily involved in the progression of the cirrhosis that pre-dates HCC onset,” he said.

That would suggest the relationship between antibiotics and perturbation of the gut microbiome is dictated by something more than changes in antitumor immune tolerance, he added.

“Overall, I think the interplay is more complex in HCC: cirrhosis/cancer/microbiome, not just microbiome/cancer as in many other tumors,” Dr. Pinato said. “So we are looking at microbial determinants of response in HCC patients undergoing ICI therapy, and we are hopeful to see some more mechanistic evidence behind this association.”

Dr. Pinato disclosed relationships with ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Mina Therapeutics, Eisai, Roche, and AstraZeneca. Dr. Fessas reported having no conflicts of interest. No funding source for the study was disclosed.

Exposure to antibiotics 30 days before or after starting treatment with an immune checkpoint inhibitor (ICI) was associated with a benefit in progression-free survival (PFS) among patients with hepatocellular carcinoma (HCC) in an international study.

Response rates and overall survival (OS), on the other hand, did not seem to be affected by antibiotic administration, according to investigator Petros Fessas, MD, of Imperial College London.

Dr. Fessas and colleagues presented these findings in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 485).

Dr. Fessas noted that, in other cancers, antibiotics have been shown to reduce both response and survival rates after ICI.

To assess the impact of early antibiotic exposure on ICI efficacy in HCC, Dr. Fessas and colleagues examined data from 449 patients treated at 12 centers in the United States, Europe, and Asia.

The patients’ median age was 65 years, and 79.1% were men. Nearly three-quarters (73.3%) were cirrhotic (60.4% because of viral hepatitis), 79.9% were Child-Pugh class A, 72.4% were Barcelona Clinic Liver Cancer stage C, and 79% had an Eastern Cooperative Oncology Group performance status of 0-1.
 

Response and survival results

The investigators compared outcomes between patients with and without antibiotic exposure in the early immunotherapy period (EIOP) 30 days before and after ICI initiation.

In all, 170 patients (37.9%) received antibiotics in the EIOP. There were no differences in response rates, disease control rates, or median OS between patients who received antibiotics and those who did not.

The objective response rate was 20.2% in patients who received antibiotics in the EIOP and 16.1% in patients who did not (P = .2808). Disease control rates were 63.1% and 55.4%, respectively (P = .1144). The median OS was 15.3 months and 15.4 months, respectively (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21; P = .6275).

The median PFS, however, was significantly longer in patients who received antibiotics than in patients who did not – 6.1 months and 3.7 months, respectively (HR, 0.74; 95% CI, 0.60-0.93; P = .0135).

To overcome possible bias introduced by misclassification of patients who received antibiotics but discontinued immunotherapy within 30 days of initiation, the investigators conducted a landmark selection analysis among only those patients with a median follow-up for PFS of 30 days or longer (n = 402). This analysis confirmed the prior findings.

“Antibiotic exposure in the 30 days before or after immune checkpoint initiation in hepatocellular carcinoma is associated with prolonged progression-free survival,” Dr. Fessas concluded.

He added that a key question for future research is to discover the immune-microbiologic determinants of response to initiation of ICIs.
 

Positive effect surprising

“My group has shown that antibiotic therapy is normally detrimental in patients with cancer,” investigator David J. Pinato, MD, PhD, of Imperial College London, said in an interview. “So we were very surprised to see a positive effect on PFS.”

He added that the new findings should be interpreted with caution.

“My feeling is that, unlike with many other malignancies, the gut microbiome is heavily involved in the progression of the cirrhosis that pre-dates HCC onset,” he said.

That would suggest the relationship between antibiotics and perturbation of the gut microbiome is dictated by something more than changes in antitumor immune tolerance, he added.

“Overall, I think the interplay is more complex in HCC: cirrhosis/cancer/microbiome, not just microbiome/cancer as in many other tumors,” Dr. Pinato said. “So we are looking at microbial determinants of response in HCC patients undergoing ICI therapy, and we are hopeful to see some more mechanistic evidence behind this association.”

Dr. Pinato disclosed relationships with ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Mina Therapeutics, Eisai, Roche, and AstraZeneca. Dr. Fessas reported having no conflicts of interest. No funding source for the study was disclosed.

A quarter of children receiving treatment with rituximab developed hypogammaglobulinemia within 18 months of starting the drug, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance. The findings lend support to previous research identifying a risk of hypogammaglobulinemia in children and adolescents taking rituximab and the need for monitoring immunoglobulin levels in those prescribed it.

Marija Stepanovic/Getty Images Marija Stepanovic

“Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinemia and infections in pediatric patients with rheumatic conditions,” Mei-Sing Ong, PhD, of Harvard Medical School and the Harvard Pilgrim Health Care Institute, both in Boston, and colleagues concluded. “Increased risks appeared to be mediated, at least in part, by exposure to glucocorticoids (hypogammaglobulinemia and serious infections) or cyclophosphamide (hypogammaglobulinemia) administered prior to rituximab.”

The observational study involved a cohort of 93 patients, aged 2-25 years, treated at Boston Children’s Hospital during 2009-2019. The patients received rituximab for a wide range of rheumatic diseases, including systemic lupus erythematosus, vasculitis, juvenile idiopathic arthritis, and juvenile dermatomyositis or other polymyositis. The researchers excluded patients who had previously had hypogammaglobulinemia before using rituximab.

In this cohort, 26.9% of patients developed hypogammaglobulinemia, and 20.4% of patients developed an infectious complication within 18 months of beginning rituximab treatment. The infection was serious enough to require inpatient treatment in more than half of those who developed infections (57.9%).

Risk of new-onset hypogammaglobulinemia increased with decreasing age (P = .004), and males were more than four times more likely to develop the condition (odds ratio, 4.55; P = .012). Risk of an infection was also more likely among younger patients (OR, 0.87; P = .039).

Patients with vasculitis were fivefold more likely to develop the hypogammaglobulinemia than were those with other rheumatic diseases after the researchers accounted for age, sex, underlying disease, and medication use (OR, 5.04; P = .017). Risk was also greater in patients with exposure to cyclophosphamide in the year before starting rituximab (OR, 3.76; P = .032), although the finding narrowly reached statistical significance after adjustment for those covariates (OR, 4.41; P = .048).

Glucocorticoid treatment in the month before rituximab was associated with an elevated risk of hypogammaglobulinemia before adjustment (OR, 4.53; P = .007) but lost significance after adjustment. Those taking glucocorticoids had a greater than eightfold increase in infection risk (OR, 8.5; P = .006) before adjustment, which dropped to a fivefold risk after accounting for age, sex, underlying disease, and medication use (OR, 5.4; P = .040).

Monitoring needed for relatively common side effect

The findings are consistent with those seen in a cohort study conducted at Lurie Children’s Hospital of Chicago and published in 2019, said Amer M. Khojah, MD, an attending physician in allergy, immunology, and rheumatology at Lurie and an assistant professor of pediatrics at Northwestern University, also in Chicago. He was not involved in the current study.

“The main takeaway from this study is that we need to be careful about this side effect because it’s relatively common,” Dr. Khojah said in an interview.

At his institution, all patients undergo baseline labs to measure IgG levels prior to initiating rituximab and then have labs drawn again at 3 months and 1 year after starting the drug. Transient hypogammaglobulinemia may not require treatment, he said, but if it persists or the patient develops an infection, treatment with intravenous immunoglobulin is indicated. Yet the drug is so commonly used across a wide range of specialties that there’s a great deal of variability in clinical practice in terms of monitoring and follow-up, Dr. Khojah said.

“The problem is, if you don’t measure it, the patient might be get hypogammaglobulinemia and you don’t know it,” potentially leading to infections that the physician may or may not hear about, he said. “If you are the one who gives them the rituximab, you need to make sure they don’t get the side effects” or that they receive treatment if they do, he said.

“These data are supportive of the necessity to follow patients closely for infection after rituximab, especially considering that many infections may be severe and require hospitalization,” Dr. McAtee said in an interview. “The period of immunosuppression and subsequent infection risk following rituximab, even after single courses, may last well beyond a year following a single course. This is particularly true in patients receiving concurrent immunosuppressive therapy.”

Dr. McAtee similarly published data this year finding frequent infections among young patients receiving rituximab. Hypogammaglobulinemia is already more likely in patients who require rituximab because of other immunosuppressive medication they often take, but the risk “jumped substantially following rituximab,” he said. In addition to patients with low levels of IgG, 41% of patients showed low levels of IgM in that study.

“Nearly a third of patients with normal baseline IgM had persistently low levels more than a year after rituximab, consistent with prolonged B-cell recovery,” Dr. McAtee said. “It is necessary to highlight the importance of IgM in these patients, as common strategies to treat hypogammaglobulinemia, specifically intravenous immunoglobulin, do not replete IgM.”

Neither Dr. Khojah nor Dr. McAtee saw the risk of hypogammaglobulinemia as a reason to avoid rituximab when indicated.

“It is often the best choice for patients whose diseases have not responded to first-line therapies,” Dr. McAtee said. “This and similar studies inform the risk-benefit decision that the medical team must make, as well as the medical surveillance to be considered for patients following a course of rituximab. Going forward, strategies to mitigate infection risk after rituximab, particularly in the first 3 months when they are most common, should be pursued.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. The authors did not note whether they had any disclosures. Dr. Khojah and Dr. McAtee had no disclosures.

A quarter of children receiving treatment with rituximab developed hypogammaglobulinemia within 18 months of starting the drug, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance. The findings lend support to previous research identifying a risk of hypogammaglobulinemia in children and adolescents taking rituximab and the need for monitoring immunoglobulin levels in those prescribed it.

Marija Stepanovic/Getty Images Marija Stepanovic

“Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinemia and infections in pediatric patients with rheumatic conditions,” Mei-Sing Ong, PhD, of Harvard Medical School and the Harvard Pilgrim Health Care Institute, both in Boston, and colleagues concluded. “Increased risks appeared to be mediated, at least in part, by exposure to glucocorticoids (hypogammaglobulinemia and serious infections) or cyclophosphamide (hypogammaglobulinemia) administered prior to rituximab.”

The observational study involved a cohort of 93 patients, aged 2-25 years, treated at Boston Children’s Hospital during 2009-2019. The patients received rituximab for a wide range of rheumatic diseases, including systemic lupus erythematosus, vasculitis, juvenile idiopathic arthritis, and juvenile dermatomyositis or other polymyositis. The researchers excluded patients who had previously had hypogammaglobulinemia before using rituximab.

In this cohort, 26.9% of patients developed hypogammaglobulinemia, and 20.4% of patients developed an infectious complication within 18 months of beginning rituximab treatment. The infection was serious enough to require inpatient treatment in more than half of those who developed infections (57.9%).

Risk of new-onset hypogammaglobulinemia increased with decreasing age (P = .004), and males were more than four times more likely to develop the condition (odds ratio, 4.55; P = .012). Risk of an infection was also more likely among younger patients (OR, 0.87; P = .039).

Patients with vasculitis were fivefold more likely to develop the hypogammaglobulinemia than were those with other rheumatic diseases after the researchers accounted for age, sex, underlying disease, and medication use (OR, 5.04; P = .017). Risk was also greater in patients with exposure to cyclophosphamide in the year before starting rituximab (OR, 3.76; P = .032), although the finding narrowly reached statistical significance after adjustment for those covariates (OR, 4.41; P = .048).

Glucocorticoid treatment in the month before rituximab was associated with an elevated risk of hypogammaglobulinemia before adjustment (OR, 4.53; P = .007) but lost significance after adjustment. Those taking glucocorticoids had a greater than eightfold increase in infection risk (OR, 8.5; P = .006) before adjustment, which dropped to a fivefold risk after accounting for age, sex, underlying disease, and medication use (OR, 5.4; P = .040).

Monitoring needed for relatively common side effect

The findings are consistent with those seen in a cohort study conducted at Lurie Children’s Hospital of Chicago and published in 2019, said Amer M. Khojah, MD, an attending physician in allergy, immunology, and rheumatology at Lurie and an assistant professor of pediatrics at Northwestern University, also in Chicago. He was not involved in the current study.

“The main takeaway from this study is that we need to be careful about this side effect because it’s relatively common,” Dr. Khojah said in an interview.

At his institution, all patients undergo baseline labs to measure IgG levels prior to initiating rituximab and then have labs drawn again at 3 months and 1 year after starting the drug. Transient hypogammaglobulinemia may not require treatment, he said, but if it persists or the patient develops an infection, treatment with intravenous immunoglobulin is indicated. Yet the drug is so commonly used across a wide range of specialties that there’s a great deal of variability in clinical practice in terms of monitoring and follow-up, Dr. Khojah said.

“The problem is, if you don’t measure it, the patient might be get hypogammaglobulinemia and you don’t know it,” potentially leading to infections that the physician may or may not hear about, he said. “If you are the one who gives them the rituximab, you need to make sure they don’t get the side effects” or that they receive treatment if they do, he said.

“These data are supportive of the necessity to follow patients closely for infection after rituximab, especially considering that many infections may be severe and require hospitalization,” Dr. McAtee said in an interview. “The period of immunosuppression and subsequent infection risk following rituximab, even after single courses, may last well beyond a year following a single course. This is particularly true in patients receiving concurrent immunosuppressive therapy.”

Dr. McAtee similarly published data this year finding frequent infections among young patients receiving rituximab. Hypogammaglobulinemia is already more likely in patients who require rituximab because of other immunosuppressive medication they often take, but the risk “jumped substantially following rituximab,” he said. In addition to patients with low levels of IgG, 41% of patients showed low levels of IgM in that study.

“Nearly a third of patients with normal baseline IgM had persistently low levels more than a year after rituximab, consistent with prolonged B-cell recovery,” Dr. McAtee said. “It is necessary to highlight the importance of IgM in these patients, as common strategies to treat hypogammaglobulinemia, specifically intravenous immunoglobulin, do not replete IgM.”

Neither Dr. Khojah nor Dr. McAtee saw the risk of hypogammaglobulinemia as a reason to avoid rituximab when indicated.

“It is often the best choice for patients whose diseases have not responded to first-line therapies,” Dr. McAtee said. “This and similar studies inform the risk-benefit decision that the medical team must make, as well as the medical surveillance to be considered for patients following a course of rituximab. Going forward, strategies to mitigate infection risk after rituximab, particularly in the first 3 months when they are most common, should be pursued.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. The authors did not note whether they had any disclosures. Dr. Khojah and Dr. McAtee had no disclosures.

A quarter of children receiving treatment with rituximab developed hypogammaglobulinemia within 18 months of starting the drug, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance. The findings lend support to previous research identifying a risk of hypogammaglobulinemia in children and adolescents taking rituximab and the need for monitoring immunoglobulin levels in those prescribed it.

Marija Stepanovic/Getty Images Marija Stepanovic

“Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinemia and infections in pediatric patients with rheumatic conditions,” Mei-Sing Ong, PhD, of Harvard Medical School and the Harvard Pilgrim Health Care Institute, both in Boston, and colleagues concluded. “Increased risks appeared to be mediated, at least in part, by exposure to glucocorticoids (hypogammaglobulinemia and serious infections) or cyclophosphamide (hypogammaglobulinemia) administered prior to rituximab.”

The observational study involved a cohort of 93 patients, aged 2-25 years, treated at Boston Children’s Hospital during 2009-2019. The patients received rituximab for a wide range of rheumatic diseases, including systemic lupus erythematosus, vasculitis, juvenile idiopathic arthritis, and juvenile dermatomyositis or other polymyositis. The researchers excluded patients who had previously had hypogammaglobulinemia before using rituximab.

In this cohort, 26.9% of patients developed hypogammaglobulinemia, and 20.4% of patients developed an infectious complication within 18 months of beginning rituximab treatment. The infection was serious enough to require inpatient treatment in more than half of those who developed infections (57.9%).

Risk of new-onset hypogammaglobulinemia increased with decreasing age (P = .004), and males were more than four times more likely to develop the condition (odds ratio, 4.55; P = .012). Risk of an infection was also more likely among younger patients (OR, 0.87; P = .039).

Patients with vasculitis were fivefold more likely to develop the hypogammaglobulinemia than were those with other rheumatic diseases after the researchers accounted for age, sex, underlying disease, and medication use (OR, 5.04; P = .017). Risk was also greater in patients with exposure to cyclophosphamide in the year before starting rituximab (OR, 3.76; P = .032), although the finding narrowly reached statistical significance after adjustment for those covariates (OR, 4.41; P = .048).

Glucocorticoid treatment in the month before rituximab was associated with an elevated risk of hypogammaglobulinemia before adjustment (OR, 4.53; P = .007) but lost significance after adjustment. Those taking glucocorticoids had a greater than eightfold increase in infection risk (OR, 8.5; P = .006) before adjustment, which dropped to a fivefold risk after accounting for age, sex, underlying disease, and medication use (OR, 5.4; P = .040).

Monitoring needed for relatively common side effect

The findings are consistent with those seen in a cohort study conducted at Lurie Children’s Hospital of Chicago and published in 2019, said Amer M. Khojah, MD, an attending physician in allergy, immunology, and rheumatology at Lurie and an assistant professor of pediatrics at Northwestern University, also in Chicago. He was not involved in the current study.

“The main takeaway from this study is that we need to be careful about this side effect because it’s relatively common,” Dr. Khojah said in an interview.

At his institution, all patients undergo baseline labs to measure IgG levels prior to initiating rituximab and then have labs drawn again at 3 months and 1 year after starting the drug. Transient hypogammaglobulinemia may not require treatment, he said, but if it persists or the patient develops an infection, treatment with intravenous immunoglobulin is indicated. Yet the drug is so commonly used across a wide range of specialties that there’s a great deal of variability in clinical practice in terms of monitoring and follow-up, Dr. Khojah said.

“The problem is, if you don’t measure it, the patient might be get hypogammaglobulinemia and you don’t know it,” potentially leading to infections that the physician may or may not hear about, he said. “If you are the one who gives them the rituximab, you need to make sure they don’t get the side effects” or that they receive treatment if they do, he said.

“These data are supportive of the necessity to follow patients closely for infection after rituximab, especially considering that many infections may be severe and require hospitalization,” Dr. McAtee said in an interview. “The period of immunosuppression and subsequent infection risk following rituximab, even after single courses, may last well beyond a year following a single course. This is particularly true in patients receiving concurrent immunosuppressive therapy.”

Dr. McAtee similarly published data this year finding frequent infections among young patients receiving rituximab. Hypogammaglobulinemia is already more likely in patients who require rituximab because of other immunosuppressive medication they often take, but the risk “jumped substantially following rituximab,” he said. In addition to patients with low levels of IgG, 41% of patients showed low levels of IgM in that study.

“Nearly a third of patients with normal baseline IgM had persistently low levels more than a year after rituximab, consistent with prolonged B-cell recovery,” Dr. McAtee said. “It is necessary to highlight the importance of IgM in these patients, as common strategies to treat hypogammaglobulinemia, specifically intravenous immunoglobulin, do not replete IgM.”

Neither Dr. Khojah nor Dr. McAtee saw the risk of hypogammaglobulinemia as a reason to avoid rituximab when indicated.

“It is often the best choice for patients whose diseases have not responded to first-line therapies,” Dr. McAtee said. “This and similar studies inform the risk-benefit decision that the medical team must make, as well as the medical surveillance to be considered for patients following a course of rituximab. Going forward, strategies to mitigate infection risk after rituximab, particularly in the first 3 months when they are most common, should be pursued.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. The authors did not note whether they had any disclosures. Dr. Khojah and Dr. McAtee had no disclosures.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

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

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

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

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

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

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Read the supplement here or by clicking on the image

Elevations in serum neurofilament light chain levels in people with multiple sclerosis (MS) are significantly linked to worse neurologic function, clinical disability, and lower brain volumes, according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore. “An important strength of this cohort is that it is a realworld cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.” The research was presented at the 2021 ACTRIMS Forum.

Read the supplement here or by clicking on the image

Elevations in serum neurofilament light chain levels in people with multiple sclerosis (MS) are significantly linked to worse neurologic function, clinical disability, and lower brain volumes, according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore. “An important strength of this cohort is that it is a realworld cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.” The research was presented at the 2021 ACTRIMS Forum.

Read the supplement here or by clicking on the image

Elevations in serum neurofilament light chain levels in people with multiple sclerosis (MS) are significantly linked to worse neurologic function, clinical disability, and lower brain volumes, according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore. “An important strength of this cohort is that it is a realworld cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.” The research was presented at the 2021 ACTRIMS Forum.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.

The new analysis shows benefit even in patients with high-risk disease.

The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).

Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.

“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.

Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
 

Benefit seen also in high-risk group

At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).

High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted. 

In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.

The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said. 

Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.

“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.

However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.

Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.

In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
 

What’s next?

In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.

“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.

“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.

The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.

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

Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.

The new analysis shows benefit even in patients with high-risk disease.

The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).

Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.

“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.

Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
 

Benefit seen also in high-risk group

At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).

High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted. 

In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.

The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said. 

Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.

“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.

However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.

Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.

In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
 

What’s next?

In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.

“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.

“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.

The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.

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

Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.

The new analysis shows benefit even in patients with high-risk disease.

The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).

Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.

“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.

Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
 

Benefit seen also in high-risk group

At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).

High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted. 

In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.

The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said. 

Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.

“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.

However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.

Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.

In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
 

What’s next?

In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.

“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.

“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.

The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.

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

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.