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DEA ruling may have stoked illicit opioid sales
Illicit online sales of opioids increased significantly following a 2014 regulatory decision that restricted the legal supply of opioids in the United States, results of a recent analysis show.
Opioid sales in the so-called cryptomarkets also shifted toward more potent drugs, including fentanyl, after the U.S. Drug Enforcement Administration rescheduled hydrocodone combination products, making them harder to access, authors of the analysis reported.
Those results suggest “the possibility of a causal relation” between the schedule change and sales trends on cryptomarket sites, according to James Martin, PhD, of Swinburne University, Melbourne, Australia, and co-authors.
“Our analysis cannot rule out other possible causal explanatory factors, but our results are consistent with the possibility that the schedule change might have directly contributed to the changes we observed in the supply of illicit opioids,” Dr. Martin and colleagues wrote in the BMJ.
Cryptomarkets outside the United States had no such uptick in opioid traffic over time, reinforcing the possibility that the 2014 DEA decision caused an increase in the illicit opioid supply. The analysis included 31 online illicit markets operating between October 2013 and July 2016.
Investigators collected data using web crawling software that downloaded HTML pages on the cryptomarket sites and extracted relevant information such as listing titles and drug types for later analysis. Generally, each market was fully crawled every 2 weeks. After data was scraped and extracted, they conducted an interrupted time series analysis of drug sales for each day of the data collection period.
Opioids represented 13.7% of all drug sales through U.S. cryptomarkets in July 2016, they found, compared with a modeled estimate of 6.7% of sales that would have occurred in the absence of the new schedule introduction.
“This represents an approximate doubling of the percentage of the total drug sales through cryptomarkets within the United States,” the authors wrote.
Fentanyl was the least purchased product at the beginning of the analysis, but by July 2016 it was the second most frequently purchased. No other drug category had any meaningful changes in the proportion of sales over time.
There was no way for researchers to confirm that U.S.-based cryptomarket sites were selling to customers in the United States or elsewhere. However, they said, cryptomarket buyers often use sites in the same country to avoid shipment losses and increased delivery time.
Part of the study were funded by the Social Sciences and Humanities Research Council of Canada, Macquarie University internal grants, and the Ministry of Justice and Security of the Netherlands. Study authors had no current financial relationships relevant to the study.
SOURCE: Martin J, et al. BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2270.
The overdose crisis in the United States will likely worsen if “supply-side” measures, such as the tighter prescribing regulations evaluated in this study, are not coupled with interventions to reduce harm and decrease demand, according to Scott E. Hadland, MD, and Leo Beletsky.
On a more basic level, the analysis by James Martin and colleagues raises questions about the use of drug scheduling to regulate public health, the authors concluded in an accompanying editorial.
“The U.S. scheduling scheme inexplicably holds such disparate substances as cannabis, heroin, and psilocybin to be equally dangerous,” they wrote. “It is high time to rethink how, why, and when this regulatory framework is deployed to curb drug-related harms.”
The shift from schedule III to schedule II creates barriers to medication access that disproportionately affect individuals in rural areas and those with limited mobility, since refills for schedule II drugs can only be obtained through an in-person visit to a provider and pharmacist, the authors wrote.
Scott E Hadland, MD, is with Grayken Center for Addiction/Department of Pediatrics, Boston Medical Center, and Leo Beletsky is with the School of Law and Bouvé College of Health Sciences, Northeastern University, Boston. Mr. Beletsky reported sitting on the advisory board of a data analytics company that has an interest in the U.S. opioid crisis. These comments are from their accompanying editorial (BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2480 ). Mr. Beletsky reported sitting on the advisory board of a data analytics company that has an interest in the U.S. opioid crisis.
The overdose crisis in the United States will likely worsen if “supply-side” measures, such as the tighter prescribing regulations evaluated in this study, are not coupled with interventions to reduce harm and decrease demand, according to Scott E. Hadland, MD, and Leo Beletsky.
On a more basic level, the analysis by James Martin and colleagues raises questions about the use of drug scheduling to regulate public health, the authors concluded in an accompanying editorial.
“The U.S. scheduling scheme inexplicably holds such disparate substances as cannabis, heroin, and psilocybin to be equally dangerous,” they wrote. “It is high time to rethink how, why, and when this regulatory framework is deployed to curb drug-related harms.”
The shift from schedule III to schedule II creates barriers to medication access that disproportionately affect individuals in rural areas and those with limited mobility, since refills for schedule II drugs can only be obtained through an in-person visit to a provider and pharmacist, the authors wrote.
Scott E Hadland, MD, is with Grayken Center for Addiction/Department of Pediatrics, Boston Medical Center, and Leo Beletsky is with the School of Law and Bouvé College of Health Sciences, Northeastern University, Boston. Mr. Beletsky reported sitting on the advisory board of a data analytics company that has an interest in the U.S. opioid crisis. These comments are from their accompanying editorial (BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2480 ). Mr. Beletsky reported sitting on the advisory board of a data analytics company that has an interest in the U.S. opioid crisis.
The overdose crisis in the United States will likely worsen if “supply-side” measures, such as the tighter prescribing regulations evaluated in this study, are not coupled with interventions to reduce harm and decrease demand, according to Scott E. Hadland, MD, and Leo Beletsky.
On a more basic level, the analysis by James Martin and colleagues raises questions about the use of drug scheduling to regulate public health, the authors concluded in an accompanying editorial.
“The U.S. scheduling scheme inexplicably holds such disparate substances as cannabis, heroin, and psilocybin to be equally dangerous,” they wrote. “It is high time to rethink how, why, and when this regulatory framework is deployed to curb drug-related harms.”
The shift from schedule III to schedule II creates barriers to medication access that disproportionately affect individuals in rural areas and those with limited mobility, since refills for schedule II drugs can only be obtained through an in-person visit to a provider and pharmacist, the authors wrote.
Scott E Hadland, MD, is with Grayken Center for Addiction/Department of Pediatrics, Boston Medical Center, and Leo Beletsky is with the School of Law and Bouvé College of Health Sciences, Northeastern University, Boston. Mr. Beletsky reported sitting on the advisory board of a data analytics company that has an interest in the U.S. opioid crisis. These comments are from their accompanying editorial (BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2480 ). Mr. Beletsky reported sitting on the advisory board of a data analytics company that has an interest in the U.S. opioid crisis.
Illicit online sales of opioids increased significantly following a 2014 regulatory decision that restricted the legal supply of opioids in the United States, results of a recent analysis show.
Opioid sales in the so-called cryptomarkets also shifted toward more potent drugs, including fentanyl, after the U.S. Drug Enforcement Administration rescheduled hydrocodone combination products, making them harder to access, authors of the analysis reported.
Those results suggest “the possibility of a causal relation” between the schedule change and sales trends on cryptomarket sites, according to James Martin, PhD, of Swinburne University, Melbourne, Australia, and co-authors.
“Our analysis cannot rule out other possible causal explanatory factors, but our results are consistent with the possibility that the schedule change might have directly contributed to the changes we observed in the supply of illicit opioids,” Dr. Martin and colleagues wrote in the BMJ.
Cryptomarkets outside the United States had no such uptick in opioid traffic over time, reinforcing the possibility that the 2014 DEA decision caused an increase in the illicit opioid supply. The analysis included 31 online illicit markets operating between October 2013 and July 2016.
Investigators collected data using web crawling software that downloaded HTML pages on the cryptomarket sites and extracted relevant information such as listing titles and drug types for later analysis. Generally, each market was fully crawled every 2 weeks. After data was scraped and extracted, they conducted an interrupted time series analysis of drug sales for each day of the data collection period.
Opioids represented 13.7% of all drug sales through U.S. cryptomarkets in July 2016, they found, compared with a modeled estimate of 6.7% of sales that would have occurred in the absence of the new schedule introduction.
“This represents an approximate doubling of the percentage of the total drug sales through cryptomarkets within the United States,” the authors wrote.
Fentanyl was the least purchased product at the beginning of the analysis, but by July 2016 it was the second most frequently purchased. No other drug category had any meaningful changes in the proportion of sales over time.
There was no way for researchers to confirm that U.S.-based cryptomarket sites were selling to customers in the United States or elsewhere. However, they said, cryptomarket buyers often use sites in the same country to avoid shipment losses and increased delivery time.
Part of the study were funded by the Social Sciences and Humanities Research Council of Canada, Macquarie University internal grants, and the Ministry of Justice and Security of the Netherlands. Study authors had no current financial relationships relevant to the study.
SOURCE: Martin J, et al. BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2270.
Illicit online sales of opioids increased significantly following a 2014 regulatory decision that restricted the legal supply of opioids in the United States, results of a recent analysis show.
Opioid sales in the so-called cryptomarkets also shifted toward more potent drugs, including fentanyl, after the U.S. Drug Enforcement Administration rescheduled hydrocodone combination products, making them harder to access, authors of the analysis reported.
Those results suggest “the possibility of a causal relation” between the schedule change and sales trends on cryptomarket sites, according to James Martin, PhD, of Swinburne University, Melbourne, Australia, and co-authors.
“Our analysis cannot rule out other possible causal explanatory factors, but our results are consistent with the possibility that the schedule change might have directly contributed to the changes we observed in the supply of illicit opioids,” Dr. Martin and colleagues wrote in the BMJ.
Cryptomarkets outside the United States had no such uptick in opioid traffic over time, reinforcing the possibility that the 2014 DEA decision caused an increase in the illicit opioid supply. The analysis included 31 online illicit markets operating between October 2013 and July 2016.
Investigators collected data using web crawling software that downloaded HTML pages on the cryptomarket sites and extracted relevant information such as listing titles and drug types for later analysis. Generally, each market was fully crawled every 2 weeks. After data was scraped and extracted, they conducted an interrupted time series analysis of drug sales for each day of the data collection period.
Opioids represented 13.7% of all drug sales through U.S. cryptomarkets in July 2016, they found, compared with a modeled estimate of 6.7% of sales that would have occurred in the absence of the new schedule introduction.
“This represents an approximate doubling of the percentage of the total drug sales through cryptomarkets within the United States,” the authors wrote.
Fentanyl was the least purchased product at the beginning of the analysis, but by July 2016 it was the second most frequently purchased. No other drug category had any meaningful changes in the proportion of sales over time.
There was no way for researchers to confirm that U.S.-based cryptomarket sites were selling to customers in the United States or elsewhere. However, they said, cryptomarket buyers often use sites in the same country to avoid shipment losses and increased delivery time.
Part of the study were funded by the Social Sciences and Humanities Research Council of Canada, Macquarie University internal grants, and the Ministry of Justice and Security of the Netherlands. Study authors had no current financial relationships relevant to the study.
SOURCE: Martin J, et al. BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2270.
FROM BMJ
Key clinical point: Major finding: Opioids represented 13.7% of all drug sales through U.S. cryptomarkets in July 2016, compared with a modeled estimate of 6.7%.
Study details: An analysis of 31 online cryptomarkets operating between October 2013 and July 2016.
Disclosures: Part of the study were funded by the Social Sciences and Humanities Research Council of Canada, Macquarie University internal grants, and the Ministry of Justice and Security of the Netherlands. Study authors reported having no current financial relationships relevant to the study.
Source: Martin J, et al. BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2270.
RBC transfusions with surgery may increase VTE risk
In patients undergoing surgery, RBC transfusions may be associated with the development of new or progressive venous thromboembolism within 30 days of the procedure, results of a recent registry study suggest.
Patients who received perioperative RBC transfusions had significantly higher odds of developing postoperative venous thromboembolism (VTE) overall, as well as higher odds specifically for deep venous thrombosis (DVT) and pulmonary embolism (PE), according to results published in JAMA Surgery.
“In a subset of patients receiving perioperative RBC transfusions, a synergistic and incremental dose-related risk for VTE development may exist,” Dr. Goel and her coauthors wrote.
The analysis was based on prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014, of which 47,410 (6.3%) received one or more perioperative RBC transfusions. VTE occurred in 6,309 patients (0.8%), of which 4,336 cases were DVT (0.6%) and 2,514 were PE (0.3%).
The patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3) versus those who had no transfusions, according to results of a multivariable analysis adjusting for age, sex, length of hospital stay, use of mechanical ventilation, and other potentially confounding factors.
Similarly, researchers found transfused patients had higher odds of both DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1).
Odds of VTE increased significantly along with increasing number of perioperative RBC transfusions from an aOR of 2.1 for those with just one transfusion to 4.5 for those who had three or more transfusion events (P less than .001 for trend), results of a dose-response analysis showed.
The association between RBC transfusions perioperatively and VTE postoperatively remained robust after propensity score matching and was statistically significant in all surgical subspecialties, the researchers reported.
However, they also noted that these results will require validation in prospective cohort studies and randomized clinical trials. “If proven, they underscore the continued need for more stringent and optimal perioperative blood management practices in addition to rigorous VTE prophylaxis in patients undergoing surgery.”
The study was funded in part by grants from the National Institutes of Health and Cornell University. The researchers reported having no conflicts of interest.
SOURCE: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
In patients undergoing surgery, RBC transfusions may be associated with the development of new or progressive venous thromboembolism within 30 days of the procedure, results of a recent registry study suggest.
Patients who received perioperative RBC transfusions had significantly higher odds of developing postoperative venous thromboembolism (VTE) overall, as well as higher odds specifically for deep venous thrombosis (DVT) and pulmonary embolism (PE), according to results published in JAMA Surgery.
“In a subset of patients receiving perioperative RBC transfusions, a synergistic and incremental dose-related risk for VTE development may exist,” Dr. Goel and her coauthors wrote.
The analysis was based on prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014, of which 47,410 (6.3%) received one or more perioperative RBC transfusions. VTE occurred in 6,309 patients (0.8%), of which 4,336 cases were DVT (0.6%) and 2,514 were PE (0.3%).
The patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3) versus those who had no transfusions, according to results of a multivariable analysis adjusting for age, sex, length of hospital stay, use of mechanical ventilation, and other potentially confounding factors.
Similarly, researchers found transfused patients had higher odds of both DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1).
Odds of VTE increased significantly along with increasing number of perioperative RBC transfusions from an aOR of 2.1 for those with just one transfusion to 4.5 for those who had three or more transfusion events (P less than .001 for trend), results of a dose-response analysis showed.
The association between RBC transfusions perioperatively and VTE postoperatively remained robust after propensity score matching and was statistically significant in all surgical subspecialties, the researchers reported.
However, they also noted that these results will require validation in prospective cohort studies and randomized clinical trials. “If proven, they underscore the continued need for more stringent and optimal perioperative blood management practices in addition to rigorous VTE prophylaxis in patients undergoing surgery.”
The study was funded in part by grants from the National Institutes of Health and Cornell University. The researchers reported having no conflicts of interest.
SOURCE: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
In patients undergoing surgery, RBC transfusions may be associated with the development of new or progressive venous thromboembolism within 30 days of the procedure, results of a recent registry study suggest.
Patients who received perioperative RBC transfusions had significantly higher odds of developing postoperative venous thromboembolism (VTE) overall, as well as higher odds specifically for deep venous thrombosis (DVT) and pulmonary embolism (PE), according to results published in JAMA Surgery.
“In a subset of patients receiving perioperative RBC transfusions, a synergistic and incremental dose-related risk for VTE development may exist,” Dr. Goel and her coauthors wrote.
The analysis was based on prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014, of which 47,410 (6.3%) received one or more perioperative RBC transfusions. VTE occurred in 6,309 patients (0.8%), of which 4,336 cases were DVT (0.6%) and 2,514 were PE (0.3%).
The patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3) versus those who had no transfusions, according to results of a multivariable analysis adjusting for age, sex, length of hospital stay, use of mechanical ventilation, and other potentially confounding factors.
Similarly, researchers found transfused patients had higher odds of both DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1).
Odds of VTE increased significantly along with increasing number of perioperative RBC transfusions from an aOR of 2.1 for those with just one transfusion to 4.5 for those who had three or more transfusion events (P less than .001 for trend), results of a dose-response analysis showed.
The association between RBC transfusions perioperatively and VTE postoperatively remained robust after propensity score matching and was statistically significant in all surgical subspecialties, the researchers reported.
However, they also noted that these results will require validation in prospective cohort studies and randomized clinical trials. “If proven, they underscore the continued need for more stringent and optimal perioperative blood management practices in addition to rigorous VTE prophylaxis in patients undergoing surgery.”
The study was funded in part by grants from the National Institutes of Health and Cornell University. The researchers reported having no conflicts of interest.
SOURCE: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
FROM JAMA SURGERY
Key clinical point:
Major finding: Patients who received perioperative RBC transfusions had significantly increased odds of developing VTE in the 30-day postoperative period (adjusted odds ratio, 2.1; 95% confidence interval, 2.0-2.3), compared with patients who did not receive transfusions.
Study details: An analysis of prospectively collected North American registry data including 750,937 patients who underwent a surgical procedure in 2014.
Disclosures: The study was funded in part by grants from the National Institutes of Health and Cornell University, New York. The researchers reported having no conflicts of interest.
Source: Goel R et al. JAMA Surg. 2018 Jun 13. doi: 10.1001/jamasurg.2018.1565.
Thyroid markers linked to risk of gestational diabetes
Thyroid dysfunction early in pregnancy may increase risk of gestational diabetes, results of a longitudinal study suggest.
Increased levels of free triiodothyronine (fT3) and the ratio of fT3 to free thyroxine (fT4) were associated with increased risk of this common metabolic complication of pregnancy, study authors reported in the Journal of Clinical Endocrinology & Metabolism.
“To our knowledge, this is the first study to identify fT3 and the fT3:fT4 ratio measured early in pregnancy as independent risk factors of gestational diabetes,” wrote Shristi Rawal, PhD, of the National Institute of Child Health and Human Development (NICHD) , and her colleagues.
Although routine thyroid function screening during pregnancy remains controversial, Dr. Rawal and colleagues said their results support the “potential benefits” of the practice, particularly in light of other recent evidence suggesting thyroid-related adverse pregnancy outcomes.
The current case control study by Dr. Rawal and her coinvestigators included 107 women with gestational diabetes and 214 nongestational diabetes controls selected from a 12-center pregnancy cohort, which included 2,802 women aged between 18 and 40 years. The thyroid markers fT3, fT4, and thyroid-stimulating hormone (TSH) were measured at four pregnancy visits, including first trimester (weeks 10-14) and second trimester (weeks 15-26).
The fT3:fT4 ratio had the strongest association with gestational diabetes. In the second trimester measurement, women in the highest quartile had an almost 14-fold increase in risk when compared to the lowest quartile, after adjusting for potential confounders including prepregnancy body mass index and diabetes family history (adjusted odds ratio, 13.60; 95% confidence interval, 3.97-46.30), Dr. Rawal and her colleagues reported. The ratio of fT3:fT4 at the first trimester was also associated with increased risk (aOR, 8.63; 95% CI, 2.87-26.00).
Similarly, fT3 was positively associated with gestational diabetes at the first trimester (aOR, 4.25; 95% CI, 1.67-10.80) and second trimester (aOR, 3.89; 95% CI, 1.50-10.10), investigators reported.
By contrast, there was no association between fT4 or TSH and gestational diabetes, they found.
“These findings, in combination with previous evidence of thyroid-related adverse pregnancy outcomes, support the benefits of thyroid screening among pregnant women in early to mid pregnancy,” senior author Cuilin Zhang, MD, MPH, PhD, of the NICHD, said in a press statement.
Thyroid function abnormalities are relatively common in pregnant women and have been associated with obstetric complications such as pregnancy loss and premature delivery, investigators noted.
Previous evidence is sparse regarding a potential link between thyroid dysfunction and gestational diabetes. There are some prospective studies that show women with hypothyroidism have an increased incidence of gestational diabetes, Dr. Rawal and her colleagues wrote. Isolated hypothyroxinema, or normal TSH and low fT4, has also been linked to increased risk in some studies, but not in others, they added.
Support for the study came from NICHD and the American Recovery and Reinvestment Act research grants. The authors reported no conflicts of interest.
SOURCE: Rawal S et al. J Clin Endocrinol Metab. 2018 Jun 7. doi: 10.1210/jc.2017-024421.
Thyroid dysfunction early in pregnancy may increase risk of gestational diabetes, results of a longitudinal study suggest.
Increased levels of free triiodothyronine (fT3) and the ratio of fT3 to free thyroxine (fT4) were associated with increased risk of this common metabolic complication of pregnancy, study authors reported in the Journal of Clinical Endocrinology & Metabolism.
“To our knowledge, this is the first study to identify fT3 and the fT3:fT4 ratio measured early in pregnancy as independent risk factors of gestational diabetes,” wrote Shristi Rawal, PhD, of the National Institute of Child Health and Human Development (NICHD) , and her colleagues.
Although routine thyroid function screening during pregnancy remains controversial, Dr. Rawal and colleagues said their results support the “potential benefits” of the practice, particularly in light of other recent evidence suggesting thyroid-related adverse pregnancy outcomes.
The current case control study by Dr. Rawal and her coinvestigators included 107 women with gestational diabetes and 214 nongestational diabetes controls selected from a 12-center pregnancy cohort, which included 2,802 women aged between 18 and 40 years. The thyroid markers fT3, fT4, and thyroid-stimulating hormone (TSH) were measured at four pregnancy visits, including first trimester (weeks 10-14) and second trimester (weeks 15-26).
The fT3:fT4 ratio had the strongest association with gestational diabetes. In the second trimester measurement, women in the highest quartile had an almost 14-fold increase in risk when compared to the lowest quartile, after adjusting for potential confounders including prepregnancy body mass index and diabetes family history (adjusted odds ratio, 13.60; 95% confidence interval, 3.97-46.30), Dr. Rawal and her colleagues reported. The ratio of fT3:fT4 at the first trimester was also associated with increased risk (aOR, 8.63; 95% CI, 2.87-26.00).
Similarly, fT3 was positively associated with gestational diabetes at the first trimester (aOR, 4.25; 95% CI, 1.67-10.80) and second trimester (aOR, 3.89; 95% CI, 1.50-10.10), investigators reported.
By contrast, there was no association between fT4 or TSH and gestational diabetes, they found.
“These findings, in combination with previous evidence of thyroid-related adverse pregnancy outcomes, support the benefits of thyroid screening among pregnant women in early to mid pregnancy,” senior author Cuilin Zhang, MD, MPH, PhD, of the NICHD, said in a press statement.
Thyroid function abnormalities are relatively common in pregnant women and have been associated with obstetric complications such as pregnancy loss and premature delivery, investigators noted.
Previous evidence is sparse regarding a potential link between thyroid dysfunction and gestational diabetes. There are some prospective studies that show women with hypothyroidism have an increased incidence of gestational diabetes, Dr. Rawal and her colleagues wrote. Isolated hypothyroxinema, or normal TSH and low fT4, has also been linked to increased risk in some studies, but not in others, they added.
Support for the study came from NICHD and the American Recovery and Reinvestment Act research grants. The authors reported no conflicts of interest.
SOURCE: Rawal S et al. J Clin Endocrinol Metab. 2018 Jun 7. doi: 10.1210/jc.2017-024421.
Thyroid dysfunction early in pregnancy may increase risk of gestational diabetes, results of a longitudinal study suggest.
Increased levels of free triiodothyronine (fT3) and the ratio of fT3 to free thyroxine (fT4) were associated with increased risk of this common metabolic complication of pregnancy, study authors reported in the Journal of Clinical Endocrinology & Metabolism.
“To our knowledge, this is the first study to identify fT3 and the fT3:fT4 ratio measured early in pregnancy as independent risk factors of gestational diabetes,” wrote Shristi Rawal, PhD, of the National Institute of Child Health and Human Development (NICHD) , and her colleagues.
Although routine thyroid function screening during pregnancy remains controversial, Dr. Rawal and colleagues said their results support the “potential benefits” of the practice, particularly in light of other recent evidence suggesting thyroid-related adverse pregnancy outcomes.
The current case control study by Dr. Rawal and her coinvestigators included 107 women with gestational diabetes and 214 nongestational diabetes controls selected from a 12-center pregnancy cohort, which included 2,802 women aged between 18 and 40 years. The thyroid markers fT3, fT4, and thyroid-stimulating hormone (TSH) were measured at four pregnancy visits, including first trimester (weeks 10-14) and second trimester (weeks 15-26).
The fT3:fT4 ratio had the strongest association with gestational diabetes. In the second trimester measurement, women in the highest quartile had an almost 14-fold increase in risk when compared to the lowest quartile, after adjusting for potential confounders including prepregnancy body mass index and diabetes family history (adjusted odds ratio, 13.60; 95% confidence interval, 3.97-46.30), Dr. Rawal and her colleagues reported. The ratio of fT3:fT4 at the first trimester was also associated with increased risk (aOR, 8.63; 95% CI, 2.87-26.00).
Similarly, fT3 was positively associated with gestational diabetes at the first trimester (aOR, 4.25; 95% CI, 1.67-10.80) and second trimester (aOR, 3.89; 95% CI, 1.50-10.10), investigators reported.
By contrast, there was no association between fT4 or TSH and gestational diabetes, they found.
“These findings, in combination with previous evidence of thyroid-related adverse pregnancy outcomes, support the benefits of thyroid screening among pregnant women in early to mid pregnancy,” senior author Cuilin Zhang, MD, MPH, PhD, of the NICHD, said in a press statement.
Thyroid function abnormalities are relatively common in pregnant women and have been associated with obstetric complications such as pregnancy loss and premature delivery, investigators noted.
Previous evidence is sparse regarding a potential link between thyroid dysfunction and gestational diabetes. There are some prospective studies that show women with hypothyroidism have an increased incidence of gestational diabetes, Dr. Rawal and her colleagues wrote. Isolated hypothyroxinema, or normal TSH and low fT4, has also been linked to increased risk in some studies, but not in others, they added.
Support for the study came from NICHD and the American Recovery and Reinvestment Act research grants. The authors reported no conflicts of interest.
SOURCE: Rawal S et al. J Clin Endocrinol Metab. 2018 Jun 7. doi: 10.1210/jc.2017-024421.
FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM.
Key clinical point: Thyroid dysfunction early in pregnancy may increase risk of gestational diabetes.
Major finding: The triiodothyronine to thyroxine ratio in the second trimester had the strongest association with gestational diabetes (adjusted odds ratio, 13.60; 95% confidence interval, 3.97-46.30).
Study details: A case control study including 107 gestational diabetes cases and 214 nongestational diabetes controls.
Disclosures: The authors had no disclosures. Support for the study came from the National Institute of Child Health and Human Development and the American Recovery and Reinvestment Act research grants.
Source: Rawal S et al. J Clin Endocrinol Metab. 2018 Jun 7. doi: 10.1210/jc.2017-024421.
Study finds widespread use of medications with depression as side effect
About one-third of U.S. adults may be using prescription medications that have depression as a possible side effect, results of a cross-sectional survey study suggest.
Use of multiple medications with depression as a possible side effect was associated with greater likelihood of concurrent depression, authors of the study reported in JAMA.
“The results suggest that physicians should consider discussing these associations with their patients who are prescribed medications that have depression as a potential adverse effect,” said authors, including Dima Mazen Qato, PharmD, MPH, PhD, Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago.
The study included data from 26,192 adults who participated in the National Health and Nutrition Examination Survey between 2005 and 2014. The mean age of participants was 46.2 years, 51.1% were women, and 7.6% reported depression.
Overall, 37.2% of participants reported using medications that had depression as an adverse effect. Use of those medications has increased over time, from 35.0% in 2005-2006 to 38.4% in 2013-2014 (P = .03 for the trend), investigators reported.
Likewise, the proportion of people using at least three medications with depression as a potential side effect, increased from 6.9% to 9.5% from the 2005-2006 to 2013-2014 time period (P = .001), they added.
The prevalence of depression increased with the number of medications with depression as a side effect, in an analysis that excluded antidepressant users. Prevalence was just 4.7% for people who did not use them, up to 15% for those using three or more, a 10.7 percentage point difference, authors noted.
In all, U.S. adults reported more than 200 different medications associated with depression or suicidal symptoms as adverse effects, said Dr. Qato and co-authors.
The most common, aside from antidepressants, which as a class have a black-box warning for risk of depression, were antihypertensive medications, analgesics, hormonal contraceptives, and proton pump inhibitors. Some are over-the-counter medications that are not labeled indicating depression risk: “Many patients may therefore not be aware of the greater likelihood of concurrent depression associated with these commonly used medications,” Dr. Qato and co-authors wrote.
Dr. Qato reported serving as a consultant for Public Citizen’s Health Research Group, and said she is supported in part by the Robert Wood Johnson Foundation. One co-author reported a grant from Janssen Scientific Affairs, LLC, to Columbia University Medical Center.
cpnews@mdedge.com
SOURCE: Qato DM, et al. JAMA
About one-third of U.S. adults may be using prescription medications that have depression as a possible side effect, results of a cross-sectional survey study suggest.
Use of multiple medications with depression as a possible side effect was associated with greater likelihood of concurrent depression, authors of the study reported in JAMA.
“The results suggest that physicians should consider discussing these associations with their patients who are prescribed medications that have depression as a potential adverse effect,” said authors, including Dima Mazen Qato, PharmD, MPH, PhD, Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago.
The study included data from 26,192 adults who participated in the National Health and Nutrition Examination Survey between 2005 and 2014. The mean age of participants was 46.2 years, 51.1% were women, and 7.6% reported depression.
Overall, 37.2% of participants reported using medications that had depression as an adverse effect. Use of those medications has increased over time, from 35.0% in 2005-2006 to 38.4% in 2013-2014 (P = .03 for the trend), investigators reported.
Likewise, the proportion of people using at least three medications with depression as a potential side effect, increased from 6.9% to 9.5% from the 2005-2006 to 2013-2014 time period (P = .001), they added.
The prevalence of depression increased with the number of medications with depression as a side effect, in an analysis that excluded antidepressant users. Prevalence was just 4.7% for people who did not use them, up to 15% for those using three or more, a 10.7 percentage point difference, authors noted.
In all, U.S. adults reported more than 200 different medications associated with depression or suicidal symptoms as adverse effects, said Dr. Qato and co-authors.
The most common, aside from antidepressants, which as a class have a black-box warning for risk of depression, were antihypertensive medications, analgesics, hormonal contraceptives, and proton pump inhibitors. Some are over-the-counter medications that are not labeled indicating depression risk: “Many patients may therefore not be aware of the greater likelihood of concurrent depression associated with these commonly used medications,” Dr. Qato and co-authors wrote.
Dr. Qato reported serving as a consultant for Public Citizen’s Health Research Group, and said she is supported in part by the Robert Wood Johnson Foundation. One co-author reported a grant from Janssen Scientific Affairs, LLC, to Columbia University Medical Center.
cpnews@mdedge.com
SOURCE: Qato DM, et al. JAMA
About one-third of U.S. adults may be using prescription medications that have depression as a possible side effect, results of a cross-sectional survey study suggest.
Use of multiple medications with depression as a possible side effect was associated with greater likelihood of concurrent depression, authors of the study reported in JAMA.
“The results suggest that physicians should consider discussing these associations with their patients who are prescribed medications that have depression as a potential adverse effect,” said authors, including Dima Mazen Qato, PharmD, MPH, PhD, Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago.
The study included data from 26,192 adults who participated in the National Health and Nutrition Examination Survey between 2005 and 2014. The mean age of participants was 46.2 years, 51.1% were women, and 7.6% reported depression.
Overall, 37.2% of participants reported using medications that had depression as an adverse effect. Use of those medications has increased over time, from 35.0% in 2005-2006 to 38.4% in 2013-2014 (P = .03 for the trend), investigators reported.
Likewise, the proportion of people using at least three medications with depression as a potential side effect, increased from 6.9% to 9.5% from the 2005-2006 to 2013-2014 time period (P = .001), they added.
The prevalence of depression increased with the number of medications with depression as a side effect, in an analysis that excluded antidepressant users. Prevalence was just 4.7% for people who did not use them, up to 15% for those using three or more, a 10.7 percentage point difference, authors noted.
In all, U.S. adults reported more than 200 different medications associated with depression or suicidal symptoms as adverse effects, said Dr. Qato and co-authors.
The most common, aside from antidepressants, which as a class have a black-box warning for risk of depression, were antihypertensive medications, analgesics, hormonal contraceptives, and proton pump inhibitors. Some are over-the-counter medications that are not labeled indicating depression risk: “Many patients may therefore not be aware of the greater likelihood of concurrent depression associated with these commonly used medications,” Dr. Qato and co-authors wrote.
Dr. Qato reported serving as a consultant for Public Citizen’s Health Research Group, and said she is supported in part by the Robert Wood Johnson Foundation. One co-author reported a grant from Janssen Scientific Affairs, LLC, to Columbia University Medical Center.
cpnews@mdedge.com
SOURCE: Qato DM, et al. JAMA
No link found between fluconazole use and neonatal death risk
Use of oral fluconazole during pregnancy is not associated with an increase in risk of stillbirth or neonatal death, results of a large European cohort study suggest.
The rate of stillbirths was 2.7 per 1,000 fluconazole-exposed pregnancies, versus 3.6 per 1,000 unexposed pregnancies (hazard ratio, 0.76, 95% confidence interval, 0.52-1.10), investigators reported based on an analysis of national registry data including nearly 1.5 million recent pregnancies in Sweden and Norway.
Neonatal deaths occurred in 1.2 per 1,000 exposed pregnancies and 1.7 per 1,000 unexposed pregnancies, investigators added in the report, which appeared in JAMA.
Results were not different for doses of 300 mg or less versus more than 300 mg, said senior researcher Björn Pasternak, MD, PhD, of Karolinska Institutet, Stockholm, and his co-authors.
“Although the data on fluconazole use in pregnancy suggest no increased risk of stillbirth, additional studies should be conducted and the collective body of data scrutinized by drug authorities before recommendations to guide clinical decision making are made, and weighed against the benefits of therapy,” the investigators wrote.
About 4% of pregnant women in the United States take oral fluconazole, even though it is generally discouraged during pregnancy due to concerns that its use may be associated with stillbirth in a previous Danish nationwide register-based study, published in JAMA.
In 2016, investigators similarly found no increased risk of stillbirth in 2,215 fluconazole-exposed women, though they noted the outcome was “relatively rare and the results therefore imprecise.” In a sensitivity analysis, they did find an association between higher doses of fluconazole (i.e., above 300 mg) and stillbirth, with a hazard ratio of 4.10 (95% CI, 1.89-8.90).
The stillbirth analysis in the present study included 10,669 fluconazole-exposed pregnancies from Sweden and Norway, though the number exposed to higher doses was small, Dr. Pasterak and co-authors said in their report.
Although more research and deliberation is needed, this new study does add one novel endpoint to the literature: “The outcome of neonatal death has not been reported previously, to our knowledge.”
Their study was supported by the Thrasher Research Fund, the Magnus Bergvall Foundation, and the Karolinska Institutet Research Foundation. Dr. Pasternak and co-authors reported no conflicts of interest.
dermnews@mdedge.com
SOURCE: Pasternak B, et al. JAMA. 2018 Jun 12;319:22.
Use of oral fluconazole during pregnancy is not associated with an increase in risk of stillbirth or neonatal death, results of a large European cohort study suggest.
The rate of stillbirths was 2.7 per 1,000 fluconazole-exposed pregnancies, versus 3.6 per 1,000 unexposed pregnancies (hazard ratio, 0.76, 95% confidence interval, 0.52-1.10), investigators reported based on an analysis of national registry data including nearly 1.5 million recent pregnancies in Sweden and Norway.
Neonatal deaths occurred in 1.2 per 1,000 exposed pregnancies and 1.7 per 1,000 unexposed pregnancies, investigators added in the report, which appeared in JAMA.
Results were not different for doses of 300 mg or less versus more than 300 mg, said senior researcher Björn Pasternak, MD, PhD, of Karolinska Institutet, Stockholm, and his co-authors.
“Although the data on fluconazole use in pregnancy suggest no increased risk of stillbirth, additional studies should be conducted and the collective body of data scrutinized by drug authorities before recommendations to guide clinical decision making are made, and weighed against the benefits of therapy,” the investigators wrote.
About 4% of pregnant women in the United States take oral fluconazole, even though it is generally discouraged during pregnancy due to concerns that its use may be associated with stillbirth in a previous Danish nationwide register-based study, published in JAMA.
In 2016, investigators similarly found no increased risk of stillbirth in 2,215 fluconazole-exposed women, though they noted the outcome was “relatively rare and the results therefore imprecise.” In a sensitivity analysis, they did find an association between higher doses of fluconazole (i.e., above 300 mg) and stillbirth, with a hazard ratio of 4.10 (95% CI, 1.89-8.90).
The stillbirth analysis in the present study included 10,669 fluconazole-exposed pregnancies from Sweden and Norway, though the number exposed to higher doses was small, Dr. Pasterak and co-authors said in their report.
Although more research and deliberation is needed, this new study does add one novel endpoint to the literature: “The outcome of neonatal death has not been reported previously, to our knowledge.”
Their study was supported by the Thrasher Research Fund, the Magnus Bergvall Foundation, and the Karolinska Institutet Research Foundation. Dr. Pasternak and co-authors reported no conflicts of interest.
dermnews@mdedge.com
SOURCE: Pasternak B, et al. JAMA. 2018 Jun 12;319:22.
Use of oral fluconazole during pregnancy is not associated with an increase in risk of stillbirth or neonatal death, results of a large European cohort study suggest.
The rate of stillbirths was 2.7 per 1,000 fluconazole-exposed pregnancies, versus 3.6 per 1,000 unexposed pregnancies (hazard ratio, 0.76, 95% confidence interval, 0.52-1.10), investigators reported based on an analysis of national registry data including nearly 1.5 million recent pregnancies in Sweden and Norway.
Neonatal deaths occurred in 1.2 per 1,000 exposed pregnancies and 1.7 per 1,000 unexposed pregnancies, investigators added in the report, which appeared in JAMA.
Results were not different for doses of 300 mg or less versus more than 300 mg, said senior researcher Björn Pasternak, MD, PhD, of Karolinska Institutet, Stockholm, and his co-authors.
“Although the data on fluconazole use in pregnancy suggest no increased risk of stillbirth, additional studies should be conducted and the collective body of data scrutinized by drug authorities before recommendations to guide clinical decision making are made, and weighed against the benefits of therapy,” the investigators wrote.
About 4% of pregnant women in the United States take oral fluconazole, even though it is generally discouraged during pregnancy due to concerns that its use may be associated with stillbirth in a previous Danish nationwide register-based study, published in JAMA.
In 2016, investigators similarly found no increased risk of stillbirth in 2,215 fluconazole-exposed women, though they noted the outcome was “relatively rare and the results therefore imprecise.” In a sensitivity analysis, they did find an association between higher doses of fluconazole (i.e., above 300 mg) and stillbirth, with a hazard ratio of 4.10 (95% CI, 1.89-8.90).
The stillbirth analysis in the present study included 10,669 fluconazole-exposed pregnancies from Sweden and Norway, though the number exposed to higher doses was small, Dr. Pasterak and co-authors said in their report.
Although more research and deliberation is needed, this new study does add one novel endpoint to the literature: “The outcome of neonatal death has not been reported previously, to our knowledge.”
Their study was supported by the Thrasher Research Fund, the Magnus Bergvall Foundation, and the Karolinska Institutet Research Foundation. Dr. Pasternak and co-authors reported no conflicts of interest.
dermnews@mdedge.com
SOURCE: Pasternak B, et al. JAMA. 2018 Jun 12;319:22.
Insurer denials of DAA therapy for HCV on the rise
About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.
“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.
The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.
Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).
Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.
While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.
“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.
The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.
SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.
About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.
“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.
The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.
Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).
Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.
While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.
“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.
The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.
SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.
About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.
“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.
The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.
Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).
Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.
While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.
“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.
The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.
SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.
FROM OPEN FORUM INFECTIOUS DISEASES
Key clinical point: Insurance denials of direct-acting antiviral (DAA) prescriptions have increased over time, contrary to expectations.
Major finding: A total of 35.5% of patients had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Study details: A cohort study including 9,025 patients who had a DAA prescription submitted to a national specialty pharmacy between January 2016 and April 2017.
Disclosures: The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Two coauthors reported grant support and/or advisory board fees from Gilead.
Source: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7.
bb2121 demonstrates durable responses, manageable toxicity in MM
CHICAGO—bb2121, the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, induced deep and durable ongoing responses in heavily pretreated multiple myeloma (MM) patients, updated results of a phase 1 study show.
At active doses (≥150 x 108 CAR+ T cells), the B-cell maturation antigen (BCMA)-targeted therapy produced an overall response rate of 95.5%, including a 50% rate of complete response (CR) or stringent CR, with a median duration of response of 10.8 months.
Median progression-free survival (PFS) was 11.8 months in the dose-escalation cohort.
Noopur S. Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston, reported these results at the 2018 ASCO Annual Meeting (abstract 8007*). The study is sponsored by Celgene Corporation and bluebird bio.
To date, bb2121 has been manageable for patients at doses as high as 800 x 108 CAR T cells, Dr Raje noted.
She updated the findings of CRB-401 (NCT02658929), which included 43 patients with relapsed/refractory MM, including 21 in a dose-escalation (DE) cohort and 22 in a dose-expansion (Exp) cohort.
Patients received one infusion of bb2121 anti-BCMA CAR T cells after a lymphodepleting conditioning regimen including fludarabine and cyclophosphamide.
Patients were a median age of 58 (range, 37 – 74) and 65 (range, 44 – 75) in the DE and Exp cohorts, respectively.
Eight patients (38%) in the DE cohort and 9 (41%) in the Exp cohort had high-risk cytogenetics and had received a median of 7 (range, 3 – 14) and 8 (range, 3 – 23) prior regimens, respectively.
All patients in the DE cohort and 86% in the Exp cohort had a prior autologous stem cell transplant (ASCT), and 29% and 23% in each cohort, respectively, had more than one ASCT.
Results
Patients in the DE cohort had a median PFS of 11.8 months at active doses.
All 16 responding patients who were evaluable for minimal residual disease (MRD) achieved MRD negativity and had a median PFS of 17.7 months.
The investigators observed a dose-response relationship across the active dose ranges and higher peak CAR T expansion in responding patients compared with those who did not respond.
The investigators also noted that the tumor response was independent of tumor BCMA expression.
bb2121 persisted for 6 months or longer in 44% of responding patients.
“This should be tested a little bit earlier now, because what we’ve done here is show the proof of concept, and really treated these very end-stage myeloma patients,” Dr Raje observed.
Adverse events of interest
“We found that this product is extremely well tolerated,” Dr Raje said. “We saw, certainly, cytokine release syndrome (CRS) in over 60% of patients, but most of the CRS was managed, and it was grade 1 and 2 with very little grade 3 CRS. [W]e just had 1 patient with grade 4 neurotoxicity who is now completely recovered.”
The 2 grade 3 CRS events observed in this study resolved in 24 hours, Dr Raje noted.
Infused patients (n=43) also experienced neutropenia (81%), thrombocytopenia (61%), and anemia (56%).
Thirty-one of 40 patients (78%) recovered their absolute neutrophil count to 1000/μL or greater by day 32, and 22 of 40 (55%) patients recovered their platelet counts to 50,000/μL or greater by day 32.
Commentary
BCMA is the “latest promising target” in MM, said Parameswaran Hari, MD, of the Medical College of Wisconsin in Milwaukee, and this bb2121 data represents the largest and most mature experience with the CAR T approach in the disease.
However, patients are still relapsing, and the meaning of MRD negativity is unclear in this setting, Dr Parameswaran said in a presentation referencing the results of the study.
“Unfortunately, this is not yet a cure, so I’m going advise my patients who are in stringent CR and on maintenance not to go for CAR T cells unless they relapse,” he said.
An ongoing global trial of bb2121, known as KarMMa, is open for enrollment in North America and Europe, and additional studies are planned in earlier lines of myeloma.
*Data presented at the meeting differ from the abstract.
CHICAGO—bb2121, the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, induced deep and durable ongoing responses in heavily pretreated multiple myeloma (MM) patients, updated results of a phase 1 study show.
At active doses (≥150 x 108 CAR+ T cells), the B-cell maturation antigen (BCMA)-targeted therapy produced an overall response rate of 95.5%, including a 50% rate of complete response (CR) or stringent CR, with a median duration of response of 10.8 months.
Median progression-free survival (PFS) was 11.8 months in the dose-escalation cohort.
Noopur S. Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston, reported these results at the 2018 ASCO Annual Meeting (abstract 8007*). The study is sponsored by Celgene Corporation and bluebird bio.
To date, bb2121 has been manageable for patients at doses as high as 800 x 108 CAR T cells, Dr Raje noted.
She updated the findings of CRB-401 (NCT02658929), which included 43 patients with relapsed/refractory MM, including 21 in a dose-escalation (DE) cohort and 22 in a dose-expansion (Exp) cohort.
Patients received one infusion of bb2121 anti-BCMA CAR T cells after a lymphodepleting conditioning regimen including fludarabine and cyclophosphamide.
Patients were a median age of 58 (range, 37 – 74) and 65 (range, 44 – 75) in the DE and Exp cohorts, respectively.
Eight patients (38%) in the DE cohort and 9 (41%) in the Exp cohort had high-risk cytogenetics and had received a median of 7 (range, 3 – 14) and 8 (range, 3 – 23) prior regimens, respectively.
All patients in the DE cohort and 86% in the Exp cohort had a prior autologous stem cell transplant (ASCT), and 29% and 23% in each cohort, respectively, had more than one ASCT.
Results
Patients in the DE cohort had a median PFS of 11.8 months at active doses.
All 16 responding patients who were evaluable for minimal residual disease (MRD) achieved MRD negativity and had a median PFS of 17.7 months.
The investigators observed a dose-response relationship across the active dose ranges and higher peak CAR T expansion in responding patients compared with those who did not respond.
The investigators also noted that the tumor response was independent of tumor BCMA expression.
bb2121 persisted for 6 months or longer in 44% of responding patients.
“This should be tested a little bit earlier now, because what we’ve done here is show the proof of concept, and really treated these very end-stage myeloma patients,” Dr Raje observed.
Adverse events of interest
“We found that this product is extremely well tolerated,” Dr Raje said. “We saw, certainly, cytokine release syndrome (CRS) in over 60% of patients, but most of the CRS was managed, and it was grade 1 and 2 with very little grade 3 CRS. [W]e just had 1 patient with grade 4 neurotoxicity who is now completely recovered.”
The 2 grade 3 CRS events observed in this study resolved in 24 hours, Dr Raje noted.
Infused patients (n=43) also experienced neutropenia (81%), thrombocytopenia (61%), and anemia (56%).
Thirty-one of 40 patients (78%) recovered their absolute neutrophil count to 1000/μL or greater by day 32, and 22 of 40 (55%) patients recovered their platelet counts to 50,000/μL or greater by day 32.
Commentary
BCMA is the “latest promising target” in MM, said Parameswaran Hari, MD, of the Medical College of Wisconsin in Milwaukee, and this bb2121 data represents the largest and most mature experience with the CAR T approach in the disease.
However, patients are still relapsing, and the meaning of MRD negativity is unclear in this setting, Dr Parameswaran said in a presentation referencing the results of the study.
“Unfortunately, this is not yet a cure, so I’m going advise my patients who are in stringent CR and on maintenance not to go for CAR T cells unless they relapse,” he said.
An ongoing global trial of bb2121, known as KarMMa, is open for enrollment in North America and Europe, and additional studies are planned in earlier lines of myeloma.
*Data presented at the meeting differ from the abstract.
CHICAGO—bb2121, the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, induced deep and durable ongoing responses in heavily pretreated multiple myeloma (MM) patients, updated results of a phase 1 study show.
At active doses (≥150 x 108 CAR+ T cells), the B-cell maturation antigen (BCMA)-targeted therapy produced an overall response rate of 95.5%, including a 50% rate of complete response (CR) or stringent CR, with a median duration of response of 10.8 months.
Median progression-free survival (PFS) was 11.8 months in the dose-escalation cohort.
Noopur S. Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston, reported these results at the 2018 ASCO Annual Meeting (abstract 8007*). The study is sponsored by Celgene Corporation and bluebird bio.
To date, bb2121 has been manageable for patients at doses as high as 800 x 108 CAR T cells, Dr Raje noted.
She updated the findings of CRB-401 (NCT02658929), which included 43 patients with relapsed/refractory MM, including 21 in a dose-escalation (DE) cohort and 22 in a dose-expansion (Exp) cohort.
Patients received one infusion of bb2121 anti-BCMA CAR T cells after a lymphodepleting conditioning regimen including fludarabine and cyclophosphamide.
Patients were a median age of 58 (range, 37 – 74) and 65 (range, 44 – 75) in the DE and Exp cohorts, respectively.
Eight patients (38%) in the DE cohort and 9 (41%) in the Exp cohort had high-risk cytogenetics and had received a median of 7 (range, 3 – 14) and 8 (range, 3 – 23) prior regimens, respectively.
All patients in the DE cohort and 86% in the Exp cohort had a prior autologous stem cell transplant (ASCT), and 29% and 23% in each cohort, respectively, had more than one ASCT.
Results
Patients in the DE cohort had a median PFS of 11.8 months at active doses.
All 16 responding patients who were evaluable for minimal residual disease (MRD) achieved MRD negativity and had a median PFS of 17.7 months.
The investigators observed a dose-response relationship across the active dose ranges and higher peak CAR T expansion in responding patients compared with those who did not respond.
The investigators also noted that the tumor response was independent of tumor BCMA expression.
bb2121 persisted for 6 months or longer in 44% of responding patients.
“This should be tested a little bit earlier now, because what we’ve done here is show the proof of concept, and really treated these very end-stage myeloma patients,” Dr Raje observed.
Adverse events of interest
“We found that this product is extremely well tolerated,” Dr Raje said. “We saw, certainly, cytokine release syndrome (CRS) in over 60% of patients, but most of the CRS was managed, and it was grade 1 and 2 with very little grade 3 CRS. [W]e just had 1 patient with grade 4 neurotoxicity who is now completely recovered.”
The 2 grade 3 CRS events observed in this study resolved in 24 hours, Dr Raje noted.
Infused patients (n=43) also experienced neutropenia (81%), thrombocytopenia (61%), and anemia (56%).
Thirty-one of 40 patients (78%) recovered their absolute neutrophil count to 1000/μL or greater by day 32, and 22 of 40 (55%) patients recovered their platelet counts to 50,000/μL or greater by day 32.
Commentary
BCMA is the “latest promising target” in MM, said Parameswaran Hari, MD, of the Medical College of Wisconsin in Milwaukee, and this bb2121 data represents the largest and most mature experience with the CAR T approach in the disease.
However, patients are still relapsing, and the meaning of MRD negativity is unclear in this setting, Dr Parameswaran said in a presentation referencing the results of the study.
“Unfortunately, this is not yet a cure, so I’m going advise my patients who are in stringent CR and on maintenance not to go for CAR T cells unless they relapse,” he said.
An ongoing global trial of bb2121, known as KarMMa, is open for enrollment in North America and Europe, and additional studies are planned in earlier lines of myeloma.
*Data presented at the meeting differ from the abstract.
Education sessions upped COPD patients’ knowledge of their disease
A brief patient-directed education program delivered at the time of hospitalization for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) improved disease-specific knowledge, according to results of a pilot randomized trial.
Patients who participated in education sessions had a significant improvement in their scores on the Bristol COPD Knowledge Questionnaire (BCKQ), compared with control patients who received no education, study investigators reported in the journal Chest.
“Early education may be a bridge to more active approaches and could provide an important contribution to self-management interventions post-AECOPD,” wrote first author Tania Janaudis-Ferreira, PhD, of the School of Physical and Occupational Therapy, McGill University, Montreal, and her co-authors.
In the study, patients admitted to a community hospital with an AECOPD were randomized to standard care plus brief education or standard care alone. The education consisted of two 30-minute sessions delivered by a physiotherapist, either in the hospital or at home up to 2 weeks after the admission.
Before and after the intervention period, participant knowledge was measured using both the BCKQ and the Lung Information Needs Questionnaire (LINQ).
A total of 31 patients participated, including 15 in the intervention group and 16 in the control group, although 3 patients in the control group did not complete the follow-up testing, investigators said in their report.
The mean change in BCKQ was 8 points for the educational intervention group, and 3.4 for the control group (P = 0.02). That result was in keeping with findings of a previous randomized study noting an 8.3-point change in BCKQ scores for COPD patients who received education in the primary care setting, Dr. Janaudis-Ferreira and co-authors said.
“The change itself is relatively modest, suggesting more frequent sessions might result in greater improvements,” they wrote. For example, they said, an 8-week educational intervention delivered in the context of pulmonary rehabilitation program in one study yielded a mean change of 18.3 points on the BCKQ in the intervention group.
By contrast, the investigators found no significant difference in LINQ score changes between the intervention and control groups (P = .8).
That may indicate that two 30-minute sessions were not sufficient to attend to patients’ learning needs, authors said, though it could also have been an issue with the instrument itself in the setting of this study.
“The majority of the questions in the LINQ ask whether or not a doctor or nurse has explained a specific question to the patient,” authors explained. “Since a physiotherapist delivered the program, had the wording been altered to include physiotherapists or a more general term for healthcare professionals, we may have seen a change in these results.”
Dr. Janaudis-Ferreira and co-authors had no conflicts of interest to disclose. The study was funded by a grant from the Canadian Respiratory Health Professionals, which did not have input in research or manuscript development.
SOURCE: Janaudis-Ferreira T, et al. Chest
A brief patient-directed education program delivered at the time of hospitalization for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) improved disease-specific knowledge, according to results of a pilot randomized trial.
Patients who participated in education sessions had a significant improvement in their scores on the Bristol COPD Knowledge Questionnaire (BCKQ), compared with control patients who received no education, study investigators reported in the journal Chest.
“Early education may be a bridge to more active approaches and could provide an important contribution to self-management interventions post-AECOPD,” wrote first author Tania Janaudis-Ferreira, PhD, of the School of Physical and Occupational Therapy, McGill University, Montreal, and her co-authors.
In the study, patients admitted to a community hospital with an AECOPD were randomized to standard care plus brief education or standard care alone. The education consisted of two 30-minute sessions delivered by a physiotherapist, either in the hospital or at home up to 2 weeks after the admission.
Before and after the intervention period, participant knowledge was measured using both the BCKQ and the Lung Information Needs Questionnaire (LINQ).
A total of 31 patients participated, including 15 in the intervention group and 16 in the control group, although 3 patients in the control group did not complete the follow-up testing, investigators said in their report.
The mean change in BCKQ was 8 points for the educational intervention group, and 3.4 for the control group (P = 0.02). That result was in keeping with findings of a previous randomized study noting an 8.3-point change in BCKQ scores for COPD patients who received education in the primary care setting, Dr. Janaudis-Ferreira and co-authors said.
“The change itself is relatively modest, suggesting more frequent sessions might result in greater improvements,” they wrote. For example, they said, an 8-week educational intervention delivered in the context of pulmonary rehabilitation program in one study yielded a mean change of 18.3 points on the BCKQ in the intervention group.
By contrast, the investigators found no significant difference in LINQ score changes between the intervention and control groups (P = .8).
That may indicate that two 30-minute sessions were not sufficient to attend to patients’ learning needs, authors said, though it could also have been an issue with the instrument itself in the setting of this study.
“The majority of the questions in the LINQ ask whether or not a doctor or nurse has explained a specific question to the patient,” authors explained. “Since a physiotherapist delivered the program, had the wording been altered to include physiotherapists or a more general term for healthcare professionals, we may have seen a change in these results.”
Dr. Janaudis-Ferreira and co-authors had no conflicts of interest to disclose. The study was funded by a grant from the Canadian Respiratory Health Professionals, which did not have input in research or manuscript development.
SOURCE: Janaudis-Ferreira T, et al. Chest
A brief patient-directed education program delivered at the time of hospitalization for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) improved disease-specific knowledge, according to results of a pilot randomized trial.
Patients who participated in education sessions had a significant improvement in their scores on the Bristol COPD Knowledge Questionnaire (BCKQ), compared with control patients who received no education, study investigators reported in the journal Chest.
“Early education may be a bridge to more active approaches and could provide an important contribution to self-management interventions post-AECOPD,” wrote first author Tania Janaudis-Ferreira, PhD, of the School of Physical and Occupational Therapy, McGill University, Montreal, and her co-authors.
In the study, patients admitted to a community hospital with an AECOPD were randomized to standard care plus brief education or standard care alone. The education consisted of two 30-minute sessions delivered by a physiotherapist, either in the hospital or at home up to 2 weeks after the admission.
Before and after the intervention period, participant knowledge was measured using both the BCKQ and the Lung Information Needs Questionnaire (LINQ).
A total of 31 patients participated, including 15 in the intervention group and 16 in the control group, although 3 patients in the control group did not complete the follow-up testing, investigators said in their report.
The mean change in BCKQ was 8 points for the educational intervention group, and 3.4 for the control group (P = 0.02). That result was in keeping with findings of a previous randomized study noting an 8.3-point change in BCKQ scores for COPD patients who received education in the primary care setting, Dr. Janaudis-Ferreira and co-authors said.
“The change itself is relatively modest, suggesting more frequent sessions might result in greater improvements,” they wrote. For example, they said, an 8-week educational intervention delivered in the context of pulmonary rehabilitation program in one study yielded a mean change of 18.3 points on the BCKQ in the intervention group.
By contrast, the investigators found no significant difference in LINQ score changes between the intervention and control groups (P = .8).
That may indicate that two 30-minute sessions were not sufficient to attend to patients’ learning needs, authors said, though it could also have been an issue with the instrument itself in the setting of this study.
“The majority of the questions in the LINQ ask whether or not a doctor or nurse has explained a specific question to the patient,” authors explained. “Since a physiotherapist delivered the program, had the wording been altered to include physiotherapists or a more general term for healthcare professionals, we may have seen a change in these results.”
Dr. Janaudis-Ferreira and co-authors had no conflicts of interest to disclose. The study was funded by a grant from the Canadian Respiratory Health Professionals, which did not have input in research or manuscript development.
SOURCE: Janaudis-Ferreira T, et al. Chest
FROM CHEST
Key clinical point: Two 30-minute education sessions improved patients’ disease-specific knowledge for an acute exacerbation of COPD.
Major finding: Mean change on the Bristol COPD Knowledge Questionnaire (BCKQ) was 8 points for the educational intervention, and 3.4 for controls.
Study details: A pilot randomized controlled trial of 31 patients admitted to a community hospital.
Disclosures: Authors had no conflicts of interest to disclose. The study was funded by a grant from the Canadian Respiratory Health Professionals, which did not have input in research or manuscript development.
Source: Janaudis-Ferreira T, et al. Chest 2018 Jun 4.
Venetoclax plus ibrutinib yields encouraging MRD results in first-line CLL
CHICAGO – The combination of ibrutinib plus venetoclax yielded a high rate of undetectable minimal residual disease (MRD) when used as first-line treatment for chronic lymphocytic leukemia (CLL), according to preliminary results of the CAPTIVATE trial.
Of the first 30 patients in the trial, 23 (77%) had undetectable blood MRD after just six cycles of combined treatment, said investigator William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” Dr. Wierda said in a presentation of the CAPTIVATE results at the annual meeting of the American Society of Clinical Oncology.
Those MRD results are “at least as good as we can achieve with chemoimmunotherapy,” Bruce D. Cheson, MD, head of hematology at Georgetown University, Washington, said during a discussion of the CAPTIVATE study results.
Dr. Cheson referenced MRD results from a 2016 analysis of the CLL8 and CLL10 trials, which included patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) and bendamustine plus rituximab (BR). In that analysis, 33.6% of patients achieved MRD-negative complete response and 29.1% achieved MRD-negative partial response.
In CAPTIVATE, by contrast, all of the complete remissions were MRD negative, as were a majority of the partial responders, Dr. Cheson noted.
Venetoclax and ibrutinib have “clinically complimentary activity” that provided a rationale for combining the two, Dr. Wierda said at ASCO. Ibrutinib is a BTK inhibitor that has a high rate of response and durable disease control, though continuous treatment is indicated, he said, because most patients achieve partial remissions as best response and continue to have residual disease in blood or bone marrow. Venetoclax, he added, is a BCL-2 inhibitor that produces durable partial remissions, though “residual disease is typically present in the form of persistently enlarged lymph nodes,” he said. “Venetoclax is highly effective at clearing disease from blood and bone marrow.”
The phase 2 CAPTIVATE trial includes a total of 164 patients younger than 70 years of age who receive a 3-cycle ibrutinib lead-in, followed by ibrutinib plus venetoclax for 12 cycles. At that point, patients are randomized according to MRD status. Patients with confirmed undetectable MRD are randomized to further treatment with ibrutinib or placebo, and those with undetectable MRD not confirmed are randomized to ibrutinib versus ibrutinib plus venetoclax.
In addition to early efficacy data, Dr. Wierda also reported some safety data. Compared with the single-agent ibrutinib lead-in period, combined ibrutinib plus venetoclax treatment had more gastrointestinal-associated events and neutropenia. Almost half of patients (45%) have had a treatment-related grade 3-4 adverse event, though just 18 (11%) have had treatment-related adverse events classified as serious, and there have been no adverse event-related deaths on study.
The high activity of ibrutinib plus venetoclax in CAPTIVATE supports further study of the combination, Dr. Wierda said. A randomized, open-label phase 3 trial of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab as first-line treatment for CLL is currently recruiting.
The study was sponsored by Pharmacyclics, an AbbVie company. Dr. Wierda reported consulting and research funding from Pharmacyclics, AbbVie, and several other companies.
SOURCE: Wierda WG et al. ASCO 2018, Abstract 7502.
CHICAGO – The combination of ibrutinib plus venetoclax yielded a high rate of undetectable minimal residual disease (MRD) when used as first-line treatment for chronic lymphocytic leukemia (CLL), according to preliminary results of the CAPTIVATE trial.
Of the first 30 patients in the trial, 23 (77%) had undetectable blood MRD after just six cycles of combined treatment, said investigator William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” Dr. Wierda said in a presentation of the CAPTIVATE results at the annual meeting of the American Society of Clinical Oncology.
Those MRD results are “at least as good as we can achieve with chemoimmunotherapy,” Bruce D. Cheson, MD, head of hematology at Georgetown University, Washington, said during a discussion of the CAPTIVATE study results.
Dr. Cheson referenced MRD results from a 2016 analysis of the CLL8 and CLL10 trials, which included patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) and bendamustine plus rituximab (BR). In that analysis, 33.6% of patients achieved MRD-negative complete response and 29.1% achieved MRD-negative partial response.
In CAPTIVATE, by contrast, all of the complete remissions were MRD negative, as were a majority of the partial responders, Dr. Cheson noted.
Venetoclax and ibrutinib have “clinically complimentary activity” that provided a rationale for combining the two, Dr. Wierda said at ASCO. Ibrutinib is a BTK inhibitor that has a high rate of response and durable disease control, though continuous treatment is indicated, he said, because most patients achieve partial remissions as best response and continue to have residual disease in blood or bone marrow. Venetoclax, he added, is a BCL-2 inhibitor that produces durable partial remissions, though “residual disease is typically present in the form of persistently enlarged lymph nodes,” he said. “Venetoclax is highly effective at clearing disease from blood and bone marrow.”
The phase 2 CAPTIVATE trial includes a total of 164 patients younger than 70 years of age who receive a 3-cycle ibrutinib lead-in, followed by ibrutinib plus venetoclax for 12 cycles. At that point, patients are randomized according to MRD status. Patients with confirmed undetectable MRD are randomized to further treatment with ibrutinib or placebo, and those with undetectable MRD not confirmed are randomized to ibrutinib versus ibrutinib plus venetoclax.
In addition to early efficacy data, Dr. Wierda also reported some safety data. Compared with the single-agent ibrutinib lead-in period, combined ibrutinib plus venetoclax treatment had more gastrointestinal-associated events and neutropenia. Almost half of patients (45%) have had a treatment-related grade 3-4 adverse event, though just 18 (11%) have had treatment-related adverse events classified as serious, and there have been no adverse event-related deaths on study.
The high activity of ibrutinib plus venetoclax in CAPTIVATE supports further study of the combination, Dr. Wierda said. A randomized, open-label phase 3 trial of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab as first-line treatment for CLL is currently recruiting.
The study was sponsored by Pharmacyclics, an AbbVie company. Dr. Wierda reported consulting and research funding from Pharmacyclics, AbbVie, and several other companies.
SOURCE: Wierda WG et al. ASCO 2018, Abstract 7502.
CHICAGO – The combination of ibrutinib plus venetoclax yielded a high rate of undetectable minimal residual disease (MRD) when used as first-line treatment for chronic lymphocytic leukemia (CLL), according to preliminary results of the CAPTIVATE trial.
Of the first 30 patients in the trial, 23 (77%) had undetectable blood MRD after just six cycles of combined treatment, said investigator William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” Dr. Wierda said in a presentation of the CAPTIVATE results at the annual meeting of the American Society of Clinical Oncology.
Those MRD results are “at least as good as we can achieve with chemoimmunotherapy,” Bruce D. Cheson, MD, head of hematology at Georgetown University, Washington, said during a discussion of the CAPTIVATE study results.
Dr. Cheson referenced MRD results from a 2016 analysis of the CLL8 and CLL10 trials, which included patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) and bendamustine plus rituximab (BR). In that analysis, 33.6% of patients achieved MRD-negative complete response and 29.1% achieved MRD-negative partial response.
In CAPTIVATE, by contrast, all of the complete remissions were MRD negative, as were a majority of the partial responders, Dr. Cheson noted.
Venetoclax and ibrutinib have “clinically complimentary activity” that provided a rationale for combining the two, Dr. Wierda said at ASCO. Ibrutinib is a BTK inhibitor that has a high rate of response and durable disease control, though continuous treatment is indicated, he said, because most patients achieve partial remissions as best response and continue to have residual disease in blood or bone marrow. Venetoclax, he added, is a BCL-2 inhibitor that produces durable partial remissions, though “residual disease is typically present in the form of persistently enlarged lymph nodes,” he said. “Venetoclax is highly effective at clearing disease from blood and bone marrow.”
The phase 2 CAPTIVATE trial includes a total of 164 patients younger than 70 years of age who receive a 3-cycle ibrutinib lead-in, followed by ibrutinib plus venetoclax for 12 cycles. At that point, patients are randomized according to MRD status. Patients with confirmed undetectable MRD are randomized to further treatment with ibrutinib or placebo, and those with undetectable MRD not confirmed are randomized to ibrutinib versus ibrutinib plus venetoclax.
In addition to early efficacy data, Dr. Wierda also reported some safety data. Compared with the single-agent ibrutinib lead-in period, combined ibrutinib plus venetoclax treatment had more gastrointestinal-associated events and neutropenia. Almost half of patients (45%) have had a treatment-related grade 3-4 adverse event, though just 18 (11%) have had treatment-related adverse events classified as serious, and there have been no adverse event-related deaths on study.
The high activity of ibrutinib plus venetoclax in CAPTIVATE supports further study of the combination, Dr. Wierda said. A randomized, open-label phase 3 trial of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab as first-line treatment for CLL is currently recruiting.
The study was sponsored by Pharmacyclics, an AbbVie company. Dr. Wierda reported consulting and research funding from Pharmacyclics, AbbVie, and several other companies.
SOURCE: Wierda WG et al. ASCO 2018, Abstract 7502.
REPORTING FROM ASCO 2018
Key clinical point:
Major finding: Of 14 patients, 12 (86%) who completed 12 cycles of treatment had undetectable bone marrow MRD.
Study details: Early results of the phase 2 CAPTIVATE trial including 164 patients younger than 70 years of age with previously untreated CLL.
Disclosures: The study was sponsored by Pharmacyclics, an Abbvie company. Dr. Wierda reported consulting and research funding from Pharmacyclics, AbbVie, and several other companies.
Source: Wierda WG et al. ASCO 2018, Abstract 7502.
Polatuzumab plus BR improves efficacy in DLBCL
CHICAGO—Polatuzumab vedotin, when added to bendamustine (B) and rituximab (R), significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 2 study.
By contrast, there were no such improvements in a cohort of follicular lymphoma (FL) patients, at least in short-term follow-up, investigator Laurie Helen Sehn, MD, of the BC Cancer Agency in Vancouver, Canada, said at the 2018 ASCO Annual Meeting.
However, the improvement in overall survival in DLBCL patients is “remarkable,” Dr Sehn affirmed in an oral presentation (abstract 7507).
“Based on these encouraging results, polatuzumab vedotin has received breakthrough therapy designation and priority medicines designation by the FDA and EMA for patients with relapsed or refractory DLBCL,” she said.
Polatuzumab-BR study (NCT02257567)
The study by Dr Sehn and colleagues included a cohort of 80 DLBCL patients randomized to BR or polatuzumab-BR for 6 planned 21-day cycles.
Investigators randomized another cohort of 80 FL patients to BR or polatuzumab-BR for 6 planned 28-day cycles.
The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.
DLBCL patients
A total of 40% of polatuzumab-BR-treated DLBCL patients achieved CR at the end of treatment, versus 15% of BR-treated patients (P=0.012).
That CR improvement translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab-BR vs 2.0 months for BR, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008), according to Dr Sehn.
The FDG-PET CR rates were higher in the polatuzumab-BR arm regardless of the number of prior lines of treatment for DLBCL, and regardless of relapsed versus refractory status, Dr. Sehn added.
FL patients
By contrast, in the FL cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab-BR and 63% for BR.
And there was no significant difference in progression-free survival (P=0.58) with “relatively short-term follow-up,” she said.
Adverse events
The most common grades 3 – 5 adverse events for both DLBCL and FL patients were higher in the polatuzumab-BR arm than the BR arm and included cytopenias, febrile neutropenia, and infections.
Serious AEs were also higher in the polatuzumab-BR arm and included febrile neutropenia for both FL and DLBCL patients and infection for FL patients.
Five percent of FL patients and 18% of DLBCL had a grade 5 event.
Commentary
Whether polatuzumab vedotin will change treatment paradigms for DLBCL patients may be answered by the ongoing POLARIX study, according to Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.
The randomized phase 3 POLARIX study (abstract TPS7589) is comparing polatuzumab plus R-CHP to R-CHOP in patients with previously untreated DLBCL.
“Certainly, there are patients who do very well with R-CHOP chemotherapy alone, and so we need to learn whether this is necessary for all patients, or only the high-risk patients,” Dr Moskowitz said in a talk at ASCO commenting on the results of the polatuzumab-BR study.
Hoffman-LaRoche is the sponsor of the study.
CHICAGO—Polatuzumab vedotin, when added to bendamustine (B) and rituximab (R), significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 2 study.
By contrast, there were no such improvements in a cohort of follicular lymphoma (FL) patients, at least in short-term follow-up, investigator Laurie Helen Sehn, MD, of the BC Cancer Agency in Vancouver, Canada, said at the 2018 ASCO Annual Meeting.
However, the improvement in overall survival in DLBCL patients is “remarkable,” Dr Sehn affirmed in an oral presentation (abstract 7507).
“Based on these encouraging results, polatuzumab vedotin has received breakthrough therapy designation and priority medicines designation by the FDA and EMA for patients with relapsed or refractory DLBCL,” she said.
Polatuzumab-BR study (NCT02257567)
The study by Dr Sehn and colleagues included a cohort of 80 DLBCL patients randomized to BR or polatuzumab-BR for 6 planned 21-day cycles.
Investigators randomized another cohort of 80 FL patients to BR or polatuzumab-BR for 6 planned 28-day cycles.
The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.
DLBCL patients
A total of 40% of polatuzumab-BR-treated DLBCL patients achieved CR at the end of treatment, versus 15% of BR-treated patients (P=0.012).
That CR improvement translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab-BR vs 2.0 months for BR, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008), according to Dr Sehn.
The FDG-PET CR rates were higher in the polatuzumab-BR arm regardless of the number of prior lines of treatment for DLBCL, and regardless of relapsed versus refractory status, Dr. Sehn added.
FL patients
By contrast, in the FL cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab-BR and 63% for BR.
And there was no significant difference in progression-free survival (P=0.58) with “relatively short-term follow-up,” she said.
Adverse events
The most common grades 3 – 5 adverse events for both DLBCL and FL patients were higher in the polatuzumab-BR arm than the BR arm and included cytopenias, febrile neutropenia, and infections.
Serious AEs were also higher in the polatuzumab-BR arm and included febrile neutropenia for both FL and DLBCL patients and infection for FL patients.
Five percent of FL patients and 18% of DLBCL had a grade 5 event.
Commentary
Whether polatuzumab vedotin will change treatment paradigms for DLBCL patients may be answered by the ongoing POLARIX study, according to Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.
The randomized phase 3 POLARIX study (abstract TPS7589) is comparing polatuzumab plus R-CHP to R-CHOP in patients with previously untreated DLBCL.
“Certainly, there are patients who do very well with R-CHOP chemotherapy alone, and so we need to learn whether this is necessary for all patients, or only the high-risk patients,” Dr Moskowitz said in a talk at ASCO commenting on the results of the polatuzumab-BR study.
Hoffman-LaRoche is the sponsor of the study.
CHICAGO—Polatuzumab vedotin, when added to bendamustine (B) and rituximab (R), significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 2 study.
By contrast, there were no such improvements in a cohort of follicular lymphoma (FL) patients, at least in short-term follow-up, investigator Laurie Helen Sehn, MD, of the BC Cancer Agency in Vancouver, Canada, said at the 2018 ASCO Annual Meeting.
However, the improvement in overall survival in DLBCL patients is “remarkable,” Dr Sehn affirmed in an oral presentation (abstract 7507).
“Based on these encouraging results, polatuzumab vedotin has received breakthrough therapy designation and priority medicines designation by the FDA and EMA for patients with relapsed or refractory DLBCL,” she said.
Polatuzumab-BR study (NCT02257567)
The study by Dr Sehn and colleagues included a cohort of 80 DLBCL patients randomized to BR or polatuzumab-BR for 6 planned 21-day cycles.
Investigators randomized another cohort of 80 FL patients to BR or polatuzumab-BR for 6 planned 28-day cycles.
The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.
DLBCL patients
A total of 40% of polatuzumab-BR-treated DLBCL patients achieved CR at the end of treatment, versus 15% of BR-treated patients (P=0.012).
That CR improvement translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab-BR vs 2.0 months for BR, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008), according to Dr Sehn.
The FDG-PET CR rates were higher in the polatuzumab-BR arm regardless of the number of prior lines of treatment for DLBCL, and regardless of relapsed versus refractory status, Dr. Sehn added.
FL patients
By contrast, in the FL cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab-BR and 63% for BR.
And there was no significant difference in progression-free survival (P=0.58) with “relatively short-term follow-up,” she said.
Adverse events
The most common grades 3 – 5 adverse events for both DLBCL and FL patients were higher in the polatuzumab-BR arm than the BR arm and included cytopenias, febrile neutropenia, and infections.
Serious AEs were also higher in the polatuzumab-BR arm and included febrile neutropenia for both FL and DLBCL patients and infection for FL patients.
Five percent of FL patients and 18% of DLBCL had a grade 5 event.
Commentary
Whether polatuzumab vedotin will change treatment paradigms for DLBCL patients may be answered by the ongoing POLARIX study, according to Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.
The randomized phase 3 POLARIX study (abstract TPS7589) is comparing polatuzumab plus R-CHP to R-CHOP in patients with previously untreated DLBCL.
“Certainly, there are patients who do very well with R-CHOP chemotherapy alone, and so we need to learn whether this is necessary for all patients, or only the high-risk patients,” Dr Moskowitz said in a talk at ASCO commenting on the results of the polatuzumab-BR study.
Hoffman-LaRoche is the sponsor of the study.