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Lung cancer risk misperceptions impede lifesaving screenings
according to analysis of data from the SUMMIT study recently published in the Journal of Thoracic Oncology. Such an approach may be more effective than trying to change risk perceptions.
While 1-year survival among patients diagnosed with early-stage lung cancer is 88%, it is only 19% for those diagnosed with advanced disease. But only 27% of patients are diagnosed with early-stage disease. Screening high-risk asymptomatic adults using LDCT detects early-stage disease and significantly reduces lung cancer mortality, according to Samantha L. Quaife, PhD, of the Wolfson Institute of Population Health at Queen Mary University of London, and associates.
The effectiveness and equity of LDCT lung cancer screening as a population-level early detection strategy is compromised by low uptake among high-risk groups, the authors wrote.
In the United States, only 2% of eligible smokers have been screened since screening was first recommended in 2013. To provide a scientific evidence base for intervention, an understanding of factors making high-risk groups less likely to participate in LDCT screening is critical, Dr. Quaife and colleagues wrote.
Their longitudinal cohort study evaluating psychological correlates of lung cancer screening uptake included 44,000 ever-smokers (aged 55-77 years) who were invited to mail a self-regulatory questionnaire for lung cancer screening. Eligibility for LDCT lung cancer screening and inclusion in the SUMMIT study were further determined through telephone and in-person Lung Health Check (LHC) appointments. The primary outcome was uptake of the invitation to book an LHC appointment by telephone.
Of those invited, 7,966 (18.1%) returned the questionnaire with 7,730 (45% female; mean age, about 64 years) linked to screening uptake data. About 30% reported being current smokers with high tobacco dependence (60.3% smoking within 30 minutes of waking). The analysis from Dr. Quaife and colleagues looked at psychological correlates of lung cancer screening uptake using a psychometrically validated self-regulatory questionnaire for lung cancer screening (SRQ-LCS) to measure psychological constructs hypothesized to be associated with uptake which included consequences, emotional representation, coherence (lung cancer knowledge), treatment control, personal control, risk perception, perceived stigma, response efficacy of smoking cessation, early diagnosis behavioral response, survival from lung cancer, and treatment intention.
Among those who perceived early diagnosis to be more beneficial as a behavioral response, the positive association with uptake was strongest (adjusted odds ratio, 1.37; 95% confidence interval, 1.33-1.41). Those who perceived greater personal control (aOR, 1.09; 95% CI, 1.05-1.11) or believed their risk of lung cancer was high (aOR, 1.08; 95% CI, 1.05-1.10) were also more likely to respond. Other uptake increases were found for those who perceived smoking cessation as an effective means of reducing lung cancer risk or thought the chances of surviving early-stage lung cancer were good or fair (P < .01), and for those who perceived lung cancer as stigmatized (aOR, 1.26; 95% CI, 1.14-1.40). Most of these constructs were also perceived more negatively by current than former smokers.
Income, employment, education, social class, and housing conditions were significantly associated with many of the constructs. Greater affluence correlated with perceived personal control and benefit from early diagnosis, but more negative perceptions of the consequences of lung cancer. Also, those from more affluent areas were more likely to perceive lung cancer to be stigmatized and perceive smoking cessation to be less effective in reducing risk. Current daily smokers were less willing to be treated for early-stage disease, more pessimistic about survival, but had the highest-risk perception scores, at odds with their lower participation in lung screening trials. This contradiction, Dr. Quaife and colleagues suggested, may be explained by current smokers also holding more negative perceptions associated with lower uptake, including negative perceptions of lung cancer controllability, early diagnosis and survival, lower willingness to be treated, and belief that smoking cessation is less effective in reducing risk. All of these undermine positive responses to their high perceived risk.
“These findings pinpoint specific psychological targets for intervention,” the authors wrote. Experimental studies investigating the methods and mechanisms through which these perceptions could be changed are needed.
The study was funded by Cancer Research UK Population Research Fellowship (C50664/A24460) awarded to Dr. Quaife. The study investigators declared no support from financial organizations that might have an interest in the submitted work in the previous 3 years.
according to analysis of data from the SUMMIT study recently published in the Journal of Thoracic Oncology. Such an approach may be more effective than trying to change risk perceptions.
While 1-year survival among patients diagnosed with early-stage lung cancer is 88%, it is only 19% for those diagnosed with advanced disease. But only 27% of patients are diagnosed with early-stage disease. Screening high-risk asymptomatic adults using LDCT detects early-stage disease and significantly reduces lung cancer mortality, according to Samantha L. Quaife, PhD, of the Wolfson Institute of Population Health at Queen Mary University of London, and associates.
The effectiveness and equity of LDCT lung cancer screening as a population-level early detection strategy is compromised by low uptake among high-risk groups, the authors wrote.
In the United States, only 2% of eligible smokers have been screened since screening was first recommended in 2013. To provide a scientific evidence base for intervention, an understanding of factors making high-risk groups less likely to participate in LDCT screening is critical, Dr. Quaife and colleagues wrote.
Their longitudinal cohort study evaluating psychological correlates of lung cancer screening uptake included 44,000 ever-smokers (aged 55-77 years) who were invited to mail a self-regulatory questionnaire for lung cancer screening. Eligibility for LDCT lung cancer screening and inclusion in the SUMMIT study were further determined through telephone and in-person Lung Health Check (LHC) appointments. The primary outcome was uptake of the invitation to book an LHC appointment by telephone.
Of those invited, 7,966 (18.1%) returned the questionnaire with 7,730 (45% female; mean age, about 64 years) linked to screening uptake data. About 30% reported being current smokers with high tobacco dependence (60.3% smoking within 30 minutes of waking). The analysis from Dr. Quaife and colleagues looked at psychological correlates of lung cancer screening uptake using a psychometrically validated self-regulatory questionnaire for lung cancer screening (SRQ-LCS) to measure psychological constructs hypothesized to be associated with uptake which included consequences, emotional representation, coherence (lung cancer knowledge), treatment control, personal control, risk perception, perceived stigma, response efficacy of smoking cessation, early diagnosis behavioral response, survival from lung cancer, and treatment intention.
Among those who perceived early diagnosis to be more beneficial as a behavioral response, the positive association with uptake was strongest (adjusted odds ratio, 1.37; 95% confidence interval, 1.33-1.41). Those who perceived greater personal control (aOR, 1.09; 95% CI, 1.05-1.11) or believed their risk of lung cancer was high (aOR, 1.08; 95% CI, 1.05-1.10) were also more likely to respond. Other uptake increases were found for those who perceived smoking cessation as an effective means of reducing lung cancer risk or thought the chances of surviving early-stage lung cancer were good or fair (P < .01), and for those who perceived lung cancer as stigmatized (aOR, 1.26; 95% CI, 1.14-1.40). Most of these constructs were also perceived more negatively by current than former smokers.
Income, employment, education, social class, and housing conditions were significantly associated with many of the constructs. Greater affluence correlated with perceived personal control and benefit from early diagnosis, but more negative perceptions of the consequences of lung cancer. Also, those from more affluent areas were more likely to perceive lung cancer to be stigmatized and perceive smoking cessation to be less effective in reducing risk. Current daily smokers were less willing to be treated for early-stage disease, more pessimistic about survival, but had the highest-risk perception scores, at odds with their lower participation in lung screening trials. This contradiction, Dr. Quaife and colleagues suggested, may be explained by current smokers also holding more negative perceptions associated with lower uptake, including negative perceptions of lung cancer controllability, early diagnosis and survival, lower willingness to be treated, and belief that smoking cessation is less effective in reducing risk. All of these undermine positive responses to their high perceived risk.
“These findings pinpoint specific psychological targets for intervention,” the authors wrote. Experimental studies investigating the methods and mechanisms through which these perceptions could be changed are needed.
The study was funded by Cancer Research UK Population Research Fellowship (C50664/A24460) awarded to Dr. Quaife. The study investigators declared no support from financial organizations that might have an interest in the submitted work in the previous 3 years.
according to analysis of data from the SUMMIT study recently published in the Journal of Thoracic Oncology. Such an approach may be more effective than trying to change risk perceptions.
While 1-year survival among patients diagnosed with early-stage lung cancer is 88%, it is only 19% for those diagnosed with advanced disease. But only 27% of patients are diagnosed with early-stage disease. Screening high-risk asymptomatic adults using LDCT detects early-stage disease and significantly reduces lung cancer mortality, according to Samantha L. Quaife, PhD, of the Wolfson Institute of Population Health at Queen Mary University of London, and associates.
The effectiveness and equity of LDCT lung cancer screening as a population-level early detection strategy is compromised by low uptake among high-risk groups, the authors wrote.
In the United States, only 2% of eligible smokers have been screened since screening was first recommended in 2013. To provide a scientific evidence base for intervention, an understanding of factors making high-risk groups less likely to participate in LDCT screening is critical, Dr. Quaife and colleagues wrote.
Their longitudinal cohort study evaluating psychological correlates of lung cancer screening uptake included 44,000 ever-smokers (aged 55-77 years) who were invited to mail a self-regulatory questionnaire for lung cancer screening. Eligibility for LDCT lung cancer screening and inclusion in the SUMMIT study were further determined through telephone and in-person Lung Health Check (LHC) appointments. The primary outcome was uptake of the invitation to book an LHC appointment by telephone.
Of those invited, 7,966 (18.1%) returned the questionnaire with 7,730 (45% female; mean age, about 64 years) linked to screening uptake data. About 30% reported being current smokers with high tobacco dependence (60.3% smoking within 30 minutes of waking). The analysis from Dr. Quaife and colleagues looked at psychological correlates of lung cancer screening uptake using a psychometrically validated self-regulatory questionnaire for lung cancer screening (SRQ-LCS) to measure psychological constructs hypothesized to be associated with uptake which included consequences, emotional representation, coherence (lung cancer knowledge), treatment control, personal control, risk perception, perceived stigma, response efficacy of smoking cessation, early diagnosis behavioral response, survival from lung cancer, and treatment intention.
Among those who perceived early diagnosis to be more beneficial as a behavioral response, the positive association with uptake was strongest (adjusted odds ratio, 1.37; 95% confidence interval, 1.33-1.41). Those who perceived greater personal control (aOR, 1.09; 95% CI, 1.05-1.11) or believed their risk of lung cancer was high (aOR, 1.08; 95% CI, 1.05-1.10) were also more likely to respond. Other uptake increases were found for those who perceived smoking cessation as an effective means of reducing lung cancer risk or thought the chances of surviving early-stage lung cancer were good or fair (P < .01), and for those who perceived lung cancer as stigmatized (aOR, 1.26; 95% CI, 1.14-1.40). Most of these constructs were also perceived more negatively by current than former smokers.
Income, employment, education, social class, and housing conditions were significantly associated with many of the constructs. Greater affluence correlated with perceived personal control and benefit from early diagnosis, but more negative perceptions of the consequences of lung cancer. Also, those from more affluent areas were more likely to perceive lung cancer to be stigmatized and perceive smoking cessation to be less effective in reducing risk. Current daily smokers were less willing to be treated for early-stage disease, more pessimistic about survival, but had the highest-risk perception scores, at odds with their lower participation in lung screening trials. This contradiction, Dr. Quaife and colleagues suggested, may be explained by current smokers also holding more negative perceptions associated with lower uptake, including negative perceptions of lung cancer controllability, early diagnosis and survival, lower willingness to be treated, and belief that smoking cessation is less effective in reducing risk. All of these undermine positive responses to their high perceived risk.
“These findings pinpoint specific psychological targets for intervention,” the authors wrote. Experimental studies investigating the methods and mechanisms through which these perceptions could be changed are needed.
The study was funded by Cancer Research UK Population Research Fellowship (C50664/A24460) awarded to Dr. Quaife. The study investigators declared no support from financial organizations that might have an interest in the submitted work in the previous 3 years.
FROM THE JOURNAL OF THORACIC ONCOLOGY
NSCLC therapies associated with cardiac events
A new analysis of cardiovascular adverse drug reactions for non–small cell lung cancer (NCSLC)–targeted therapies finds that ALK and ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than BRAF and EGFR inhibitors.
The findings are especially important because cardiovascular disease is known to be associated with NSCLC. Even before the start of therapy, 14%-22% of patients with stage I-IV NSCLC have heart failure and 26%-31% of patients have arrhythmias. No other study to date has described cardiovascular effects to this extent as a result of treatment.
The findings were published in the Journal of Thoracic Oncology.
Led by Joel W. Neal, MD, PhD, a medical oncologist at Stanford (Calif.) Health Care, researchers evaluated the association between NSCLC-targeted agents with arrhythmia and heart failure. Their findings are based on analysis of data from the World Health Organization pharmacovigilance database VigiBase. They found that of 98,765 adverse reactions, 61,383 occurred in patients treated with EGFR inhibitors, 15,540 were associated with ALK inhibitors, and 21,842 were associated with BRAF and MEK inhibitors. Arrhythmias occurred in 1,783 patients and 1,146 patients had heart failure.
The specifics
Strong associations with conduction disease and QT prolongation were found for ALK and ROS1 inhibitors, especially crizotinib. Of QT prolongation cases, 38.5% of patients on ceritinib and 18.4% of patients on crizotinib also had conduction disease and 7.9% of alectinib-associated conduction disease cases also had prolongation.
BRAF and MEK inhibitors had stronger associations with heart failure, while osimertinib, a third-generation EGFR tyrosine kinase inhibitor, was strongly associated with QT prolongation, supraventricular tachycardia, and heart failure.
ALK inhibitors were found to be 13 times more likely to lead to conduction disease and five times more likely to lead to lead to long QT syndrome as compared to all NSCLC-targeted therapies together. ALK inhibitor crizotinib had significantly higher odds of conduction disease, compared with all other targeted therapies, but of all ALK inhibitors, ceritinib and lorlatinib had the lowest odds of conduction disease. Crizotinib was 1.9 times more likely to lead to QT prolongation than other ALK inhibitors.
The EGFR inhibitor osimertinib was associated with 49 times more like to lead to long QT syndrome than other EGFR inhibitors and 6 times more likely as compared with all other targeted therapies. The EGFR inhibitor gefitinib was twice as likely than other EGFR inhibitors to lead to conduction disease. The third-generation EGFR inhibitor osimertinib had approximately two times higher odds of supraventricular tachycardia than other EGFR inhibitors.
Osimertinib was associated with 6.8 times higher chances of heart failure, compared with other EGFR inhibitors, and 3.6 times more than other targeted therapies. Dabrafenib and trametinib were associated with two to three times higher odds of heart failure as compared with other targeted therapies.
“There is a need for an understanding of the mechanisms underlying these toxicities and for additional studies to establish standardized guidelines for monitoring, particularly for osimertinib, crizotinib, and alectinib,” the authors wrote
The authors disclosed a number of paid advisory roles with various pharmaceutical companies.
A new analysis of cardiovascular adverse drug reactions for non–small cell lung cancer (NCSLC)–targeted therapies finds that ALK and ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than BRAF and EGFR inhibitors.
The findings are especially important because cardiovascular disease is known to be associated with NSCLC. Even before the start of therapy, 14%-22% of patients with stage I-IV NSCLC have heart failure and 26%-31% of patients have arrhythmias. No other study to date has described cardiovascular effects to this extent as a result of treatment.
The findings were published in the Journal of Thoracic Oncology.
Led by Joel W. Neal, MD, PhD, a medical oncologist at Stanford (Calif.) Health Care, researchers evaluated the association between NSCLC-targeted agents with arrhythmia and heart failure. Their findings are based on analysis of data from the World Health Organization pharmacovigilance database VigiBase. They found that of 98,765 adverse reactions, 61,383 occurred in patients treated with EGFR inhibitors, 15,540 were associated with ALK inhibitors, and 21,842 were associated with BRAF and MEK inhibitors. Arrhythmias occurred in 1,783 patients and 1,146 patients had heart failure.
The specifics
Strong associations with conduction disease and QT prolongation were found for ALK and ROS1 inhibitors, especially crizotinib. Of QT prolongation cases, 38.5% of patients on ceritinib and 18.4% of patients on crizotinib also had conduction disease and 7.9% of alectinib-associated conduction disease cases also had prolongation.
BRAF and MEK inhibitors had stronger associations with heart failure, while osimertinib, a third-generation EGFR tyrosine kinase inhibitor, was strongly associated with QT prolongation, supraventricular tachycardia, and heart failure.
ALK inhibitors were found to be 13 times more likely to lead to conduction disease and five times more likely to lead to lead to long QT syndrome as compared to all NSCLC-targeted therapies together. ALK inhibitor crizotinib had significantly higher odds of conduction disease, compared with all other targeted therapies, but of all ALK inhibitors, ceritinib and lorlatinib had the lowest odds of conduction disease. Crizotinib was 1.9 times more likely to lead to QT prolongation than other ALK inhibitors.
The EGFR inhibitor osimertinib was associated with 49 times more like to lead to long QT syndrome than other EGFR inhibitors and 6 times more likely as compared with all other targeted therapies. The EGFR inhibitor gefitinib was twice as likely than other EGFR inhibitors to lead to conduction disease. The third-generation EGFR inhibitor osimertinib had approximately two times higher odds of supraventricular tachycardia than other EGFR inhibitors.
Osimertinib was associated with 6.8 times higher chances of heart failure, compared with other EGFR inhibitors, and 3.6 times more than other targeted therapies. Dabrafenib and trametinib were associated with two to three times higher odds of heart failure as compared with other targeted therapies.
“There is a need for an understanding of the mechanisms underlying these toxicities and for additional studies to establish standardized guidelines for monitoring, particularly for osimertinib, crizotinib, and alectinib,” the authors wrote
The authors disclosed a number of paid advisory roles with various pharmaceutical companies.
A new analysis of cardiovascular adverse drug reactions for non–small cell lung cancer (NCSLC)–targeted therapies finds that ALK and ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than BRAF and EGFR inhibitors.
The findings are especially important because cardiovascular disease is known to be associated with NSCLC. Even before the start of therapy, 14%-22% of patients with stage I-IV NSCLC have heart failure and 26%-31% of patients have arrhythmias. No other study to date has described cardiovascular effects to this extent as a result of treatment.
The findings were published in the Journal of Thoracic Oncology.
Led by Joel W. Neal, MD, PhD, a medical oncologist at Stanford (Calif.) Health Care, researchers evaluated the association between NSCLC-targeted agents with arrhythmia and heart failure. Their findings are based on analysis of data from the World Health Organization pharmacovigilance database VigiBase. They found that of 98,765 adverse reactions, 61,383 occurred in patients treated with EGFR inhibitors, 15,540 were associated with ALK inhibitors, and 21,842 were associated with BRAF and MEK inhibitors. Arrhythmias occurred in 1,783 patients and 1,146 patients had heart failure.
The specifics
Strong associations with conduction disease and QT prolongation were found for ALK and ROS1 inhibitors, especially crizotinib. Of QT prolongation cases, 38.5% of patients on ceritinib and 18.4% of patients on crizotinib also had conduction disease and 7.9% of alectinib-associated conduction disease cases also had prolongation.
BRAF and MEK inhibitors had stronger associations with heart failure, while osimertinib, a third-generation EGFR tyrosine kinase inhibitor, was strongly associated with QT prolongation, supraventricular tachycardia, and heart failure.
ALK inhibitors were found to be 13 times more likely to lead to conduction disease and five times more likely to lead to lead to long QT syndrome as compared to all NSCLC-targeted therapies together. ALK inhibitor crizotinib had significantly higher odds of conduction disease, compared with all other targeted therapies, but of all ALK inhibitors, ceritinib and lorlatinib had the lowest odds of conduction disease. Crizotinib was 1.9 times more likely to lead to QT prolongation than other ALK inhibitors.
The EGFR inhibitor osimertinib was associated with 49 times more like to lead to long QT syndrome than other EGFR inhibitors and 6 times more likely as compared with all other targeted therapies. The EGFR inhibitor gefitinib was twice as likely than other EGFR inhibitors to lead to conduction disease. The third-generation EGFR inhibitor osimertinib had approximately two times higher odds of supraventricular tachycardia than other EGFR inhibitors.
Osimertinib was associated with 6.8 times higher chances of heart failure, compared with other EGFR inhibitors, and 3.6 times more than other targeted therapies. Dabrafenib and trametinib were associated with two to three times higher odds of heart failure as compared with other targeted therapies.
“There is a need for an understanding of the mechanisms underlying these toxicities and for additional studies to establish standardized guidelines for monitoring, particularly for osimertinib, crizotinib, and alectinib,” the authors wrote
The authors disclosed a number of paid advisory roles with various pharmaceutical companies.
FROM THE JOURNAL OF THORACIC ONCOLOGY
Cancer risk tied to some manufactured foods
SAN ANTONIO –
The findings were reported in three poster presentations (P1-09-01, P1-09-02 and P3-12-35) at the 2021 San Antonio Breast Cancer Symposium from the ongoing French NutriNet-Santé web-based study of 171,000 people that was launched in France in 2009 to investigate nutrition and health relationships. The authors of the analyses note that while evidence of deleterious health effects has been established for the dietary focus of their studies, and cancer risks have been suspected, strong evidence of a cancer association has been lacking.
Nitrates and nitrites are used in processed meats to increase shelf life and to avoid bacterial growth, said Eloi Chazelas, PhD, Nutritional Epidemiology Research Team (EREN) at Sorbonne Paris Nord University. Dr. Chazelas looked at consumption of nitrites and nitrates through repeated 24 hour dietary records, linked to a comprehensive food composition database. The study’s main outcome measure was adjusted associations between nitrite and nitrate exposures and the risk of cancer (overall and by main cancer sites).
During follow-up, 966 breast and 400 prostate cancers were diagnosed among 3,311 first incident cancer cases. Breast cancer risk was elevated (HR = 1.24 [1.03-1.48], P = 0.02) among higher consumers of nitrates from food additives, especially with potassium nitrate consumption (HR = 1.25 [1.04-1.50], P = 0.01). Elevated prostate cancer risk was associated with nitrites (HR = 1.58 [1.14-2.18], P = 0.008), specifically for sodium nitrite (HR = 1.62 [1.17-2.25], P = 0.004). Nitrates and nitrites from natural sources were not associated significantly with higher cancer risk, Dr. Chazelas said.
He and his team found that food additive nitrates were positively associated with breast cancer risk, and food additive nitrites were positively associated with prostate cancer risk. “While these results need confirmation in other large-scale prospective studies, they provide new insights in a context of lively debate around the ban of nitrite additives in the food industry,” said Dr. Chazelas, who is a doctoral candidate at Sorbonne Paris Nord University.
In “Breast and prostate cancer risk associated with nitrites and nitrates from food additives (P1-09-01),” the study included 102,046 adults from the French NutriNet-Santé prospective cohort (2009-2021). It examined associations between artificial sweetener intakes (total from all dietary sources, the most frequently consumed ones [aspartame e951, acesulfame-K e950 and sucralose e955]) and cancer risk (overall and by sites: breast, prostate and obesity-related cancers).
Overall cancer risk in people who consumed higher amounts of total sweeteners (i.e. above the median exposure in consumers) was elevated (n = 2,527 cases, hazard ratio = 1.12, 95 percent confidence interval = 1.00-1.25, P-trend=0.005), especially for aspartame (HR = 1.20 [1.05-1.38] P = 0.001) and acesulfame-K (HR = 1.18 [1.04-1.34] P = 0.003). Elevated breast cancer risks (among 723 cases) were observed for total sweeteners (HR = 1.25 [1.02-1.53] P = 0.01), for aspartame (HR = 1.33 [1.05-1.69] P = 0.007), and for acesulfame-K (HR = 1.39 [1.11-1.74] P = 0.003). Also, obesity-related cancers (1,509 cases) were increased for total sweeteners (HR = 1.16 [1.00-1.33] P = 0.02), for aspartame (HR = 1.22 [1.02-1.45] P = 0.01) and for acesulfame-K (HR = 1.23 [1.04-1.45] P = 0.01).
Artificial sweeteners are found in more than 10,000 foods and beverages, said Charlotte Debras, a doctoral candidate in nutritional epidemiology at Sorbonne Paris Nord University. “These findings provide important and novel insights for the ongoing re-evaluation of food additive sweeteners by the European Food Safety Authority and other health agencies globally,” she said.
Trans fatty acid intakes and cancer risk
Investigating associations between trans fatty acid intake (total ruminant [rTFAs], industrial [iTFAs], and corresponding specific isomers and cancer risk), the analysis of Gaëlle Wendeu-Foyet, PhD, Sorbonne Paris Nord University, found a total of 3,374 incident cancer cases (982 breast, 405 prostate) in an overall population of 104,909. Dietary intake of total TFAs was associated with higher prostate cancer risk (hazard ration for quartile 4 versus 1: 1.27, 1.11-1.77 P-trend = 0.005). Also, rTFAs were associated with increased overall cancer risk (1.16, 1.02-1.32 P-trend = 0.07), in particular the conjugated linoleic acid isomers (CLA) (1.19, 1.04-1.36 P-trend = 0.04). These associations were specifically observed for breast cancer (rTFAs: 1.35, 1.06-1.72 P-trend = 0.01; CLA: 1.29, 1.00-1.66 P-trend = 0.048), in particular before menopause (rTFAs: 1.68, 1.06-2.67 P-trend = 0.02; CLA: 2.013, 1.25-3.23 P-trend = 0.003). Several iTFAs were associated with overall (1.18, 1.06-1.31 P-trend = 0.02 for transdocosenoic acid), breast (isomer 18:2t: 1.30, 1.06-1.58 P-trend = 0.01; hexadecenoic acid: 1.28, 1.05-1.56 P-trend = 0.02) and prostate (transdocosenoic acid: 1.52, 1.09-2.12 P-trend = 0.07) cancer risks.
“These results support the WHO’s goal of achieving elimination from food supplies of industrially produced TFAs,” Dr. Foyet said. “The consumption of food products containing partially hydrogenated oils should be avoided.”
Nutrition, along with avoiding tobacco intake, is one of the main modifiable risk factors for chronic diseases. “There is a lot at stake in terms of prevention. This requires a combination of actions at the individual level to the public level by informing the public through food labeling,” Ms. Debras said.
It also requires influencing the context in which citizens evolve by encouraging manufacturers to improve their products (pricing policies, commitment charters for product reformulation, etc.), and limiting advertising and marketing for products of poor nutritional quality (especially among children),” she said.
SAN ANTONIO –
The findings were reported in three poster presentations (P1-09-01, P1-09-02 and P3-12-35) at the 2021 San Antonio Breast Cancer Symposium from the ongoing French NutriNet-Santé web-based study of 171,000 people that was launched in France in 2009 to investigate nutrition and health relationships. The authors of the analyses note that while evidence of deleterious health effects has been established for the dietary focus of their studies, and cancer risks have been suspected, strong evidence of a cancer association has been lacking.
Nitrates and nitrites are used in processed meats to increase shelf life and to avoid bacterial growth, said Eloi Chazelas, PhD, Nutritional Epidemiology Research Team (EREN) at Sorbonne Paris Nord University. Dr. Chazelas looked at consumption of nitrites and nitrates through repeated 24 hour dietary records, linked to a comprehensive food composition database. The study’s main outcome measure was adjusted associations between nitrite and nitrate exposures and the risk of cancer (overall and by main cancer sites).
During follow-up, 966 breast and 400 prostate cancers were diagnosed among 3,311 first incident cancer cases. Breast cancer risk was elevated (HR = 1.24 [1.03-1.48], P = 0.02) among higher consumers of nitrates from food additives, especially with potassium nitrate consumption (HR = 1.25 [1.04-1.50], P = 0.01). Elevated prostate cancer risk was associated with nitrites (HR = 1.58 [1.14-2.18], P = 0.008), specifically for sodium nitrite (HR = 1.62 [1.17-2.25], P = 0.004). Nitrates and nitrites from natural sources were not associated significantly with higher cancer risk, Dr. Chazelas said.
He and his team found that food additive nitrates were positively associated with breast cancer risk, and food additive nitrites were positively associated with prostate cancer risk. “While these results need confirmation in other large-scale prospective studies, they provide new insights in a context of lively debate around the ban of nitrite additives in the food industry,” said Dr. Chazelas, who is a doctoral candidate at Sorbonne Paris Nord University.
In “Breast and prostate cancer risk associated with nitrites and nitrates from food additives (P1-09-01),” the study included 102,046 adults from the French NutriNet-Santé prospective cohort (2009-2021). It examined associations between artificial sweetener intakes (total from all dietary sources, the most frequently consumed ones [aspartame e951, acesulfame-K e950 and sucralose e955]) and cancer risk (overall and by sites: breast, prostate and obesity-related cancers).
Overall cancer risk in people who consumed higher amounts of total sweeteners (i.e. above the median exposure in consumers) was elevated (n = 2,527 cases, hazard ratio = 1.12, 95 percent confidence interval = 1.00-1.25, P-trend=0.005), especially for aspartame (HR = 1.20 [1.05-1.38] P = 0.001) and acesulfame-K (HR = 1.18 [1.04-1.34] P = 0.003). Elevated breast cancer risks (among 723 cases) were observed for total sweeteners (HR = 1.25 [1.02-1.53] P = 0.01), for aspartame (HR = 1.33 [1.05-1.69] P = 0.007), and for acesulfame-K (HR = 1.39 [1.11-1.74] P = 0.003). Also, obesity-related cancers (1,509 cases) were increased for total sweeteners (HR = 1.16 [1.00-1.33] P = 0.02), for aspartame (HR = 1.22 [1.02-1.45] P = 0.01) and for acesulfame-K (HR = 1.23 [1.04-1.45] P = 0.01).
Artificial sweeteners are found in more than 10,000 foods and beverages, said Charlotte Debras, a doctoral candidate in nutritional epidemiology at Sorbonne Paris Nord University. “These findings provide important and novel insights for the ongoing re-evaluation of food additive sweeteners by the European Food Safety Authority and other health agencies globally,” she said.
Trans fatty acid intakes and cancer risk
Investigating associations between trans fatty acid intake (total ruminant [rTFAs], industrial [iTFAs], and corresponding specific isomers and cancer risk), the analysis of Gaëlle Wendeu-Foyet, PhD, Sorbonne Paris Nord University, found a total of 3,374 incident cancer cases (982 breast, 405 prostate) in an overall population of 104,909. Dietary intake of total TFAs was associated with higher prostate cancer risk (hazard ration for quartile 4 versus 1: 1.27, 1.11-1.77 P-trend = 0.005). Also, rTFAs were associated with increased overall cancer risk (1.16, 1.02-1.32 P-trend = 0.07), in particular the conjugated linoleic acid isomers (CLA) (1.19, 1.04-1.36 P-trend = 0.04). These associations were specifically observed for breast cancer (rTFAs: 1.35, 1.06-1.72 P-trend = 0.01; CLA: 1.29, 1.00-1.66 P-trend = 0.048), in particular before menopause (rTFAs: 1.68, 1.06-2.67 P-trend = 0.02; CLA: 2.013, 1.25-3.23 P-trend = 0.003). Several iTFAs were associated with overall (1.18, 1.06-1.31 P-trend = 0.02 for transdocosenoic acid), breast (isomer 18:2t: 1.30, 1.06-1.58 P-trend = 0.01; hexadecenoic acid: 1.28, 1.05-1.56 P-trend = 0.02) and prostate (transdocosenoic acid: 1.52, 1.09-2.12 P-trend = 0.07) cancer risks.
“These results support the WHO’s goal of achieving elimination from food supplies of industrially produced TFAs,” Dr. Foyet said. “The consumption of food products containing partially hydrogenated oils should be avoided.”
Nutrition, along with avoiding tobacco intake, is one of the main modifiable risk factors for chronic diseases. “There is a lot at stake in terms of prevention. This requires a combination of actions at the individual level to the public level by informing the public through food labeling,” Ms. Debras said.
It also requires influencing the context in which citizens evolve by encouraging manufacturers to improve their products (pricing policies, commitment charters for product reformulation, etc.), and limiting advertising and marketing for products of poor nutritional quality (especially among children),” she said.
SAN ANTONIO –
The findings were reported in three poster presentations (P1-09-01, P1-09-02 and P3-12-35) at the 2021 San Antonio Breast Cancer Symposium from the ongoing French NutriNet-Santé web-based study of 171,000 people that was launched in France in 2009 to investigate nutrition and health relationships. The authors of the analyses note that while evidence of deleterious health effects has been established for the dietary focus of their studies, and cancer risks have been suspected, strong evidence of a cancer association has been lacking.
Nitrates and nitrites are used in processed meats to increase shelf life and to avoid bacterial growth, said Eloi Chazelas, PhD, Nutritional Epidemiology Research Team (EREN) at Sorbonne Paris Nord University. Dr. Chazelas looked at consumption of nitrites and nitrates through repeated 24 hour dietary records, linked to a comprehensive food composition database. The study’s main outcome measure was adjusted associations between nitrite and nitrate exposures and the risk of cancer (overall and by main cancer sites).
During follow-up, 966 breast and 400 prostate cancers were diagnosed among 3,311 first incident cancer cases. Breast cancer risk was elevated (HR = 1.24 [1.03-1.48], P = 0.02) among higher consumers of nitrates from food additives, especially with potassium nitrate consumption (HR = 1.25 [1.04-1.50], P = 0.01). Elevated prostate cancer risk was associated with nitrites (HR = 1.58 [1.14-2.18], P = 0.008), specifically for sodium nitrite (HR = 1.62 [1.17-2.25], P = 0.004). Nitrates and nitrites from natural sources were not associated significantly with higher cancer risk, Dr. Chazelas said.
He and his team found that food additive nitrates were positively associated with breast cancer risk, and food additive nitrites were positively associated with prostate cancer risk. “While these results need confirmation in other large-scale prospective studies, they provide new insights in a context of lively debate around the ban of nitrite additives in the food industry,” said Dr. Chazelas, who is a doctoral candidate at Sorbonne Paris Nord University.
In “Breast and prostate cancer risk associated with nitrites and nitrates from food additives (P1-09-01),” the study included 102,046 adults from the French NutriNet-Santé prospective cohort (2009-2021). It examined associations between artificial sweetener intakes (total from all dietary sources, the most frequently consumed ones [aspartame e951, acesulfame-K e950 and sucralose e955]) and cancer risk (overall and by sites: breast, prostate and obesity-related cancers).
Overall cancer risk in people who consumed higher amounts of total sweeteners (i.e. above the median exposure in consumers) was elevated (n = 2,527 cases, hazard ratio = 1.12, 95 percent confidence interval = 1.00-1.25, P-trend=0.005), especially for aspartame (HR = 1.20 [1.05-1.38] P = 0.001) and acesulfame-K (HR = 1.18 [1.04-1.34] P = 0.003). Elevated breast cancer risks (among 723 cases) were observed for total sweeteners (HR = 1.25 [1.02-1.53] P = 0.01), for aspartame (HR = 1.33 [1.05-1.69] P = 0.007), and for acesulfame-K (HR = 1.39 [1.11-1.74] P = 0.003). Also, obesity-related cancers (1,509 cases) were increased for total sweeteners (HR = 1.16 [1.00-1.33] P = 0.02), for aspartame (HR = 1.22 [1.02-1.45] P = 0.01) and for acesulfame-K (HR = 1.23 [1.04-1.45] P = 0.01).
Artificial sweeteners are found in more than 10,000 foods and beverages, said Charlotte Debras, a doctoral candidate in nutritional epidemiology at Sorbonne Paris Nord University. “These findings provide important and novel insights for the ongoing re-evaluation of food additive sweeteners by the European Food Safety Authority and other health agencies globally,” she said.
Trans fatty acid intakes and cancer risk
Investigating associations between trans fatty acid intake (total ruminant [rTFAs], industrial [iTFAs], and corresponding specific isomers and cancer risk), the analysis of Gaëlle Wendeu-Foyet, PhD, Sorbonne Paris Nord University, found a total of 3,374 incident cancer cases (982 breast, 405 prostate) in an overall population of 104,909. Dietary intake of total TFAs was associated with higher prostate cancer risk (hazard ration for quartile 4 versus 1: 1.27, 1.11-1.77 P-trend = 0.005). Also, rTFAs were associated with increased overall cancer risk (1.16, 1.02-1.32 P-trend = 0.07), in particular the conjugated linoleic acid isomers (CLA) (1.19, 1.04-1.36 P-trend = 0.04). These associations were specifically observed for breast cancer (rTFAs: 1.35, 1.06-1.72 P-trend = 0.01; CLA: 1.29, 1.00-1.66 P-trend = 0.048), in particular before menopause (rTFAs: 1.68, 1.06-2.67 P-trend = 0.02; CLA: 2.013, 1.25-3.23 P-trend = 0.003). Several iTFAs were associated with overall (1.18, 1.06-1.31 P-trend = 0.02 for transdocosenoic acid), breast (isomer 18:2t: 1.30, 1.06-1.58 P-trend = 0.01; hexadecenoic acid: 1.28, 1.05-1.56 P-trend = 0.02) and prostate (transdocosenoic acid: 1.52, 1.09-2.12 P-trend = 0.07) cancer risks.
“These results support the WHO’s goal of achieving elimination from food supplies of industrially produced TFAs,” Dr. Foyet said. “The consumption of food products containing partially hydrogenated oils should be avoided.”
Nutrition, along with avoiding tobacco intake, is one of the main modifiable risk factors for chronic diseases. “There is a lot at stake in terms of prevention. This requires a combination of actions at the individual level to the public level by informing the public through food labeling,” Ms. Debras said.
It also requires influencing the context in which citizens evolve by encouraging manufacturers to improve their products (pricing policies, commitment charters for product reformulation, etc.), and limiting advertising and marketing for products of poor nutritional quality (especially among children),” she said.
FROM SABCS 2021
Breast cancer-related musculoskeletal pain alleviated with acupuncture
SAN ANTONIO –
Both techniques led to clinically meaningful and persistent reduction of pain, but electroacupuncture was more effective in reducing pain severity, according to study author Wanqing Iris Zhi, MD, PhD, of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center in New York.
Among breast cancer survivors, Dr. Zhi said, chronic musculoskeletal pain is common and debilitating. In earlier results of the PEACE (Personalized Electroacupuncture versus Auricular Acupuncture Comparative Effectiveness) trial, both electroacupuncture and auricular acupuncture improved pain control better than usual care in cancer survivors. The comparative effectiveness between electroacupuncture and auricular acupuncture among breast cancer survivors, specifically for chronic musculoskeletal pain, remains unknown.
To evaluate potential differences between electroacupuncture and auricular acupuncture, Dr. Zhi et al. examined data from PEACE, a three-arm, parallel, single center randomized trial investigating electroacupuncture and auricular acupuncture for chronic musculoskeletal pain, compared with usual care. Among 360 cancer survivors in PEACE, mean age in 165 cancer survivors with a primary diagnosis of breast cancer was 60.3 years (35.8 percent non-White) with a mean of 5.4 years since their cancer diagnoses. Patients in both the electroacupuncture and auricular acupuncture groups received 10 weekly treatments. Change in mean Brief Pain Inventory (BPI) pain severity from baseline to week 12 was the primary endpoint, with BPI change to week 24 as a secondary endpoint. Usual care patients, after week 12, could receive 10 electroacupuncture treatments.
The most common locations of chronic musculoskeletal pain, Dr. Zhi observed, were lower back (24 percent), knee/leg (24 percent) and shoulder/elbow (14 percent). About 70 percent of patients were taking pain medication. Both electroacupuncture and auricular acupuncture were associated with clinically meaningful and persistent pain reductions among the evaluated breast cancer survivors. The change in BPI severity from baseline to week 12 was –0.29 (confidence interval, –0.08, 0.28) in the UC group. In the electroacupuncture group it was –2.65 (CI, –3.06, –2.25; P ≤0.001 from baseline) and –2.37 versus usual care (CI, –3.05, –1.68; P ≤0.001 versus UC). For the auricular acupuncture group, the change from baseline was –1.75 (CI, –2.15, –1.35; P ≤0.001 from baseline) and –1.46 versus usual care (CI, –2.14, –0.78; P ≤0.001 versus UC). The difference in BPI pain severity reduction from baseline between electroacupuncture and auricular acupuncture of –0.90 (CI, –1.45, –0.36) was statistically significant (P ≤0.001). Electroacupuncture also reduced pain severity significantly more than auricular acupuncture at week 24 (CI, –0.82, [–1.38, –0.27], P = 0.004).
Dr. Zhi concluded that among breast cancer survivors, although both electroacupuncture and auricular acupuncture were associated with clinically meaningful and persistent pain reduction, electroacupuncture was more effective at reducing pain severity.
She pointed out also that neither surgery type (mastectomy versus lumpectomy; P = 0.83) nor aromatase inhibitor versus tamoxifen versus neither (P = 0.59) was associated with BPI/severity response among electroacupuncture and auricular acupuncture patients.
“Both electroacupuncture and auricular acupuncture are significantly better than usual care, so it suggests that both acupuncture methods can be utilized for treating chronic muscle skeletal pain in breast cancer survivors, but electroacupuncture is preferred,” Dr. Zhi said.
“Auricular acupuncture can be more painful,” said PEACE principal investigator Jun Mao, MD, who is chair of integrative medicine at Memorial Sloan Kettering. “Ten percent of women could not tolerate the ear pain or discomfort. Electroacupuncture is generally well tolerated. People are more relaxed after treatment. If both are available, start with electroacupuncture,” he said.
SAN ANTONIO –
Both techniques led to clinically meaningful and persistent reduction of pain, but electroacupuncture was more effective in reducing pain severity, according to study author Wanqing Iris Zhi, MD, PhD, of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center in New York.
Among breast cancer survivors, Dr. Zhi said, chronic musculoskeletal pain is common and debilitating. In earlier results of the PEACE (Personalized Electroacupuncture versus Auricular Acupuncture Comparative Effectiveness) trial, both electroacupuncture and auricular acupuncture improved pain control better than usual care in cancer survivors. The comparative effectiveness between electroacupuncture and auricular acupuncture among breast cancer survivors, specifically for chronic musculoskeletal pain, remains unknown.
To evaluate potential differences between electroacupuncture and auricular acupuncture, Dr. Zhi et al. examined data from PEACE, a three-arm, parallel, single center randomized trial investigating electroacupuncture and auricular acupuncture for chronic musculoskeletal pain, compared with usual care. Among 360 cancer survivors in PEACE, mean age in 165 cancer survivors with a primary diagnosis of breast cancer was 60.3 years (35.8 percent non-White) with a mean of 5.4 years since their cancer diagnoses. Patients in both the electroacupuncture and auricular acupuncture groups received 10 weekly treatments. Change in mean Brief Pain Inventory (BPI) pain severity from baseline to week 12 was the primary endpoint, with BPI change to week 24 as a secondary endpoint. Usual care patients, after week 12, could receive 10 electroacupuncture treatments.
The most common locations of chronic musculoskeletal pain, Dr. Zhi observed, were lower back (24 percent), knee/leg (24 percent) and shoulder/elbow (14 percent). About 70 percent of patients were taking pain medication. Both electroacupuncture and auricular acupuncture were associated with clinically meaningful and persistent pain reductions among the evaluated breast cancer survivors. The change in BPI severity from baseline to week 12 was –0.29 (confidence interval, –0.08, 0.28) in the UC group. In the electroacupuncture group it was –2.65 (CI, –3.06, –2.25; P ≤0.001 from baseline) and –2.37 versus usual care (CI, –3.05, –1.68; P ≤0.001 versus UC). For the auricular acupuncture group, the change from baseline was –1.75 (CI, –2.15, –1.35; P ≤0.001 from baseline) and –1.46 versus usual care (CI, –2.14, –0.78; P ≤0.001 versus UC). The difference in BPI pain severity reduction from baseline between electroacupuncture and auricular acupuncture of –0.90 (CI, –1.45, –0.36) was statistically significant (P ≤0.001). Electroacupuncture also reduced pain severity significantly more than auricular acupuncture at week 24 (CI, –0.82, [–1.38, –0.27], P = 0.004).
Dr. Zhi concluded that among breast cancer survivors, although both electroacupuncture and auricular acupuncture were associated with clinically meaningful and persistent pain reduction, electroacupuncture was more effective at reducing pain severity.
She pointed out also that neither surgery type (mastectomy versus lumpectomy; P = 0.83) nor aromatase inhibitor versus tamoxifen versus neither (P = 0.59) was associated with BPI/severity response among electroacupuncture and auricular acupuncture patients.
“Both electroacupuncture and auricular acupuncture are significantly better than usual care, so it suggests that both acupuncture methods can be utilized for treating chronic muscle skeletal pain in breast cancer survivors, but electroacupuncture is preferred,” Dr. Zhi said.
“Auricular acupuncture can be more painful,” said PEACE principal investigator Jun Mao, MD, who is chair of integrative medicine at Memorial Sloan Kettering. “Ten percent of women could not tolerate the ear pain or discomfort. Electroacupuncture is generally well tolerated. People are more relaxed after treatment. If both are available, start with electroacupuncture,” he said.
SAN ANTONIO –
Both techniques led to clinically meaningful and persistent reduction of pain, but electroacupuncture was more effective in reducing pain severity, according to study author Wanqing Iris Zhi, MD, PhD, of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center in New York.
Among breast cancer survivors, Dr. Zhi said, chronic musculoskeletal pain is common and debilitating. In earlier results of the PEACE (Personalized Electroacupuncture versus Auricular Acupuncture Comparative Effectiveness) trial, both electroacupuncture and auricular acupuncture improved pain control better than usual care in cancer survivors. The comparative effectiveness between electroacupuncture and auricular acupuncture among breast cancer survivors, specifically for chronic musculoskeletal pain, remains unknown.
To evaluate potential differences between electroacupuncture and auricular acupuncture, Dr. Zhi et al. examined data from PEACE, a three-arm, parallel, single center randomized trial investigating electroacupuncture and auricular acupuncture for chronic musculoskeletal pain, compared with usual care. Among 360 cancer survivors in PEACE, mean age in 165 cancer survivors with a primary diagnosis of breast cancer was 60.3 years (35.8 percent non-White) with a mean of 5.4 years since their cancer diagnoses. Patients in both the electroacupuncture and auricular acupuncture groups received 10 weekly treatments. Change in mean Brief Pain Inventory (BPI) pain severity from baseline to week 12 was the primary endpoint, with BPI change to week 24 as a secondary endpoint. Usual care patients, after week 12, could receive 10 electroacupuncture treatments.
The most common locations of chronic musculoskeletal pain, Dr. Zhi observed, were lower back (24 percent), knee/leg (24 percent) and shoulder/elbow (14 percent). About 70 percent of patients were taking pain medication. Both electroacupuncture and auricular acupuncture were associated with clinically meaningful and persistent pain reductions among the evaluated breast cancer survivors. The change in BPI severity from baseline to week 12 was –0.29 (confidence interval, –0.08, 0.28) in the UC group. In the electroacupuncture group it was –2.65 (CI, –3.06, –2.25; P ≤0.001 from baseline) and –2.37 versus usual care (CI, –3.05, –1.68; P ≤0.001 versus UC). For the auricular acupuncture group, the change from baseline was –1.75 (CI, –2.15, –1.35; P ≤0.001 from baseline) and –1.46 versus usual care (CI, –2.14, –0.78; P ≤0.001 versus UC). The difference in BPI pain severity reduction from baseline between electroacupuncture and auricular acupuncture of –0.90 (CI, –1.45, –0.36) was statistically significant (P ≤0.001). Electroacupuncture also reduced pain severity significantly more than auricular acupuncture at week 24 (CI, –0.82, [–1.38, –0.27], P = 0.004).
Dr. Zhi concluded that among breast cancer survivors, although both electroacupuncture and auricular acupuncture were associated with clinically meaningful and persistent pain reduction, electroacupuncture was more effective at reducing pain severity.
She pointed out also that neither surgery type (mastectomy versus lumpectomy; P = 0.83) nor aromatase inhibitor versus tamoxifen versus neither (P = 0.59) was associated with BPI/severity response among electroacupuncture and auricular acupuncture patients.
“Both electroacupuncture and auricular acupuncture are significantly better than usual care, so it suggests that both acupuncture methods can be utilized for treating chronic muscle skeletal pain in breast cancer survivors, but electroacupuncture is preferred,” Dr. Zhi said.
“Auricular acupuncture can be more painful,” said PEACE principal investigator Jun Mao, MD, who is chair of integrative medicine at Memorial Sloan Kettering. “Ten percent of women could not tolerate the ear pain or discomfort. Electroacupuncture is generally well tolerated. People are more relaxed after treatment. If both are available, start with electroacupuncture,” he said.
FROM SABCS 2021
Sputum biomarkers may predict COPD exacerbations
Examining sputum from patients with chronic obstructive pulmonary disease may help predict the course of the disease.
A mass spectrometric panel of biomarkers related to mucus hydration and inflammation examined in sputa showed elevated levels of metabolites from multiple pathways in patients with COPD. These correlated with sputum neutrophil counts and COPD exacerbations. In particular, sialic acid and hypoxanthine concentrations were strongly associated with disease severity, according to a study reported in the journal CHEST® authored by Charles R. Esther Jr. MD, PhD, and colleagues.
Given that an improved understanding of the pathways associated with airway pathophysiology in COPD will identify new predictive biomarkers and novel therapeutic targets, Dr. Esther and colleagues posed the question: Which physiologic pathways are altered and predict exacerbations in the airways of subjects with COPD?
They noted that in persons with COPD – characterized by dominant small airway obstruction associated with airway inflammation – multiple inflammatory pathways, as well as indices of oxidative stress (including oxidized glutathione and 8-isoprostane), are elevated in sputum. Because inflammation is a challenging therapeutic target, identification of other biologic pathways involved in COPD pathogenesis could point to novel biomarkers and therapeutic targets.
Using this approach in cystic fibrosis (CF), the authors have previously identified small molecule metabolites correlated with airway inflammation. Findings from that research supported development of a mass spectrometric biomarker panel for simultaneous measurement of inflammatory markers coupled to biomarkers of mucus hydration. The researchers applied this technology to sputum supernatants collected through the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which included subjects with COPD, as well as relevant smoking and nonsmoking controls.
Addressing inflammation
“Inhaled steroids are really more effective for allergic inflammation as in asthma and less so for the neutrophilic inflammation that dominates in COPD. The challenge is that neutrophilic inflammation is also a key response to infection, and it’s really hard to find an anti-inflammatory that suppresses neutrophilic inflammation well enough to get clinical benefit but not so much that the patient becomes vulnerable to infection. Lots of clinical trials of anti-inflammatories in cystic fibrosis or COPD have been stopped because treated subjects had more trouble with infection,” Dr. Esther stated in an interview,
The investigators analyzed cell-free sputum supernatants from 980 subjects, including samples from 77 healthy nonsmokers (NS), 341 ever-smokers with preserved spirometry (SPS), and 562 subjects with COPD (178 GOLD [Global Initiative for Chronic Obstructive Lung Disease]1, 303 GOLD 2, and 81 GOLD 3). Among the subjects with COPD, elevated biomarkers from multiple pathways correlated with sputum neutrophil counts.
The most significant analytes (at FDR [False Discovery Rate] 0.1) were sialic acid (a mucin marker), hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione, with sialic acid and hypoxanthine strongly associated with measures of disease severity. Elevation of sialic acid and hypoxanthine were associated with shorter time to exacerbation and improved prediction models of future exacerbations.
Study results
Sialic acid was elevated in all GOLD groups relative to NS healthy controls, with a 2.8-fold (0.44 log) increase in GOLD 2 and 3.7 fold (0.56 log) increase in GOLD 3 relative to NS. Sialic acid was also elevated in the most severe disease cohorts (GOLD 2 and GOLD 3) relative to smokers with preserved spirometry (SPS) and those with less severe disease (GOLD 1).
Because mucin secretion and inflammation are also related to the pathophysiology of pulmonary exacerbations, Dr. Esther and colleagues had hypothesized that sputum biomarkers would be predictive of future exacerbations. Within the full cohort, both sialic acid and hypoxanthine were significantly elevated in those who had multiple (two or more) pulmonary exacerbations relative to those who had none (P = .001). Similar, though less significant findings were observed for xanthine (P = .01), methylthioadenosine (P = .01), adenine (P = .01), and glutathione (P = .01).
Sputum tests needed
While tests still need to be developed, Dr. Esther noted in an interview that they would be based on well-established technologies commonly utilized in clinical laboratories. “Sputum biomarkers of mucus hydration and adenosine metabolism could help clinicians predict which patients with COPD are likely to experience multiple pulmonary exacerbations. Tests would be applied to patients with COPD at higher risk for exacerbations; for example, those who have low lung function or a history of prior exacerbations.”
Dr. Esther noted that these biomarkers could be helpful in developing novel therapies. “Using sialic acid to assess mucus concentrations is much easier than other methods, so it could help in developing mucolytic treatments. Also, adenosine metabolism represents a novel therapeutic target in COPD. Drugs that modify adenosine metabolism that have been approved for other diseases such as gout could be tested in COPD. As with mucus hydration, the biomarkers we identified (particularly hypoxanthine) could be utilized to make sure that novel therapies are having the intended impact on airway adenosine metabolism.”
The research was supported by SPIROMICS (funded by NIH and the COPD Foundation). Dr. Esther reported having no relevant disclosures.
Examining sputum from patients with chronic obstructive pulmonary disease may help predict the course of the disease.
A mass spectrometric panel of biomarkers related to mucus hydration and inflammation examined in sputa showed elevated levels of metabolites from multiple pathways in patients with COPD. These correlated with sputum neutrophil counts and COPD exacerbations. In particular, sialic acid and hypoxanthine concentrations were strongly associated with disease severity, according to a study reported in the journal CHEST® authored by Charles R. Esther Jr. MD, PhD, and colleagues.
Given that an improved understanding of the pathways associated with airway pathophysiology in COPD will identify new predictive biomarkers and novel therapeutic targets, Dr. Esther and colleagues posed the question: Which physiologic pathways are altered and predict exacerbations in the airways of subjects with COPD?
They noted that in persons with COPD – characterized by dominant small airway obstruction associated with airway inflammation – multiple inflammatory pathways, as well as indices of oxidative stress (including oxidized glutathione and 8-isoprostane), are elevated in sputum. Because inflammation is a challenging therapeutic target, identification of other biologic pathways involved in COPD pathogenesis could point to novel biomarkers and therapeutic targets.
Using this approach in cystic fibrosis (CF), the authors have previously identified small molecule metabolites correlated with airway inflammation. Findings from that research supported development of a mass spectrometric biomarker panel for simultaneous measurement of inflammatory markers coupled to biomarkers of mucus hydration. The researchers applied this technology to sputum supernatants collected through the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which included subjects with COPD, as well as relevant smoking and nonsmoking controls.
Addressing inflammation
“Inhaled steroids are really more effective for allergic inflammation as in asthma and less so for the neutrophilic inflammation that dominates in COPD. The challenge is that neutrophilic inflammation is also a key response to infection, and it’s really hard to find an anti-inflammatory that suppresses neutrophilic inflammation well enough to get clinical benefit but not so much that the patient becomes vulnerable to infection. Lots of clinical trials of anti-inflammatories in cystic fibrosis or COPD have been stopped because treated subjects had more trouble with infection,” Dr. Esther stated in an interview,
The investigators analyzed cell-free sputum supernatants from 980 subjects, including samples from 77 healthy nonsmokers (NS), 341 ever-smokers with preserved spirometry (SPS), and 562 subjects with COPD (178 GOLD [Global Initiative for Chronic Obstructive Lung Disease]1, 303 GOLD 2, and 81 GOLD 3). Among the subjects with COPD, elevated biomarkers from multiple pathways correlated with sputum neutrophil counts.
The most significant analytes (at FDR [False Discovery Rate] 0.1) were sialic acid (a mucin marker), hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione, with sialic acid and hypoxanthine strongly associated with measures of disease severity. Elevation of sialic acid and hypoxanthine were associated with shorter time to exacerbation and improved prediction models of future exacerbations.
Study results
Sialic acid was elevated in all GOLD groups relative to NS healthy controls, with a 2.8-fold (0.44 log) increase in GOLD 2 and 3.7 fold (0.56 log) increase in GOLD 3 relative to NS. Sialic acid was also elevated in the most severe disease cohorts (GOLD 2 and GOLD 3) relative to smokers with preserved spirometry (SPS) and those with less severe disease (GOLD 1).
Because mucin secretion and inflammation are also related to the pathophysiology of pulmonary exacerbations, Dr. Esther and colleagues had hypothesized that sputum biomarkers would be predictive of future exacerbations. Within the full cohort, both sialic acid and hypoxanthine were significantly elevated in those who had multiple (two or more) pulmonary exacerbations relative to those who had none (P = .001). Similar, though less significant findings were observed for xanthine (P = .01), methylthioadenosine (P = .01), adenine (P = .01), and glutathione (P = .01).
Sputum tests needed
While tests still need to be developed, Dr. Esther noted in an interview that they would be based on well-established technologies commonly utilized in clinical laboratories. “Sputum biomarkers of mucus hydration and adenosine metabolism could help clinicians predict which patients with COPD are likely to experience multiple pulmonary exacerbations. Tests would be applied to patients with COPD at higher risk for exacerbations; for example, those who have low lung function or a history of prior exacerbations.”
Dr. Esther noted that these biomarkers could be helpful in developing novel therapies. “Using sialic acid to assess mucus concentrations is much easier than other methods, so it could help in developing mucolytic treatments. Also, adenosine metabolism represents a novel therapeutic target in COPD. Drugs that modify adenosine metabolism that have been approved for other diseases such as gout could be tested in COPD. As with mucus hydration, the biomarkers we identified (particularly hypoxanthine) could be utilized to make sure that novel therapies are having the intended impact on airway adenosine metabolism.”
The research was supported by SPIROMICS (funded by NIH and the COPD Foundation). Dr. Esther reported having no relevant disclosures.
Examining sputum from patients with chronic obstructive pulmonary disease may help predict the course of the disease.
A mass spectrometric panel of biomarkers related to mucus hydration and inflammation examined in sputa showed elevated levels of metabolites from multiple pathways in patients with COPD. These correlated with sputum neutrophil counts and COPD exacerbations. In particular, sialic acid and hypoxanthine concentrations were strongly associated with disease severity, according to a study reported in the journal CHEST® authored by Charles R. Esther Jr. MD, PhD, and colleagues.
Given that an improved understanding of the pathways associated with airway pathophysiology in COPD will identify new predictive biomarkers and novel therapeutic targets, Dr. Esther and colleagues posed the question: Which physiologic pathways are altered and predict exacerbations in the airways of subjects with COPD?
They noted that in persons with COPD – characterized by dominant small airway obstruction associated with airway inflammation – multiple inflammatory pathways, as well as indices of oxidative stress (including oxidized glutathione and 8-isoprostane), are elevated in sputum. Because inflammation is a challenging therapeutic target, identification of other biologic pathways involved in COPD pathogenesis could point to novel biomarkers and therapeutic targets.
Using this approach in cystic fibrosis (CF), the authors have previously identified small molecule metabolites correlated with airway inflammation. Findings from that research supported development of a mass spectrometric biomarker panel for simultaneous measurement of inflammatory markers coupled to biomarkers of mucus hydration. The researchers applied this technology to sputum supernatants collected through the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which included subjects with COPD, as well as relevant smoking and nonsmoking controls.
Addressing inflammation
“Inhaled steroids are really more effective for allergic inflammation as in asthma and less so for the neutrophilic inflammation that dominates in COPD. The challenge is that neutrophilic inflammation is also a key response to infection, and it’s really hard to find an anti-inflammatory that suppresses neutrophilic inflammation well enough to get clinical benefit but not so much that the patient becomes vulnerable to infection. Lots of clinical trials of anti-inflammatories in cystic fibrosis or COPD have been stopped because treated subjects had more trouble with infection,” Dr. Esther stated in an interview,
The investigators analyzed cell-free sputum supernatants from 980 subjects, including samples from 77 healthy nonsmokers (NS), 341 ever-smokers with preserved spirometry (SPS), and 562 subjects with COPD (178 GOLD [Global Initiative for Chronic Obstructive Lung Disease]1, 303 GOLD 2, and 81 GOLD 3). Among the subjects with COPD, elevated biomarkers from multiple pathways correlated with sputum neutrophil counts.
The most significant analytes (at FDR [False Discovery Rate] 0.1) were sialic acid (a mucin marker), hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione, with sialic acid and hypoxanthine strongly associated with measures of disease severity. Elevation of sialic acid and hypoxanthine were associated with shorter time to exacerbation and improved prediction models of future exacerbations.
Study results
Sialic acid was elevated in all GOLD groups relative to NS healthy controls, with a 2.8-fold (0.44 log) increase in GOLD 2 and 3.7 fold (0.56 log) increase in GOLD 3 relative to NS. Sialic acid was also elevated in the most severe disease cohorts (GOLD 2 and GOLD 3) relative to smokers with preserved spirometry (SPS) and those with less severe disease (GOLD 1).
Because mucin secretion and inflammation are also related to the pathophysiology of pulmonary exacerbations, Dr. Esther and colleagues had hypothesized that sputum biomarkers would be predictive of future exacerbations. Within the full cohort, both sialic acid and hypoxanthine were significantly elevated in those who had multiple (two or more) pulmonary exacerbations relative to those who had none (P = .001). Similar, though less significant findings were observed for xanthine (P = .01), methylthioadenosine (P = .01), adenine (P = .01), and glutathione (P = .01).
Sputum tests needed
While tests still need to be developed, Dr. Esther noted in an interview that they would be based on well-established technologies commonly utilized in clinical laboratories. “Sputum biomarkers of mucus hydration and adenosine metabolism could help clinicians predict which patients with COPD are likely to experience multiple pulmonary exacerbations. Tests would be applied to patients with COPD at higher risk for exacerbations; for example, those who have low lung function or a history of prior exacerbations.”
Dr. Esther noted that these biomarkers could be helpful in developing novel therapies. “Using sialic acid to assess mucus concentrations is much easier than other methods, so it could help in developing mucolytic treatments. Also, adenosine metabolism represents a novel therapeutic target in COPD. Drugs that modify adenosine metabolism that have been approved for other diseases such as gout could be tested in COPD. As with mucus hydration, the biomarkers we identified (particularly hypoxanthine) could be utilized to make sure that novel therapies are having the intended impact on airway adenosine metabolism.”
The research was supported by SPIROMICS (funded by NIH and the COPD Foundation). Dr. Esther reported having no relevant disclosures.
FROM THE JOURNAL CHEST®
Meeting the unmet need in multiple myeloma
In multiple myeloma, survival has been very significantly improved by immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies. Despite these advances, multiple myeloma, which is characterized by malignant proliferation of clonal plasma cells in bone marrow, remains an incurable plasma cell disorder with near-certain relapse after successful treatment. Prognosis for patients who develop triple-class refractory disease is poor, with less than 1-year survival. The substantial unmet therapeutic need extends further to other poor survival multiple myeloma populations that include newly diagnosed patients with high cytogenic risk profiles and those with early relapse after first-line therapy. For all of these, interest in drugs with novel mechanisms of action is naturally high.
More specific, less toxic
Post allogeneic hematopoietic stem-cell transplantation and donor lymphocyte infusion sustained remissions reflect a graft-versus-myeloma effect mediated by donor T cells.1 The substantial morbidity and mortality associated with graft-versus-host disease and opportunistic infections, however, have spurred searches for alternative, more specific, and less toxic T-cell therapies with stronger antitumor activity.
Chimeric antigen receptors (CARs)
In CAR T-cell therapies for multiple myeloma, autologous T cells are harvested from the patient and reprogrammed to target multiple myeloma cells through the introduction of genes that encode CARs, which are fusion proteins coupling an antigen-recognition moiety and a transmembrane-spanning element to a T-cell activation domain (typically CD3 zeta [CD247]). The T cells are then expanded and reinfused to the patient following a lymphodepletion regimen. Five strategies using autologous CAR T cells are currently approved for diffuse large B-cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies. Notably, in patients with heavily pretreated multiple myeloma, CAR T cells have demonstrated impressive activity.
BCMA-targeting CAR T cells
The B-cell maturation antigen (BCMA; TNFRSF17), which plays an important role in the survival of long-lived plasma cells in bone marrow, is an attractive target for CAR T-cell therapy because it is expressed on normal and malignant plasma cell surfaces and by mature B cells. When ligands (TNFSF 13B/TNFSF13) bind to BCMA expressed on multiple myeloma cell surfaces, survival and proliferation pathways and drug resistance are activated.
High-quality responses have been demonstrated in several trials of anti-BCMA CAR T cells, which kill multiple myeloma cell lines and primary multiple myeloma cells through degranulation of T cells and lysis of tumor cells, even those with low BCMA expression. Based on efficacy in triple-class exposed multiple myeloma that compared favorably to conventional care with improved health-related quality of life, the U.S. Food and Drug Administration gave breakthrough designation to ciltacabtagene autoleucel in December 2019 and approval for idecabtagene vicleucel in March 2021.
Idecabtagene vicleucel
Idecabtagene vicleucel expresses a murine BCMA-targeting single-chain variable fragment with a 4-1BB costimulatory motif. The phase 2 KarMMa study2 evaluated idecabtagene vicleucel (target dose of 450 × 106 CAR T cells; range 150 × 106 to 450 × 106) activity in 128 patients with triple-class exposed multiple myeloma. Partial responses or better were observed in 94 of 128 patients (73%) (95% confidence interval, 66-81); 42 (33%) had a complete response or better (95% CI, 25-41), with a median progression-free survival of 8.8 months (95% CI, 5.6-11.6). Outcomes were improved in the highest fixed-dose group, with partial response or better in 81% (44 of 55), complete response or better in 39% (21), and median overall survival of 12.1 months (95% CI, 8.8-12.3). Patients with high-risk cytogenetic profiles, extramedullary disease, and high tumor burden also had deep and durable responses. Outcomes were less favorable in patients with revised International Staging System stage 3 disease.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel, a 4-1BB–based CAR T-cell therapy with two BCMA-targeting domains, confers high-avidity binding. In the phase 1b/2 CARTITUDE-1 study, conducted in the United States and Europe, preliminary results in 97 patients showed a 97% response rate with ciltacabtagene autoleucel (target dose 0.75 × 106 CAR T cells per kg), and in 65 patients, a complete response (67%). Progression-free survival at 12 months was 77% (95% CI, 66-84) and overall survival was 89% (95% CI, 80-94).3
In the phase 1 LEGEND-2 study4 that was conducted at four sites in China among less heavily pretreated multiple myeloma patients, while all used the same CAR construct, sites used variable conditioning regimens (split versus single). In the site using cyclophosphamide as the lymphodepletion therapy and three split CAR T-cell infusions, partial response or better was achieved in 50 patients (88%) with a median of three prior therapy lines. The complete response rate was high (74%) and minimal residual disease negativity was reached in 39 patients (68%). Median progression-free survival was 19.9 months (95% CI, 9.6-31.0), but 28.2 months among those with complete responses (95% CI, 19.9-not estimable). Median overall survival was also favorable at 36.1 months (95% CI, 26.4-not estimable); it was 35.0 months-not estimable among patients with complete responses. Results from the other three sites were comparable.
Noteworthy among other BCMA-targeting CAR T-cell products in earlier stages of clinical development is orvacabtagene autoleucel, which has a fully human BCMA-specific binding domain. At higher doses (300 × 106 to 600 × 106 CAR T cells) among 62 patients with triple-class–exposed multiple myeloma in the EVOLVE trial, 92% had a partial or better response, with complete responses or better in 36%, all with an encouraging safety profile.
BCMA-targeting CAR T cell toxicity
While van de Donk, Usmani, and Yong, in their review1 note a lack of evidence of off-target toxicity with BCMA-targeting CAR T-cell therapy in clinical studies so far, they do point to several clinical syndromes (cytokine release syndrome, infections, respiratory failure, neurotoxicity, pulmonary aspergillosis, gastrointestinal hemorrhage) caused by cytokines produced during CAR T-cell expansion and to cytopenias and infections arising from prior treatment, bridging therapy, and lymphodepleting conditioning. Deaths attributed to treatment in the above-mentioned trials underscore the need for careful monitoring and early intervention.
Cytokine release syndrome
In the BCMA-targeting CAR T-cell therapy studies, the frequency of cytokine release syndrome varies widely from 17% to 95% but is generally attributed to CAR T-cell activation and is associated with increased serum ferritin concentrations, high c-reactive proteins, and proinflammatory cytokines. High tumor load, in multiple myeloma patients receiving CD19-targeting CAR T cells, was associated with a higher incidence of severe cytokine release syndrome. In a small number of patients, macrophage activation syndrome and hemophagocytic lymphohistiocytosis, the most aggressive variants of cytokine release syndrome, are caused by severe immune activation and lead to multiorgan dysfunction.
Neurotoxicity
Immune effector cell–-associated neurotoxicity syndrome (ICANS) symptoms, in multiple myeloma patients treated with BCMA-targeting CAR T cells, may include delirium, transient confusion, aphasia, lethargy, tremor, dysgraphia, seizures, cerebral edema, and rarely, posterior reversible encephalopathy syndrome.1 While the pathophysiology of CAR T cell–related neurotoxicity is not well understood, high tumor load, higher peak concentrations of CAR T cells, and more severe cytokine release syndrome are more common in patients with severe neurotoxicity. “The frequency of neurotoxicities,” Dr. Yong noted in an interview, “has been reduced by steps taken to mitigate these risk factors.”
High interest in phase I study
A phase I study presented in Blood has attracted interest because the novel BCMA-targeting CAR agent (CT103A) being tested is fully human.4 In an accompanying editorial, Lee and Yong note that doubt for any real potential for durable CAR T therapy responses in multiple myeloma is raised by the poor persistence of multiple myeloma CAR T cells in multiple myeloma patients.3
In the earliest trials of BCMA CARs, while reported rates of objective antimyeloma responses were in the approximately 33%-88% range among patients with relapsed/refractory multiple myeloma (RRMM), persistence was typically 6 months or less. Lee and Yong point out, however, that while correlation between persistence and duration of response (DOR) has been variable, median persistence was 308 days in the phase I study. Wang and colleagues, the phase I study authors, state that levels of CAR T-cell proliferation and duration of cellular persistence may be determinants of DOR in CAR T therapy for multiple myeloma. They observe that the multiple mechanisms potentially responsible for the inability of some CAR T cells to survive in vivo, may include antigen escape, T-cell intrinsic mechanisms, tumor microenvironment–mediated suppression, and host anti-CAR immunity. CARs with humanized or fully human single-chain variable fragments (scFvs), prior studies suggest, may retain antitumor activity through bypassing potential host anti-CAR immunogenicity.
In the study, CT103A, a fully human scFv, was tested in an open-label, single-arm design for safety and preliminary efficacy in 18 patients (8 female; median age 53.5 years) with RRMM (at least three lines of prior therapies including a proteasome inhibitor and an immunomodulatory agent) who had undergone leukapheresis and had received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Four patients (22.2%) had been treated previously with murine anti-BCMA CAR T cells. Safety and tolerability (including dose-limiting toxicity) were the primary endpoints, with efficacy and pharmacokinetics secondary.
Rapid responses
Two weeks after infusion, the overall response rate (ORR) was 77.8% (14 of 18) and by 1 month it was 88.9% (16 of 18). Eventually, all responded and 72.2% (13 of 18) achieved a complete response (CR) or stringent complete response (sCR). All 17 patients evaluated for minimum residual disease (MRD) in bone marrow were MRD-negative at 10-4 nucleated cells by flow cytometry within 1 month. Median DOR was 325 days (range, 7-573 days) for all patients and 412 days (range, 213-573 days) for the 13 with CR/sCR. CAR transgenes were detectable at the cutoff date in 77.8% of patients, with a median CAR transgene persistence of 307.5 days.
During follow-up, four deaths were reported, including one patient with persistent sCR (sudden severe infection). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 58.3% and 75%, respectively. Extramedullary myeloma was associated with a shortened PFS (79.1% versus 20.0%, P = .015), but not OS (79.1% versus 60.0%, P = .328) at 1 year.
All patients experienced grade 3 or higher adverse events, most of which were expected hematologic effects of lymphodepleting chemotherapy and CT103A infusions. Grade 1 and 2 cytokine release syndromes occurred in 70.6% patients (17 of 18), with 1 grade 4 event (5.9%). The patients receiving a dose of up to 3.0 × 106 CAR+ T cells/kg required less treatment of cytokine release syndrome than the patients who received a dose of 6.0 × 106 CAR+ T cells/kg. No immune effector cell–associated neurotoxicity syndrome was observed. Antidrug antibody positivity occurred in only 1 patient.
Two characteristics of CT103A may contribute to its long persistence, stated study senior author Jianfeng Zhou, MD, PhD, chairman and professor of the department of hematology, Tongji Hospital in Wuhan, China. “One is the reduced immunogenicity achieved by the fully human construct; another is the relatively low binding affinity of the CAR binder. Notably, four patients who previously received murine BCMA CAR were included and still benefit from CT103A. It demonstrates the possibility of retreatment with a different CAR.” Dr. Zhou also emphasized that the lack of ICANS in the entire cohort reflects the excellent safety profile of CT103A.
The editorial commentary in Blood by Lydia Sarah Hui Lee, MD, and Kwee L. Yong, PhD, underscored impressive responses to CT103A, specifically to the median time to response of 15 days, the 100% ORR, and the not reached median progression-free survival at 394 days).5 The best results in other published nonhuman BCMA CAR T-cell trials, they note, were about 1 month (time to response), approximately 33%-88% (ORR), and median progression-free survival of 7-15 months.
Immune responses, Dr. Yong said in an interview, can guide subsequent treatment. “For example, if a patient previously exposed to BCMA CAR T cells in which the construct is either chimeric or humanized, but retains some murine elements, and had detectable antimurine antibodies, we may aim for a fully human one if we are considering treating with a different BCMA CAR T-cell product.” She added, “On the other hand, a similar patient whose serum did not contain such antibodies may be a candidate for a humanized product that retained some murine elements.”
Wang and colleagues concluded, “Altogether, CT103A is safe and highly active in patients with relapsed/refractory multiple myeloma and can be developed as a promising therapy for relapsed/refractory multiple myeloma.”4 An ongoing multicenter phase II trial with single-arm design is recruiting 100 patients. The infusion dosage, suggested by the phase I trial, is 1 × 106 cells/kg. Endpoints include efficacy and safety.
Improving CAR T
Optimizing CAR design and adapting manufacturing processes to generate cell products enriched for T-cell subsets, such as early memory cells, are among strategies being explored to improve CAR T effectiveness.1 Also, dual-antigen targeting to interdict antigen escape and rational combination treatments to enhance persistence are under investigation, along with efforts to improve CAR T-cell therapy safety (for example, incorporation of a suicide gene safety system). They note further that several groups are researching use of induced pluripotent stem cells to generate large quantities of off-the-shelf CAR T-cell immunotherapies that would circumvent the complex, costly, and time-consuming process of manufacturing patient-specific autologous CAR T cells.
References
1. van de Donk N et al. Lancet Haematol. 2021 June;8(6):e446-61.
2. Munshi NC et al. N Engl J Med 2021; 384:705-716.
3. Berdeja JG et al. The Lancet. 2021 July; 398:314-24.
4. Wang D et al. Blood. 2021 May;137(21):2890-901.
5. Lee L and Yong K. Blood. 2021 May;137(21):2859-60.
In multiple myeloma, survival has been very significantly improved by immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies. Despite these advances, multiple myeloma, which is characterized by malignant proliferation of clonal plasma cells in bone marrow, remains an incurable plasma cell disorder with near-certain relapse after successful treatment. Prognosis for patients who develop triple-class refractory disease is poor, with less than 1-year survival. The substantial unmet therapeutic need extends further to other poor survival multiple myeloma populations that include newly diagnosed patients with high cytogenic risk profiles and those with early relapse after first-line therapy. For all of these, interest in drugs with novel mechanisms of action is naturally high.
More specific, less toxic
Post allogeneic hematopoietic stem-cell transplantation and donor lymphocyte infusion sustained remissions reflect a graft-versus-myeloma effect mediated by donor T cells.1 The substantial morbidity and mortality associated with graft-versus-host disease and opportunistic infections, however, have spurred searches for alternative, more specific, and less toxic T-cell therapies with stronger antitumor activity.
Chimeric antigen receptors (CARs)
In CAR T-cell therapies for multiple myeloma, autologous T cells are harvested from the patient and reprogrammed to target multiple myeloma cells through the introduction of genes that encode CARs, which are fusion proteins coupling an antigen-recognition moiety and a transmembrane-spanning element to a T-cell activation domain (typically CD3 zeta [CD247]). The T cells are then expanded and reinfused to the patient following a lymphodepletion regimen. Five strategies using autologous CAR T cells are currently approved for diffuse large B-cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies. Notably, in patients with heavily pretreated multiple myeloma, CAR T cells have demonstrated impressive activity.
BCMA-targeting CAR T cells
The B-cell maturation antigen (BCMA; TNFRSF17), which plays an important role in the survival of long-lived plasma cells in bone marrow, is an attractive target for CAR T-cell therapy because it is expressed on normal and malignant plasma cell surfaces and by mature B cells. When ligands (TNFSF 13B/TNFSF13) bind to BCMA expressed on multiple myeloma cell surfaces, survival and proliferation pathways and drug resistance are activated.
High-quality responses have been demonstrated in several trials of anti-BCMA CAR T cells, which kill multiple myeloma cell lines and primary multiple myeloma cells through degranulation of T cells and lysis of tumor cells, even those with low BCMA expression. Based on efficacy in triple-class exposed multiple myeloma that compared favorably to conventional care with improved health-related quality of life, the U.S. Food and Drug Administration gave breakthrough designation to ciltacabtagene autoleucel in December 2019 and approval for idecabtagene vicleucel in March 2021.
Idecabtagene vicleucel
Idecabtagene vicleucel expresses a murine BCMA-targeting single-chain variable fragment with a 4-1BB costimulatory motif. The phase 2 KarMMa study2 evaluated idecabtagene vicleucel (target dose of 450 × 106 CAR T cells; range 150 × 106 to 450 × 106) activity in 128 patients with triple-class exposed multiple myeloma. Partial responses or better were observed in 94 of 128 patients (73%) (95% confidence interval, 66-81); 42 (33%) had a complete response or better (95% CI, 25-41), with a median progression-free survival of 8.8 months (95% CI, 5.6-11.6). Outcomes were improved in the highest fixed-dose group, with partial response or better in 81% (44 of 55), complete response or better in 39% (21), and median overall survival of 12.1 months (95% CI, 8.8-12.3). Patients with high-risk cytogenetic profiles, extramedullary disease, and high tumor burden also had deep and durable responses. Outcomes were less favorable in patients with revised International Staging System stage 3 disease.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel, a 4-1BB–based CAR T-cell therapy with two BCMA-targeting domains, confers high-avidity binding. In the phase 1b/2 CARTITUDE-1 study, conducted in the United States and Europe, preliminary results in 97 patients showed a 97% response rate with ciltacabtagene autoleucel (target dose 0.75 × 106 CAR T cells per kg), and in 65 patients, a complete response (67%). Progression-free survival at 12 months was 77% (95% CI, 66-84) and overall survival was 89% (95% CI, 80-94).3
In the phase 1 LEGEND-2 study4 that was conducted at four sites in China among less heavily pretreated multiple myeloma patients, while all used the same CAR construct, sites used variable conditioning regimens (split versus single). In the site using cyclophosphamide as the lymphodepletion therapy and three split CAR T-cell infusions, partial response or better was achieved in 50 patients (88%) with a median of three prior therapy lines. The complete response rate was high (74%) and minimal residual disease negativity was reached in 39 patients (68%). Median progression-free survival was 19.9 months (95% CI, 9.6-31.0), but 28.2 months among those with complete responses (95% CI, 19.9-not estimable). Median overall survival was also favorable at 36.1 months (95% CI, 26.4-not estimable); it was 35.0 months-not estimable among patients with complete responses. Results from the other three sites were comparable.
Noteworthy among other BCMA-targeting CAR T-cell products in earlier stages of clinical development is orvacabtagene autoleucel, which has a fully human BCMA-specific binding domain. At higher doses (300 × 106 to 600 × 106 CAR T cells) among 62 patients with triple-class–exposed multiple myeloma in the EVOLVE trial, 92% had a partial or better response, with complete responses or better in 36%, all with an encouraging safety profile.
BCMA-targeting CAR T cell toxicity
While van de Donk, Usmani, and Yong, in their review1 note a lack of evidence of off-target toxicity with BCMA-targeting CAR T-cell therapy in clinical studies so far, they do point to several clinical syndromes (cytokine release syndrome, infections, respiratory failure, neurotoxicity, pulmonary aspergillosis, gastrointestinal hemorrhage) caused by cytokines produced during CAR T-cell expansion and to cytopenias and infections arising from prior treatment, bridging therapy, and lymphodepleting conditioning. Deaths attributed to treatment in the above-mentioned trials underscore the need for careful monitoring and early intervention.
Cytokine release syndrome
In the BCMA-targeting CAR T-cell therapy studies, the frequency of cytokine release syndrome varies widely from 17% to 95% but is generally attributed to CAR T-cell activation and is associated with increased serum ferritin concentrations, high c-reactive proteins, and proinflammatory cytokines. High tumor load, in multiple myeloma patients receiving CD19-targeting CAR T cells, was associated with a higher incidence of severe cytokine release syndrome. In a small number of patients, macrophage activation syndrome and hemophagocytic lymphohistiocytosis, the most aggressive variants of cytokine release syndrome, are caused by severe immune activation and lead to multiorgan dysfunction.
Neurotoxicity
Immune effector cell–-associated neurotoxicity syndrome (ICANS) symptoms, in multiple myeloma patients treated with BCMA-targeting CAR T cells, may include delirium, transient confusion, aphasia, lethargy, tremor, dysgraphia, seizures, cerebral edema, and rarely, posterior reversible encephalopathy syndrome.1 While the pathophysiology of CAR T cell–related neurotoxicity is not well understood, high tumor load, higher peak concentrations of CAR T cells, and more severe cytokine release syndrome are more common in patients with severe neurotoxicity. “The frequency of neurotoxicities,” Dr. Yong noted in an interview, “has been reduced by steps taken to mitigate these risk factors.”
High interest in phase I study
A phase I study presented in Blood has attracted interest because the novel BCMA-targeting CAR agent (CT103A) being tested is fully human.4 In an accompanying editorial, Lee and Yong note that doubt for any real potential for durable CAR T therapy responses in multiple myeloma is raised by the poor persistence of multiple myeloma CAR T cells in multiple myeloma patients.3
In the earliest trials of BCMA CARs, while reported rates of objective antimyeloma responses were in the approximately 33%-88% range among patients with relapsed/refractory multiple myeloma (RRMM), persistence was typically 6 months or less. Lee and Yong point out, however, that while correlation between persistence and duration of response (DOR) has been variable, median persistence was 308 days in the phase I study. Wang and colleagues, the phase I study authors, state that levels of CAR T-cell proliferation and duration of cellular persistence may be determinants of DOR in CAR T therapy for multiple myeloma. They observe that the multiple mechanisms potentially responsible for the inability of some CAR T cells to survive in vivo, may include antigen escape, T-cell intrinsic mechanisms, tumor microenvironment–mediated suppression, and host anti-CAR immunity. CARs with humanized or fully human single-chain variable fragments (scFvs), prior studies suggest, may retain antitumor activity through bypassing potential host anti-CAR immunogenicity.
In the study, CT103A, a fully human scFv, was tested in an open-label, single-arm design for safety and preliminary efficacy in 18 patients (8 female; median age 53.5 years) with RRMM (at least three lines of prior therapies including a proteasome inhibitor and an immunomodulatory agent) who had undergone leukapheresis and had received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Four patients (22.2%) had been treated previously with murine anti-BCMA CAR T cells. Safety and tolerability (including dose-limiting toxicity) were the primary endpoints, with efficacy and pharmacokinetics secondary.
Rapid responses
Two weeks after infusion, the overall response rate (ORR) was 77.8% (14 of 18) and by 1 month it was 88.9% (16 of 18). Eventually, all responded and 72.2% (13 of 18) achieved a complete response (CR) or stringent complete response (sCR). All 17 patients evaluated for minimum residual disease (MRD) in bone marrow were MRD-negative at 10-4 nucleated cells by flow cytometry within 1 month. Median DOR was 325 days (range, 7-573 days) for all patients and 412 days (range, 213-573 days) for the 13 with CR/sCR. CAR transgenes were detectable at the cutoff date in 77.8% of patients, with a median CAR transgene persistence of 307.5 days.
During follow-up, four deaths were reported, including one patient with persistent sCR (sudden severe infection). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 58.3% and 75%, respectively. Extramedullary myeloma was associated with a shortened PFS (79.1% versus 20.0%, P = .015), but not OS (79.1% versus 60.0%, P = .328) at 1 year.
All patients experienced grade 3 or higher adverse events, most of which were expected hematologic effects of lymphodepleting chemotherapy and CT103A infusions. Grade 1 and 2 cytokine release syndromes occurred in 70.6% patients (17 of 18), with 1 grade 4 event (5.9%). The patients receiving a dose of up to 3.0 × 106 CAR+ T cells/kg required less treatment of cytokine release syndrome than the patients who received a dose of 6.0 × 106 CAR+ T cells/kg. No immune effector cell–associated neurotoxicity syndrome was observed. Antidrug antibody positivity occurred in only 1 patient.
Two characteristics of CT103A may contribute to its long persistence, stated study senior author Jianfeng Zhou, MD, PhD, chairman and professor of the department of hematology, Tongji Hospital in Wuhan, China. “One is the reduced immunogenicity achieved by the fully human construct; another is the relatively low binding affinity of the CAR binder. Notably, four patients who previously received murine BCMA CAR were included and still benefit from CT103A. It demonstrates the possibility of retreatment with a different CAR.” Dr. Zhou also emphasized that the lack of ICANS in the entire cohort reflects the excellent safety profile of CT103A.
The editorial commentary in Blood by Lydia Sarah Hui Lee, MD, and Kwee L. Yong, PhD, underscored impressive responses to CT103A, specifically to the median time to response of 15 days, the 100% ORR, and the not reached median progression-free survival at 394 days).5 The best results in other published nonhuman BCMA CAR T-cell trials, they note, were about 1 month (time to response), approximately 33%-88% (ORR), and median progression-free survival of 7-15 months.
Immune responses, Dr. Yong said in an interview, can guide subsequent treatment. “For example, if a patient previously exposed to BCMA CAR T cells in which the construct is either chimeric or humanized, but retains some murine elements, and had detectable antimurine antibodies, we may aim for a fully human one if we are considering treating with a different BCMA CAR T-cell product.” She added, “On the other hand, a similar patient whose serum did not contain such antibodies may be a candidate for a humanized product that retained some murine elements.”
Wang and colleagues concluded, “Altogether, CT103A is safe and highly active in patients with relapsed/refractory multiple myeloma and can be developed as a promising therapy for relapsed/refractory multiple myeloma.”4 An ongoing multicenter phase II trial with single-arm design is recruiting 100 patients. The infusion dosage, suggested by the phase I trial, is 1 × 106 cells/kg. Endpoints include efficacy and safety.
Improving CAR T
Optimizing CAR design and adapting manufacturing processes to generate cell products enriched for T-cell subsets, such as early memory cells, are among strategies being explored to improve CAR T effectiveness.1 Also, dual-antigen targeting to interdict antigen escape and rational combination treatments to enhance persistence are under investigation, along with efforts to improve CAR T-cell therapy safety (for example, incorporation of a suicide gene safety system). They note further that several groups are researching use of induced pluripotent stem cells to generate large quantities of off-the-shelf CAR T-cell immunotherapies that would circumvent the complex, costly, and time-consuming process of manufacturing patient-specific autologous CAR T cells.
References
1. van de Donk N et al. Lancet Haematol. 2021 June;8(6):e446-61.
2. Munshi NC et al. N Engl J Med 2021; 384:705-716.
3. Berdeja JG et al. The Lancet. 2021 July; 398:314-24.
4. Wang D et al. Blood. 2021 May;137(21):2890-901.
5. Lee L and Yong K. Blood. 2021 May;137(21):2859-60.
In multiple myeloma, survival has been very significantly improved by immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies. Despite these advances, multiple myeloma, which is characterized by malignant proliferation of clonal plasma cells in bone marrow, remains an incurable plasma cell disorder with near-certain relapse after successful treatment. Prognosis for patients who develop triple-class refractory disease is poor, with less than 1-year survival. The substantial unmet therapeutic need extends further to other poor survival multiple myeloma populations that include newly diagnosed patients with high cytogenic risk profiles and those with early relapse after first-line therapy. For all of these, interest in drugs with novel mechanisms of action is naturally high.
More specific, less toxic
Post allogeneic hematopoietic stem-cell transplantation and donor lymphocyte infusion sustained remissions reflect a graft-versus-myeloma effect mediated by donor T cells.1 The substantial morbidity and mortality associated with graft-versus-host disease and opportunistic infections, however, have spurred searches for alternative, more specific, and less toxic T-cell therapies with stronger antitumor activity.
Chimeric antigen receptors (CARs)
In CAR T-cell therapies for multiple myeloma, autologous T cells are harvested from the patient and reprogrammed to target multiple myeloma cells through the introduction of genes that encode CARs, which are fusion proteins coupling an antigen-recognition moiety and a transmembrane-spanning element to a T-cell activation domain (typically CD3 zeta [CD247]). The T cells are then expanded and reinfused to the patient following a lymphodepletion regimen. Five strategies using autologous CAR T cells are currently approved for diffuse large B-cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies. Notably, in patients with heavily pretreated multiple myeloma, CAR T cells have demonstrated impressive activity.
BCMA-targeting CAR T cells
The B-cell maturation antigen (BCMA; TNFRSF17), which plays an important role in the survival of long-lived plasma cells in bone marrow, is an attractive target for CAR T-cell therapy because it is expressed on normal and malignant plasma cell surfaces and by mature B cells. When ligands (TNFSF 13B/TNFSF13) bind to BCMA expressed on multiple myeloma cell surfaces, survival and proliferation pathways and drug resistance are activated.
High-quality responses have been demonstrated in several trials of anti-BCMA CAR T cells, which kill multiple myeloma cell lines and primary multiple myeloma cells through degranulation of T cells and lysis of tumor cells, even those with low BCMA expression. Based on efficacy in triple-class exposed multiple myeloma that compared favorably to conventional care with improved health-related quality of life, the U.S. Food and Drug Administration gave breakthrough designation to ciltacabtagene autoleucel in December 2019 and approval for idecabtagene vicleucel in March 2021.
Idecabtagene vicleucel
Idecabtagene vicleucel expresses a murine BCMA-targeting single-chain variable fragment with a 4-1BB costimulatory motif. The phase 2 KarMMa study2 evaluated idecabtagene vicleucel (target dose of 450 × 106 CAR T cells; range 150 × 106 to 450 × 106) activity in 128 patients with triple-class exposed multiple myeloma. Partial responses or better were observed in 94 of 128 patients (73%) (95% confidence interval, 66-81); 42 (33%) had a complete response or better (95% CI, 25-41), with a median progression-free survival of 8.8 months (95% CI, 5.6-11.6). Outcomes were improved in the highest fixed-dose group, with partial response or better in 81% (44 of 55), complete response or better in 39% (21), and median overall survival of 12.1 months (95% CI, 8.8-12.3). Patients with high-risk cytogenetic profiles, extramedullary disease, and high tumor burden also had deep and durable responses. Outcomes were less favorable in patients with revised International Staging System stage 3 disease.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel, a 4-1BB–based CAR T-cell therapy with two BCMA-targeting domains, confers high-avidity binding. In the phase 1b/2 CARTITUDE-1 study, conducted in the United States and Europe, preliminary results in 97 patients showed a 97% response rate with ciltacabtagene autoleucel (target dose 0.75 × 106 CAR T cells per kg), and in 65 patients, a complete response (67%). Progression-free survival at 12 months was 77% (95% CI, 66-84) and overall survival was 89% (95% CI, 80-94).3
In the phase 1 LEGEND-2 study4 that was conducted at four sites in China among less heavily pretreated multiple myeloma patients, while all used the same CAR construct, sites used variable conditioning regimens (split versus single). In the site using cyclophosphamide as the lymphodepletion therapy and three split CAR T-cell infusions, partial response or better was achieved in 50 patients (88%) with a median of three prior therapy lines. The complete response rate was high (74%) and minimal residual disease negativity was reached in 39 patients (68%). Median progression-free survival was 19.9 months (95% CI, 9.6-31.0), but 28.2 months among those with complete responses (95% CI, 19.9-not estimable). Median overall survival was also favorable at 36.1 months (95% CI, 26.4-not estimable); it was 35.0 months-not estimable among patients with complete responses. Results from the other three sites were comparable.
Noteworthy among other BCMA-targeting CAR T-cell products in earlier stages of clinical development is orvacabtagene autoleucel, which has a fully human BCMA-specific binding domain. At higher doses (300 × 106 to 600 × 106 CAR T cells) among 62 patients with triple-class–exposed multiple myeloma in the EVOLVE trial, 92% had a partial or better response, with complete responses or better in 36%, all with an encouraging safety profile.
BCMA-targeting CAR T cell toxicity
While van de Donk, Usmani, and Yong, in their review1 note a lack of evidence of off-target toxicity with BCMA-targeting CAR T-cell therapy in clinical studies so far, they do point to several clinical syndromes (cytokine release syndrome, infections, respiratory failure, neurotoxicity, pulmonary aspergillosis, gastrointestinal hemorrhage) caused by cytokines produced during CAR T-cell expansion and to cytopenias and infections arising from prior treatment, bridging therapy, and lymphodepleting conditioning. Deaths attributed to treatment in the above-mentioned trials underscore the need for careful monitoring and early intervention.
Cytokine release syndrome
In the BCMA-targeting CAR T-cell therapy studies, the frequency of cytokine release syndrome varies widely from 17% to 95% but is generally attributed to CAR T-cell activation and is associated with increased serum ferritin concentrations, high c-reactive proteins, and proinflammatory cytokines. High tumor load, in multiple myeloma patients receiving CD19-targeting CAR T cells, was associated with a higher incidence of severe cytokine release syndrome. In a small number of patients, macrophage activation syndrome and hemophagocytic lymphohistiocytosis, the most aggressive variants of cytokine release syndrome, are caused by severe immune activation and lead to multiorgan dysfunction.
Neurotoxicity
Immune effector cell–-associated neurotoxicity syndrome (ICANS) symptoms, in multiple myeloma patients treated with BCMA-targeting CAR T cells, may include delirium, transient confusion, aphasia, lethargy, tremor, dysgraphia, seizures, cerebral edema, and rarely, posterior reversible encephalopathy syndrome.1 While the pathophysiology of CAR T cell–related neurotoxicity is not well understood, high tumor load, higher peak concentrations of CAR T cells, and more severe cytokine release syndrome are more common in patients with severe neurotoxicity. “The frequency of neurotoxicities,” Dr. Yong noted in an interview, “has been reduced by steps taken to mitigate these risk factors.”
High interest in phase I study
A phase I study presented in Blood has attracted interest because the novel BCMA-targeting CAR agent (CT103A) being tested is fully human.4 In an accompanying editorial, Lee and Yong note that doubt for any real potential for durable CAR T therapy responses in multiple myeloma is raised by the poor persistence of multiple myeloma CAR T cells in multiple myeloma patients.3
In the earliest trials of BCMA CARs, while reported rates of objective antimyeloma responses were in the approximately 33%-88% range among patients with relapsed/refractory multiple myeloma (RRMM), persistence was typically 6 months or less. Lee and Yong point out, however, that while correlation between persistence and duration of response (DOR) has been variable, median persistence was 308 days in the phase I study. Wang and colleagues, the phase I study authors, state that levels of CAR T-cell proliferation and duration of cellular persistence may be determinants of DOR in CAR T therapy for multiple myeloma. They observe that the multiple mechanisms potentially responsible for the inability of some CAR T cells to survive in vivo, may include antigen escape, T-cell intrinsic mechanisms, tumor microenvironment–mediated suppression, and host anti-CAR immunity. CARs with humanized or fully human single-chain variable fragments (scFvs), prior studies suggest, may retain antitumor activity through bypassing potential host anti-CAR immunogenicity.
In the study, CT103A, a fully human scFv, was tested in an open-label, single-arm design for safety and preliminary efficacy in 18 patients (8 female; median age 53.5 years) with RRMM (at least three lines of prior therapies including a proteasome inhibitor and an immunomodulatory agent) who had undergone leukapheresis and had received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Four patients (22.2%) had been treated previously with murine anti-BCMA CAR T cells. Safety and tolerability (including dose-limiting toxicity) were the primary endpoints, with efficacy and pharmacokinetics secondary.
Rapid responses
Two weeks after infusion, the overall response rate (ORR) was 77.8% (14 of 18) and by 1 month it was 88.9% (16 of 18). Eventually, all responded and 72.2% (13 of 18) achieved a complete response (CR) or stringent complete response (sCR). All 17 patients evaluated for minimum residual disease (MRD) in bone marrow were MRD-negative at 10-4 nucleated cells by flow cytometry within 1 month. Median DOR was 325 days (range, 7-573 days) for all patients and 412 days (range, 213-573 days) for the 13 with CR/sCR. CAR transgenes were detectable at the cutoff date in 77.8% of patients, with a median CAR transgene persistence of 307.5 days.
During follow-up, four deaths were reported, including one patient with persistent sCR (sudden severe infection). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 58.3% and 75%, respectively. Extramedullary myeloma was associated with a shortened PFS (79.1% versus 20.0%, P = .015), but not OS (79.1% versus 60.0%, P = .328) at 1 year.
All patients experienced grade 3 or higher adverse events, most of which were expected hematologic effects of lymphodepleting chemotherapy and CT103A infusions. Grade 1 and 2 cytokine release syndromes occurred in 70.6% patients (17 of 18), with 1 grade 4 event (5.9%). The patients receiving a dose of up to 3.0 × 106 CAR+ T cells/kg required less treatment of cytokine release syndrome than the patients who received a dose of 6.0 × 106 CAR+ T cells/kg. No immune effector cell–associated neurotoxicity syndrome was observed. Antidrug antibody positivity occurred in only 1 patient.
Two characteristics of CT103A may contribute to its long persistence, stated study senior author Jianfeng Zhou, MD, PhD, chairman and professor of the department of hematology, Tongji Hospital in Wuhan, China. “One is the reduced immunogenicity achieved by the fully human construct; another is the relatively low binding affinity of the CAR binder. Notably, four patients who previously received murine BCMA CAR were included and still benefit from CT103A. It demonstrates the possibility of retreatment with a different CAR.” Dr. Zhou also emphasized that the lack of ICANS in the entire cohort reflects the excellent safety profile of CT103A.
The editorial commentary in Blood by Lydia Sarah Hui Lee, MD, and Kwee L. Yong, PhD, underscored impressive responses to CT103A, specifically to the median time to response of 15 days, the 100% ORR, and the not reached median progression-free survival at 394 days).5 The best results in other published nonhuman BCMA CAR T-cell trials, they note, were about 1 month (time to response), approximately 33%-88% (ORR), and median progression-free survival of 7-15 months.
Immune responses, Dr. Yong said in an interview, can guide subsequent treatment. “For example, if a patient previously exposed to BCMA CAR T cells in which the construct is either chimeric or humanized, but retains some murine elements, and had detectable antimurine antibodies, we may aim for a fully human one if we are considering treating with a different BCMA CAR T-cell product.” She added, “On the other hand, a similar patient whose serum did not contain such antibodies may be a candidate for a humanized product that retained some murine elements.”
Wang and colleagues concluded, “Altogether, CT103A is safe and highly active in patients with relapsed/refractory multiple myeloma and can be developed as a promising therapy for relapsed/refractory multiple myeloma.”4 An ongoing multicenter phase II trial with single-arm design is recruiting 100 patients. The infusion dosage, suggested by the phase I trial, is 1 × 106 cells/kg. Endpoints include efficacy and safety.
Improving CAR T
Optimizing CAR design and adapting manufacturing processes to generate cell products enriched for T-cell subsets, such as early memory cells, are among strategies being explored to improve CAR T effectiveness.1 Also, dual-antigen targeting to interdict antigen escape and rational combination treatments to enhance persistence are under investigation, along with efforts to improve CAR T-cell therapy safety (for example, incorporation of a suicide gene safety system). They note further that several groups are researching use of induced pluripotent stem cells to generate large quantities of off-the-shelf CAR T-cell immunotherapies that would circumvent the complex, costly, and time-consuming process of manufacturing patient-specific autologous CAR T cells.
References
1. van de Donk N et al. Lancet Haematol. 2021 June;8(6):e446-61.
2. Munshi NC et al. N Engl J Med 2021; 384:705-716.
3. Berdeja JG et al. The Lancet. 2021 July; 398:314-24.
4. Wang D et al. Blood. 2021 May;137(21):2890-901.
5. Lee L and Yong K. Blood. 2021 May;137(21):2859-60.
Antibiotic use associated with triple-negative breast cancer mortality
SAN ANTONIO –
The study was recently presented at the San Antonio Breast Cancer Symposium by Julia D. Ransohoff, MD, of Stanford (Calif.) University.
Gut-associated lymphoid tissues are the largest component of the immune system. They influence both local and systemic immune responses, but the use of antimicrobials can decrease circulating and tumor-infiltrating lymphocytes that effect the immune repertoire and in turn, the survival of women with triple-negative breast cancer.
Dr. Ransohoff and colleagues hypothesized that increasing antimicrobial exposure in the presence of time-varying absolute lymphocyte counts may lead to higher overall and breast cancer–specific mortality. Their analysis is based on data from the population-based Surveillance, Epidemiology, and End Results registry and electronic medical records from Stanford University and Sutter Health. It included 772 women who were treated for triple-negative breast cancer between 2000 and 2014. The women were followed for an average of 104 months.
In an earlier analysis of this same group, Dr. Ransohoff found that higher minimum absolute lymphocyte counts were associated with lower overall mortality (hazard ratio, 0.23; 95% confidence interval, 0.16-0.35) and breast cancer mortality (HR, 0.19; 95% CI, 0.11-0.34) The association between higher peripheral lymphocyte counts and tumor-infiltrating lymphocytes was significant.
In the analysis of relationships between antibiotic use and mortality, 85% of women (n = 654) were prescribed antibiotics after having been diagnosed with triple-negative breast cancer. The death rate among patients who were prescribed antibiotics was 23% (153/654), compared with 20% (24/118) among the patients who were not treated with antibiotics (which accounts for 15% of the entire group).
For total antibiotic exposure, the HR for overall mortality was 1.06 (95% CI, 1.03-1.09; P < .001) and 1.07 for breast cancer–specific mortality (95% CI, 1.04-1.10; P < .001). For unique antibiotic exposure (not counting repeat prescriptions of the same antibiotic), the HR for overall mortality was 1.17 (95% CI, 1.12-1.22; P < .001) and 1.18 for breast cancer–specific mortality (95% CI, 1.12-1.24; P < .001).
“These were all statistically significant associations derived from a statistical model that takes into account baseline patient characteristics, so the reported hazard ratios, to the best of our ability, represent the risk of death associated with antibiotic use adjusted for other baseline covariates. We’ve attempted to account for differences at baseline that may indicate patients are sicker, and so the reported risk represents mortality related with antibiotic exposure,” Dr. Ransohoff said.
Elucidating the role of the microbiome in mediating absolute lymphocyte counts and immune response may inform interventions to reduce triple-negative mortality, she said.
SAN ANTONIO –
The study was recently presented at the San Antonio Breast Cancer Symposium by Julia D. Ransohoff, MD, of Stanford (Calif.) University.
Gut-associated lymphoid tissues are the largest component of the immune system. They influence both local and systemic immune responses, but the use of antimicrobials can decrease circulating and tumor-infiltrating lymphocytes that effect the immune repertoire and in turn, the survival of women with triple-negative breast cancer.
Dr. Ransohoff and colleagues hypothesized that increasing antimicrobial exposure in the presence of time-varying absolute lymphocyte counts may lead to higher overall and breast cancer–specific mortality. Their analysis is based on data from the population-based Surveillance, Epidemiology, and End Results registry and electronic medical records from Stanford University and Sutter Health. It included 772 women who were treated for triple-negative breast cancer between 2000 and 2014. The women were followed for an average of 104 months.
In an earlier analysis of this same group, Dr. Ransohoff found that higher minimum absolute lymphocyte counts were associated with lower overall mortality (hazard ratio, 0.23; 95% confidence interval, 0.16-0.35) and breast cancer mortality (HR, 0.19; 95% CI, 0.11-0.34) The association between higher peripheral lymphocyte counts and tumor-infiltrating lymphocytes was significant.
In the analysis of relationships between antibiotic use and mortality, 85% of women (n = 654) were prescribed antibiotics after having been diagnosed with triple-negative breast cancer. The death rate among patients who were prescribed antibiotics was 23% (153/654), compared with 20% (24/118) among the patients who were not treated with antibiotics (which accounts for 15% of the entire group).
For total antibiotic exposure, the HR for overall mortality was 1.06 (95% CI, 1.03-1.09; P < .001) and 1.07 for breast cancer–specific mortality (95% CI, 1.04-1.10; P < .001). For unique antibiotic exposure (not counting repeat prescriptions of the same antibiotic), the HR for overall mortality was 1.17 (95% CI, 1.12-1.22; P < .001) and 1.18 for breast cancer–specific mortality (95% CI, 1.12-1.24; P < .001).
“These were all statistically significant associations derived from a statistical model that takes into account baseline patient characteristics, so the reported hazard ratios, to the best of our ability, represent the risk of death associated with antibiotic use adjusted for other baseline covariates. We’ve attempted to account for differences at baseline that may indicate patients are sicker, and so the reported risk represents mortality related with antibiotic exposure,” Dr. Ransohoff said.
Elucidating the role of the microbiome in mediating absolute lymphocyte counts and immune response may inform interventions to reduce triple-negative mortality, she said.
SAN ANTONIO –
The study was recently presented at the San Antonio Breast Cancer Symposium by Julia D. Ransohoff, MD, of Stanford (Calif.) University.
Gut-associated lymphoid tissues are the largest component of the immune system. They influence both local and systemic immune responses, but the use of antimicrobials can decrease circulating and tumor-infiltrating lymphocytes that effect the immune repertoire and in turn, the survival of women with triple-negative breast cancer.
Dr. Ransohoff and colleagues hypothesized that increasing antimicrobial exposure in the presence of time-varying absolute lymphocyte counts may lead to higher overall and breast cancer–specific mortality. Their analysis is based on data from the population-based Surveillance, Epidemiology, and End Results registry and electronic medical records from Stanford University and Sutter Health. It included 772 women who were treated for triple-negative breast cancer between 2000 and 2014. The women were followed for an average of 104 months.
In an earlier analysis of this same group, Dr. Ransohoff found that higher minimum absolute lymphocyte counts were associated with lower overall mortality (hazard ratio, 0.23; 95% confidence interval, 0.16-0.35) and breast cancer mortality (HR, 0.19; 95% CI, 0.11-0.34) The association between higher peripheral lymphocyte counts and tumor-infiltrating lymphocytes was significant.
In the analysis of relationships between antibiotic use and mortality, 85% of women (n = 654) were prescribed antibiotics after having been diagnosed with triple-negative breast cancer. The death rate among patients who were prescribed antibiotics was 23% (153/654), compared with 20% (24/118) among the patients who were not treated with antibiotics (which accounts for 15% of the entire group).
For total antibiotic exposure, the HR for overall mortality was 1.06 (95% CI, 1.03-1.09; P < .001) and 1.07 for breast cancer–specific mortality (95% CI, 1.04-1.10; P < .001). For unique antibiotic exposure (not counting repeat prescriptions of the same antibiotic), the HR for overall mortality was 1.17 (95% CI, 1.12-1.22; P < .001) and 1.18 for breast cancer–specific mortality (95% CI, 1.12-1.24; P < .001).
“These were all statistically significant associations derived from a statistical model that takes into account baseline patient characteristics, so the reported hazard ratios, to the best of our ability, represent the risk of death associated with antibiotic use adjusted for other baseline covariates. We’ve attempted to account for differences at baseline that may indicate patients are sicker, and so the reported risk represents mortality related with antibiotic exposure,” Dr. Ransohoff said.
Elucidating the role of the microbiome in mediating absolute lymphocyte counts and immune response may inform interventions to reduce triple-negative mortality, she said.
AT SABCS 2021
Women struggle with benzodiazepine addiction post chemotherapy treatment
SAN ANTONIO – shows a new study.
While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.
The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.
Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.
New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).
It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”
Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.
There were no funding or other conflicts of interest associated with this study.
SAN ANTONIO – shows a new study.
While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.
The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.
Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.
New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).
It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”
Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.
There were no funding or other conflicts of interest associated with this study.
SAN ANTONIO – shows a new study.
While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.
The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.
Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.
New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).
It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”
Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.
There were no funding or other conflicts of interest associated with this study.
AT SABCS 2021
High triglycerides in normal-weight men with obstructive sleep apnea
, according to results of a study published in Nature and Science of Sleep (2021:13 1771-82).
Layla B. Guscoth, MD, of the South Australian Health and Medical Research Institute and Faculty of Health and Medical Sciences, University of Adelaide, Australia, and colleagues assessed unselected male community-dwelling participants in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) and the Florey Adelaide Male Aging Study (FAMAS) studies.
They examined the association of OSA and nocturnal hypoxemia with serum lipid profiles, and suggested that the cardiometabolic risk profiles of healthy weight individuals with OSA require clinical attention, according to the researchers.
The partial or complete obstruction of upper airways found in the OSA syndrome results in intermittent hypoxia, accompanied variably by sleep fragmentation and daytime sleepiness. While the prevalence of moderate to severe OSA was 49.7% in the Swiss HypnoLaus cohort, it was 74.7% in men aged 40 or older (or having OSA syndrome according to ICD-3 criteria). Dr. Guscoth and colleagues point out, however, that OSA is frequently underdiagnosed or unrecognized in clinical settings, and that OSA has been implicated in development of cardiovascular conditions. Furthermore, the nocturnal hypoxemia resulting from OSA during rapid eye movement (REM) sleep is longitudinally associated with cardiovascular disease and its risk factors (hypertension, insulin resistance, metabolic syndrome and carotid atherosclerosis).
Study details
Prior research suggests that intermittent hypoxemia activates the sympathetic nervous system, increases oxidative stress and systemic inflammation, and that when chronic, reduces clearance of triglyceride-rich lipoproteins and inhibits adipose tissue lipoprotein lipase activity. To clarify inconsistent results in studies investigating potential OSA-dyslipidemia associations, and to confirm research suggesting an independent association with severe OSA (apnea-hypopnea index [AHI] ≥ 30/h), the authors conducted analyses stratified by waist circumference to observe an obesity-independent association between OSA metrics and dyslipidemia.
The investigators assessed 753 MAILES participants (mean age 60.8 years) who underwent full in-home polysomnography (Embletta X100). They looked at triglycerides, high- (HDL) and low-density lipoprotein (LDL), total cholesterol, associations between lipids and continuous measures of nocturnal hypoxemia (oxygen desaturation index [ODI], AHI, and REM-AHI), and adjusted for chronic conditions, risk behavior, and sociodemographic factors.
Mean waist circumference was 99.3 cm and OSA (AHI ≥ 10) prevalence was 52.6%. No significant associations were found between OSA metrics and lipid measures in an overall analysis, nor in a sensitivity analysis excluding lipid-lowering therapies.
In a covariate adjusted analysis stratified according to waist circumference (< 95 cm, 95-100 cm, > 100 cm) to minimize the contribution of obesity to hypertriglyceridemia, triglyceride levels were positively associated with AHI, ODI and REM-AHI in the participants with a waist circumference < 95 cm (P < .05), but not in participants with waist circumferences of 95-100 cm or > 100 cm.
Worse during REM
The authors observed also that OSA during REM sleep is marked by longer obstructive events with greater oxygen desaturations. Obstructive events during REM sleep, research has shown, may be more harmful than obstructive events during non-REM sleep with respect to hypertension, cardiovascular disease, and glycemic control in type 2 diabetes.
Looking at clinical categories of OSA, Dr. Guscoth and colleagues found that severe OSA was significantly associated with higher likelihood of triglyceride levels ≥ 1.7 mmol/L (odds ratio, 4.1, 95% confidence interval, 1.1-15.5, P = .039). Analysis according to waist circumference confirmed the relationship only among men with waist circumference < 95 cm.
Clinical concern
“We therefore suggest that with our data unstratified by weight circumference, metabolic derangements associated with insulin resistance induced by intermittent hypoxia due to OSA cannot be separated from the predominant effect of visceral obesity. When stratified by weight circumference, our data show that these derangements in triglycerides are observed only in lean participants where obesity does not have a dominant effect,” the researchers concluded.
“These findings of high prevalence of metabolic risk in lean patients with OSA, I find very worrying,” coauthor Sarah Appleton, PhD, Flinders Medical Center, Adelaide, Australia, said in an interview. She cited a study showing a 61% risk of dyslipidemia in lean patients with OSA (AHI > 5/hr, body mass index < 25 kg/m2, and waist < 80 cm in women, < 90 cm in men), and two of three metabolic syndrome components in 64%. “Annual fasting blood tests would identify metabolic problems such as elevated fasting glucose and triglyceride levels,” she noted.
This work was supported by a National Health and Medical Research Council of Australia Project Grant (627227), the Hospital Research Foundation and ResMed Foundation. There were no relevant conflicts reported.
, according to results of a study published in Nature and Science of Sleep (2021:13 1771-82).
Layla B. Guscoth, MD, of the South Australian Health and Medical Research Institute and Faculty of Health and Medical Sciences, University of Adelaide, Australia, and colleagues assessed unselected male community-dwelling participants in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) and the Florey Adelaide Male Aging Study (FAMAS) studies.
They examined the association of OSA and nocturnal hypoxemia with serum lipid profiles, and suggested that the cardiometabolic risk profiles of healthy weight individuals with OSA require clinical attention, according to the researchers.
The partial or complete obstruction of upper airways found in the OSA syndrome results in intermittent hypoxia, accompanied variably by sleep fragmentation and daytime sleepiness. While the prevalence of moderate to severe OSA was 49.7% in the Swiss HypnoLaus cohort, it was 74.7% in men aged 40 or older (or having OSA syndrome according to ICD-3 criteria). Dr. Guscoth and colleagues point out, however, that OSA is frequently underdiagnosed or unrecognized in clinical settings, and that OSA has been implicated in development of cardiovascular conditions. Furthermore, the nocturnal hypoxemia resulting from OSA during rapid eye movement (REM) sleep is longitudinally associated with cardiovascular disease and its risk factors (hypertension, insulin resistance, metabolic syndrome and carotid atherosclerosis).
Study details
Prior research suggests that intermittent hypoxemia activates the sympathetic nervous system, increases oxidative stress and systemic inflammation, and that when chronic, reduces clearance of triglyceride-rich lipoproteins and inhibits adipose tissue lipoprotein lipase activity. To clarify inconsistent results in studies investigating potential OSA-dyslipidemia associations, and to confirm research suggesting an independent association with severe OSA (apnea-hypopnea index [AHI] ≥ 30/h), the authors conducted analyses stratified by waist circumference to observe an obesity-independent association between OSA metrics and dyslipidemia.
The investigators assessed 753 MAILES participants (mean age 60.8 years) who underwent full in-home polysomnography (Embletta X100). They looked at triglycerides, high- (HDL) and low-density lipoprotein (LDL), total cholesterol, associations between lipids and continuous measures of nocturnal hypoxemia (oxygen desaturation index [ODI], AHI, and REM-AHI), and adjusted for chronic conditions, risk behavior, and sociodemographic factors.
Mean waist circumference was 99.3 cm and OSA (AHI ≥ 10) prevalence was 52.6%. No significant associations were found between OSA metrics and lipid measures in an overall analysis, nor in a sensitivity analysis excluding lipid-lowering therapies.
In a covariate adjusted analysis stratified according to waist circumference (< 95 cm, 95-100 cm, > 100 cm) to minimize the contribution of obesity to hypertriglyceridemia, triglyceride levels were positively associated with AHI, ODI and REM-AHI in the participants with a waist circumference < 95 cm (P < .05), but not in participants with waist circumferences of 95-100 cm or > 100 cm.
Worse during REM
The authors observed also that OSA during REM sleep is marked by longer obstructive events with greater oxygen desaturations. Obstructive events during REM sleep, research has shown, may be more harmful than obstructive events during non-REM sleep with respect to hypertension, cardiovascular disease, and glycemic control in type 2 diabetes.
Looking at clinical categories of OSA, Dr. Guscoth and colleagues found that severe OSA was significantly associated with higher likelihood of triglyceride levels ≥ 1.7 mmol/L (odds ratio, 4.1, 95% confidence interval, 1.1-15.5, P = .039). Analysis according to waist circumference confirmed the relationship only among men with waist circumference < 95 cm.
Clinical concern
“We therefore suggest that with our data unstratified by weight circumference, metabolic derangements associated with insulin resistance induced by intermittent hypoxia due to OSA cannot be separated from the predominant effect of visceral obesity. When stratified by weight circumference, our data show that these derangements in triglycerides are observed only in lean participants where obesity does not have a dominant effect,” the researchers concluded.
“These findings of high prevalence of metabolic risk in lean patients with OSA, I find very worrying,” coauthor Sarah Appleton, PhD, Flinders Medical Center, Adelaide, Australia, said in an interview. She cited a study showing a 61% risk of dyslipidemia in lean patients with OSA (AHI > 5/hr, body mass index < 25 kg/m2, and waist < 80 cm in women, < 90 cm in men), and two of three metabolic syndrome components in 64%. “Annual fasting blood tests would identify metabolic problems such as elevated fasting glucose and triglyceride levels,” she noted.
This work was supported by a National Health and Medical Research Council of Australia Project Grant (627227), the Hospital Research Foundation and ResMed Foundation. There were no relevant conflicts reported.
, according to results of a study published in Nature and Science of Sleep (2021:13 1771-82).
Layla B. Guscoth, MD, of the South Australian Health and Medical Research Institute and Faculty of Health and Medical Sciences, University of Adelaide, Australia, and colleagues assessed unselected male community-dwelling participants in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) and the Florey Adelaide Male Aging Study (FAMAS) studies.
They examined the association of OSA and nocturnal hypoxemia with serum lipid profiles, and suggested that the cardiometabolic risk profiles of healthy weight individuals with OSA require clinical attention, according to the researchers.
The partial or complete obstruction of upper airways found in the OSA syndrome results in intermittent hypoxia, accompanied variably by sleep fragmentation and daytime sleepiness. While the prevalence of moderate to severe OSA was 49.7% in the Swiss HypnoLaus cohort, it was 74.7% in men aged 40 or older (or having OSA syndrome according to ICD-3 criteria). Dr. Guscoth and colleagues point out, however, that OSA is frequently underdiagnosed or unrecognized in clinical settings, and that OSA has been implicated in development of cardiovascular conditions. Furthermore, the nocturnal hypoxemia resulting from OSA during rapid eye movement (REM) sleep is longitudinally associated with cardiovascular disease and its risk factors (hypertension, insulin resistance, metabolic syndrome and carotid atherosclerosis).
Study details
Prior research suggests that intermittent hypoxemia activates the sympathetic nervous system, increases oxidative stress and systemic inflammation, and that when chronic, reduces clearance of triglyceride-rich lipoproteins and inhibits adipose tissue lipoprotein lipase activity. To clarify inconsistent results in studies investigating potential OSA-dyslipidemia associations, and to confirm research suggesting an independent association with severe OSA (apnea-hypopnea index [AHI] ≥ 30/h), the authors conducted analyses stratified by waist circumference to observe an obesity-independent association between OSA metrics and dyslipidemia.
The investigators assessed 753 MAILES participants (mean age 60.8 years) who underwent full in-home polysomnography (Embletta X100). They looked at triglycerides, high- (HDL) and low-density lipoprotein (LDL), total cholesterol, associations between lipids and continuous measures of nocturnal hypoxemia (oxygen desaturation index [ODI], AHI, and REM-AHI), and adjusted for chronic conditions, risk behavior, and sociodemographic factors.
Mean waist circumference was 99.3 cm and OSA (AHI ≥ 10) prevalence was 52.6%. No significant associations were found between OSA metrics and lipid measures in an overall analysis, nor in a sensitivity analysis excluding lipid-lowering therapies.
In a covariate adjusted analysis stratified according to waist circumference (< 95 cm, 95-100 cm, > 100 cm) to minimize the contribution of obesity to hypertriglyceridemia, triglyceride levels were positively associated with AHI, ODI and REM-AHI in the participants with a waist circumference < 95 cm (P < .05), but not in participants with waist circumferences of 95-100 cm or > 100 cm.
Worse during REM
The authors observed also that OSA during REM sleep is marked by longer obstructive events with greater oxygen desaturations. Obstructive events during REM sleep, research has shown, may be more harmful than obstructive events during non-REM sleep with respect to hypertension, cardiovascular disease, and glycemic control in type 2 diabetes.
Looking at clinical categories of OSA, Dr. Guscoth and colleagues found that severe OSA was significantly associated with higher likelihood of triglyceride levels ≥ 1.7 mmol/L (odds ratio, 4.1, 95% confidence interval, 1.1-15.5, P = .039). Analysis according to waist circumference confirmed the relationship only among men with waist circumference < 95 cm.
Clinical concern
“We therefore suggest that with our data unstratified by weight circumference, metabolic derangements associated with insulin resistance induced by intermittent hypoxia due to OSA cannot be separated from the predominant effect of visceral obesity. When stratified by weight circumference, our data show that these derangements in triglycerides are observed only in lean participants where obesity does not have a dominant effect,” the researchers concluded.
“These findings of high prevalence of metabolic risk in lean patients with OSA, I find very worrying,” coauthor Sarah Appleton, PhD, Flinders Medical Center, Adelaide, Australia, said in an interview. She cited a study showing a 61% risk of dyslipidemia in lean patients with OSA (AHI > 5/hr, body mass index < 25 kg/m2, and waist < 80 cm in women, < 90 cm in men), and two of three metabolic syndrome components in 64%. “Annual fasting blood tests would identify metabolic problems such as elevated fasting glucose and triglyceride levels,” she noted.
This work was supported by a National Health and Medical Research Council of Australia Project Grant (627227), the Hospital Research Foundation and ResMed Foundation. There were no relevant conflicts reported.
FROM NATURE AND SCIENCE OF SLEEP
Venetoclax heralded a new class of small-molecule blood cancer drugs
Venetoclax’s regulatory approvals, its success as monotherapy for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms, and its activity in combination against acute myeloid leukemia (AML) have helped pave the way for BCL2 and MCL1 inhibitors that target prosurvival, antiapoptosis proteins.
A first-in-class specific inhibitor of BCL2, A review by Andrew W. Roberts, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne, and associates details their key features, including their activity and tolerability and resistance issues. The review was published in Blood .
BH3 mimetics
BH3 mimetics, a new class of small-molecule anticancer drugs, enable specific targeting of BCL2 and MCL1, commonly expressed antiapoptotic proteins in hematologic cancers. The BH3 mimetics inhibit prosurvival BCL2 proteins, enabling activation of the apoptosis effectors BAX and BK that make the outer mitochondrial membranes permeable. This result triggers apoptosis in many cells, while sensitizing others to cell death when the BH3 mimetics are combined with other antineoplastic drugs. The BAX/BAK–driven effect on mitochondrial membranes is to undermine normal energy production, allowing leakage of cell contents, including cytochrome c, a trigger of proteolytic enzymes and cellular demolition.
Navitoclax was the first potent BCL2 inhibitor to enter clinical trials. While it demonstrated moderate single-agent activity in relapsed CLL and indolent B-cell lymphomas, its dose-limiting toxicity of thrombocytopenia precluded further exploration of BCL2 inhibition. Navitoclax is being developed for hematologic disease (for example, myelofibrosis and acute lymphoblastic leukemia). Clinical development of other BH3 mimetics is only in the earliest stages, the authors wrote.
Venetoclax, to avoid this on-target thrombocytopenia, was designed to specifically inhibit BCL2 with great selectivity, a feature not found in naturally occurring BH3-only proteins. The fact that it could inhibit a single prosurvival protein and have important clinical activity proved enormously stimulating to development of this drug class. Potent BH3 mimetics now can also selectively target MCL1, which plays a central role in plasma cells (mature B lymphocytes are highly reliant on BCL2).
In CLL, dependence on BCL2 is high. Venetoclax, since it was first approved by the Food and Drug Administration in April 2016 as monotherapy for relapsed/refractory del(17p) CLL, has been approved widely in combination with rituximab in relapsed/refractory CLL and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. With venetoclax monotherapy, quickly achieved high objective response rates (79%) and complete remissions (20%) revealed the drug’s dose-limiting toxicity of tumor lysis syndrome (TLS). This necessitated gradual ramp-up dosing in those with high disease burden or reduced renal function. Also, despite the adoption of a venetoclax/rituximab combination as standard for relapsed/refractory CLL, the authors underscored that evidence for an additive rituximab benefit is modest and limited.
Resistance
While resistance to venetoclax leading to treatment failure is uncommon in the first year, secondary resistance occurs through several independently occurring mechanisms, including mutations in BCL2 (for example, Gly101Val), overexpression of MCL1, and overexpression of BCLxL. Usual venetoclax therapy is now time limited. Early data on re-exposure shows high rates (about 70%) of secondary responses.
AML
In AML, a more heterogeneous disease than CLL, BCL2 expression varies widely and can be heterogeneous even within a single patient’s leukemic cell population. While responses to venetoclax monotherapy were not durable, combination therapy with azacitidine has revealed enhanced activity. The venetoclax/azacitidine combination has been widely adopted as first-line therapy for older and unfit AML patients. Myelosuppression is the major toxicity.
“As venetoclax is the first in a new class of anticancer drug,” Andrew W. Roberts, MD, said in an interview, “we are still in the process of working out how it can be best utilized. Regimens free of DNA-damaging chemotherapy using this BCL2 inhibitor in combination with obinutuzumab or rituximab in CLL are established. Across B-cell neoplasia (e.g. CLL, mantle cell lymphoma, follicular lymphoma), the challenge is to work out whether venetoclax can enhance other ‘chemotherapy-free’ regimens.” He continued: “In contrast, for AML, learning how venetoclax can be safely combined with intensive chemotherapy is a priority, as we seek to improve outcomes for patients with poor prognosis disease. For MCL1 inhibitors, there is excitement about their potential, but their clinical development remains in its infancy.”
The authors reported multiple financial disclosures.
Venetoclax’s regulatory approvals, its success as monotherapy for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms, and its activity in combination against acute myeloid leukemia (AML) have helped pave the way for BCL2 and MCL1 inhibitors that target prosurvival, antiapoptosis proteins.
A first-in-class specific inhibitor of BCL2, A review by Andrew W. Roberts, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne, and associates details their key features, including their activity and tolerability and resistance issues. The review was published in Blood .
BH3 mimetics
BH3 mimetics, a new class of small-molecule anticancer drugs, enable specific targeting of BCL2 and MCL1, commonly expressed antiapoptotic proteins in hematologic cancers. The BH3 mimetics inhibit prosurvival BCL2 proteins, enabling activation of the apoptosis effectors BAX and BK that make the outer mitochondrial membranes permeable. This result triggers apoptosis in many cells, while sensitizing others to cell death when the BH3 mimetics are combined with other antineoplastic drugs. The BAX/BAK–driven effect on mitochondrial membranes is to undermine normal energy production, allowing leakage of cell contents, including cytochrome c, a trigger of proteolytic enzymes and cellular demolition.
Navitoclax was the first potent BCL2 inhibitor to enter clinical trials. While it demonstrated moderate single-agent activity in relapsed CLL and indolent B-cell lymphomas, its dose-limiting toxicity of thrombocytopenia precluded further exploration of BCL2 inhibition. Navitoclax is being developed for hematologic disease (for example, myelofibrosis and acute lymphoblastic leukemia). Clinical development of other BH3 mimetics is only in the earliest stages, the authors wrote.
Venetoclax, to avoid this on-target thrombocytopenia, was designed to specifically inhibit BCL2 with great selectivity, a feature not found in naturally occurring BH3-only proteins. The fact that it could inhibit a single prosurvival protein and have important clinical activity proved enormously stimulating to development of this drug class. Potent BH3 mimetics now can also selectively target MCL1, which plays a central role in plasma cells (mature B lymphocytes are highly reliant on BCL2).
In CLL, dependence on BCL2 is high. Venetoclax, since it was first approved by the Food and Drug Administration in April 2016 as monotherapy for relapsed/refractory del(17p) CLL, has been approved widely in combination with rituximab in relapsed/refractory CLL and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. With venetoclax monotherapy, quickly achieved high objective response rates (79%) and complete remissions (20%) revealed the drug’s dose-limiting toxicity of tumor lysis syndrome (TLS). This necessitated gradual ramp-up dosing in those with high disease burden or reduced renal function. Also, despite the adoption of a venetoclax/rituximab combination as standard for relapsed/refractory CLL, the authors underscored that evidence for an additive rituximab benefit is modest and limited.
Resistance
While resistance to venetoclax leading to treatment failure is uncommon in the first year, secondary resistance occurs through several independently occurring mechanisms, including mutations in BCL2 (for example, Gly101Val), overexpression of MCL1, and overexpression of BCLxL. Usual venetoclax therapy is now time limited. Early data on re-exposure shows high rates (about 70%) of secondary responses.
AML
In AML, a more heterogeneous disease than CLL, BCL2 expression varies widely and can be heterogeneous even within a single patient’s leukemic cell population. While responses to venetoclax monotherapy were not durable, combination therapy with azacitidine has revealed enhanced activity. The venetoclax/azacitidine combination has been widely adopted as first-line therapy for older and unfit AML patients. Myelosuppression is the major toxicity.
“As venetoclax is the first in a new class of anticancer drug,” Andrew W. Roberts, MD, said in an interview, “we are still in the process of working out how it can be best utilized. Regimens free of DNA-damaging chemotherapy using this BCL2 inhibitor in combination with obinutuzumab or rituximab in CLL are established. Across B-cell neoplasia (e.g. CLL, mantle cell lymphoma, follicular lymphoma), the challenge is to work out whether venetoclax can enhance other ‘chemotherapy-free’ regimens.” He continued: “In contrast, for AML, learning how venetoclax can be safely combined with intensive chemotherapy is a priority, as we seek to improve outcomes for patients with poor prognosis disease. For MCL1 inhibitors, there is excitement about their potential, but their clinical development remains in its infancy.”
The authors reported multiple financial disclosures.
Venetoclax’s regulatory approvals, its success as monotherapy for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms, and its activity in combination against acute myeloid leukemia (AML) have helped pave the way for BCL2 and MCL1 inhibitors that target prosurvival, antiapoptosis proteins.
A first-in-class specific inhibitor of BCL2, A review by Andrew W. Roberts, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne, and associates details their key features, including their activity and tolerability and resistance issues. The review was published in Blood .
BH3 mimetics
BH3 mimetics, a new class of small-molecule anticancer drugs, enable specific targeting of BCL2 and MCL1, commonly expressed antiapoptotic proteins in hematologic cancers. The BH3 mimetics inhibit prosurvival BCL2 proteins, enabling activation of the apoptosis effectors BAX and BK that make the outer mitochondrial membranes permeable. This result triggers apoptosis in many cells, while sensitizing others to cell death when the BH3 mimetics are combined with other antineoplastic drugs. The BAX/BAK–driven effect on mitochondrial membranes is to undermine normal energy production, allowing leakage of cell contents, including cytochrome c, a trigger of proteolytic enzymes and cellular demolition.
Navitoclax was the first potent BCL2 inhibitor to enter clinical trials. While it demonstrated moderate single-agent activity in relapsed CLL and indolent B-cell lymphomas, its dose-limiting toxicity of thrombocytopenia precluded further exploration of BCL2 inhibition. Navitoclax is being developed for hematologic disease (for example, myelofibrosis and acute lymphoblastic leukemia). Clinical development of other BH3 mimetics is only in the earliest stages, the authors wrote.
Venetoclax, to avoid this on-target thrombocytopenia, was designed to specifically inhibit BCL2 with great selectivity, a feature not found in naturally occurring BH3-only proteins. The fact that it could inhibit a single prosurvival protein and have important clinical activity proved enormously stimulating to development of this drug class. Potent BH3 mimetics now can also selectively target MCL1, which plays a central role in plasma cells (mature B lymphocytes are highly reliant on BCL2).
In CLL, dependence on BCL2 is high. Venetoclax, since it was first approved by the Food and Drug Administration in April 2016 as monotherapy for relapsed/refractory del(17p) CLL, has been approved widely in combination with rituximab in relapsed/refractory CLL and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. With venetoclax monotherapy, quickly achieved high objective response rates (79%) and complete remissions (20%) revealed the drug’s dose-limiting toxicity of tumor lysis syndrome (TLS). This necessitated gradual ramp-up dosing in those with high disease burden or reduced renal function. Also, despite the adoption of a venetoclax/rituximab combination as standard for relapsed/refractory CLL, the authors underscored that evidence for an additive rituximab benefit is modest and limited.
Resistance
While resistance to venetoclax leading to treatment failure is uncommon in the first year, secondary resistance occurs through several independently occurring mechanisms, including mutations in BCL2 (for example, Gly101Val), overexpression of MCL1, and overexpression of BCLxL. Usual venetoclax therapy is now time limited. Early data on re-exposure shows high rates (about 70%) of secondary responses.
AML
In AML, a more heterogeneous disease than CLL, BCL2 expression varies widely and can be heterogeneous even within a single patient’s leukemic cell population. While responses to venetoclax monotherapy were not durable, combination therapy with azacitidine has revealed enhanced activity. The venetoclax/azacitidine combination has been widely adopted as first-line therapy for older and unfit AML patients. Myelosuppression is the major toxicity.
“As venetoclax is the first in a new class of anticancer drug,” Andrew W. Roberts, MD, said in an interview, “we are still in the process of working out how it can be best utilized. Regimens free of DNA-damaging chemotherapy using this BCL2 inhibitor in combination with obinutuzumab or rituximab in CLL are established. Across B-cell neoplasia (e.g. CLL, mantle cell lymphoma, follicular lymphoma), the challenge is to work out whether venetoclax can enhance other ‘chemotherapy-free’ regimens.” He continued: “In contrast, for AML, learning how venetoclax can be safely combined with intensive chemotherapy is a priority, as we seek to improve outcomes for patients with poor prognosis disease. For MCL1 inhibitors, there is excitement about their potential, but their clinical development remains in its infancy.”
The authors reported multiple financial disclosures.
FROM BLOOD