User login
VIDEO: Gluten-free diet tied to heavy metal bioaccumulation
A gluten-free diet was associated with significantly increased blood levels of mercury, lead, and cadmium and with significantly increased urinary levels of arsenic in a large cross-sectional population-based survey study.
Source: American Gastroenterological Association
After researchers controlled for demographic characteristics, “levels of all heavy metals remained significantly higher in persons following a gluten-free diet, compared with those not following a gluten-free diet,” Stephanie L. Raehsler, MPH, of Mayo Clinic in Rochester, Minn., wrote with her associates in an article published in the February issue of Clinical Gastroenterology and Hepatology.
The purported (unproven) benefits of a gluten-free diet (GFD) have propelled them into the mainstream outside the settings of celiac disease, dermatitis herpetiformis, and wheat allergy. However, GFDs have been linked to nutritional deficits of iron, ferritin, zinc, and fiber, to increased consumption of sugar, fats, and salt, and to excessive bioaccumulation of mercury, the investigators noted.
High intake of rice, a staple of many GFDs, also has been associated with elevated urinary excretion of arsenic (PLoS One. 2014 Sep 8;9[9]:e104768. doi: 10.1371/journal.pone.0104768). To further characterize these relationships, the researchers analyzed data for 2009 through 2012 from 11,354 participants in the National Health and Nutrition Examination Survey (NHANES). Blood levels of lead, mercury, and cadmium were available from 115 participants who reported following a GFD, and data on urinary arsenic levels were available from 32 such individuals.
In the overall study group, blood mercury levels averaged 1.37 mcg/L (95% confidence interval, 1.02-1.85 mcg/L) among persons on a GFD and 0.93 mcg/L (95% CI, 0.86-1.0 mcg/L) in persons not on a GFD (P = .008). Individuals on a GFD also had significantly higher total blood levels of lead (1.42 vs. 1.13 mcg/L; P = .007 ) and cadmium (0.42 vs. 0.34; P = .03), and they had significantly higher urinary levels of total arsenic (15.2 vs. 8.4 mcg/L; P = .003). These significant differences persisted after researchers controlled for age, sex, race, and smoking status.
Additionally, among 101 individuals on GFDs who had no laboratory or clinical indication of celiac disease, blood levels of total mercury were significantly elevated, compared with individuals not on a GFD (1.40 vs. 0.93 mcg/L; P = .02), as were blood lead concentrations (1.44 vs. 1.13 mcg/L; P = .01) and urinary arsenic levels (14.7 vs. 8.3 mcg/L; P = .01). Blood cadmium levels also were increased (0.42 vs. 0.34 mcg/L), but this difference did not reach statistical significance (P = .06).
Individuals who reported eating fish or shellfish in the past month had higher blood mercury levels than those who did not, regardless of whether they were on a GFD. However, only two individuals in the study exceeded the toxicity threshold for mercury and neither was on a GFD, the researchers said. For most individuals on a GFD, levels of all heavy metals except urinary arsenic stayed under the recognized limits for toxicity, they noted.
The number of respondents following a GFD was small, but the investigators followed NHANES recommendations on sampling weights and sample design variables. Also, although the NHANES included only one question on GFDs, trained interviewers were used to help minimize bias. “Studies are needed to determine the long-term effects of accumulation of these elements in persons on a GFD,” the researchers concluded.
The Centers for Disease Control and Prevention provided partial funding. The researchers reported having no conflicts of interest.
SOURCE: Raehsler S et al. Clin Gastro Hepatol. 2018;(in press).
A gluten-free diet was associated with significantly increased blood levels of mercury, lead, and cadmium and with significantly increased urinary levels of arsenic in a large cross-sectional population-based survey study.
Source: American Gastroenterological Association
After researchers controlled for demographic characteristics, “levels of all heavy metals remained significantly higher in persons following a gluten-free diet, compared with those not following a gluten-free diet,” Stephanie L. Raehsler, MPH, of Mayo Clinic in Rochester, Minn., wrote with her associates in an article published in the February issue of Clinical Gastroenterology and Hepatology.
The purported (unproven) benefits of a gluten-free diet (GFD) have propelled them into the mainstream outside the settings of celiac disease, dermatitis herpetiformis, and wheat allergy. However, GFDs have been linked to nutritional deficits of iron, ferritin, zinc, and fiber, to increased consumption of sugar, fats, and salt, and to excessive bioaccumulation of mercury, the investigators noted.
High intake of rice, a staple of many GFDs, also has been associated with elevated urinary excretion of arsenic (PLoS One. 2014 Sep 8;9[9]:e104768. doi: 10.1371/journal.pone.0104768). To further characterize these relationships, the researchers analyzed data for 2009 through 2012 from 11,354 participants in the National Health and Nutrition Examination Survey (NHANES). Blood levels of lead, mercury, and cadmium were available from 115 participants who reported following a GFD, and data on urinary arsenic levels were available from 32 such individuals.
In the overall study group, blood mercury levels averaged 1.37 mcg/L (95% confidence interval, 1.02-1.85 mcg/L) among persons on a GFD and 0.93 mcg/L (95% CI, 0.86-1.0 mcg/L) in persons not on a GFD (P = .008). Individuals on a GFD also had significantly higher total blood levels of lead (1.42 vs. 1.13 mcg/L; P = .007 ) and cadmium (0.42 vs. 0.34; P = .03), and they had significantly higher urinary levels of total arsenic (15.2 vs. 8.4 mcg/L; P = .003). These significant differences persisted after researchers controlled for age, sex, race, and smoking status.
Additionally, among 101 individuals on GFDs who had no laboratory or clinical indication of celiac disease, blood levels of total mercury were significantly elevated, compared with individuals not on a GFD (1.40 vs. 0.93 mcg/L; P = .02), as were blood lead concentrations (1.44 vs. 1.13 mcg/L; P = .01) and urinary arsenic levels (14.7 vs. 8.3 mcg/L; P = .01). Blood cadmium levels also were increased (0.42 vs. 0.34 mcg/L), but this difference did not reach statistical significance (P = .06).
Individuals who reported eating fish or shellfish in the past month had higher blood mercury levels than those who did not, regardless of whether they were on a GFD. However, only two individuals in the study exceeded the toxicity threshold for mercury and neither was on a GFD, the researchers said. For most individuals on a GFD, levels of all heavy metals except urinary arsenic stayed under the recognized limits for toxicity, they noted.
The number of respondents following a GFD was small, but the investigators followed NHANES recommendations on sampling weights and sample design variables. Also, although the NHANES included only one question on GFDs, trained interviewers were used to help minimize bias. “Studies are needed to determine the long-term effects of accumulation of these elements in persons on a GFD,” the researchers concluded.
The Centers for Disease Control and Prevention provided partial funding. The researchers reported having no conflicts of interest.
SOURCE: Raehsler S et al. Clin Gastro Hepatol. 2018;(in press).
A gluten-free diet was associated with significantly increased blood levels of mercury, lead, and cadmium and with significantly increased urinary levels of arsenic in a large cross-sectional population-based survey study.
Source: American Gastroenterological Association
After researchers controlled for demographic characteristics, “levels of all heavy metals remained significantly higher in persons following a gluten-free diet, compared with those not following a gluten-free diet,” Stephanie L. Raehsler, MPH, of Mayo Clinic in Rochester, Minn., wrote with her associates in an article published in the February issue of Clinical Gastroenterology and Hepatology.
The purported (unproven) benefits of a gluten-free diet (GFD) have propelled them into the mainstream outside the settings of celiac disease, dermatitis herpetiformis, and wheat allergy. However, GFDs have been linked to nutritional deficits of iron, ferritin, zinc, and fiber, to increased consumption of sugar, fats, and salt, and to excessive bioaccumulation of mercury, the investigators noted.
High intake of rice, a staple of many GFDs, also has been associated with elevated urinary excretion of arsenic (PLoS One. 2014 Sep 8;9[9]:e104768. doi: 10.1371/journal.pone.0104768). To further characterize these relationships, the researchers analyzed data for 2009 through 2012 from 11,354 participants in the National Health and Nutrition Examination Survey (NHANES). Blood levels of lead, mercury, and cadmium were available from 115 participants who reported following a GFD, and data on urinary arsenic levels were available from 32 such individuals.
In the overall study group, blood mercury levels averaged 1.37 mcg/L (95% confidence interval, 1.02-1.85 mcg/L) among persons on a GFD and 0.93 mcg/L (95% CI, 0.86-1.0 mcg/L) in persons not on a GFD (P = .008). Individuals on a GFD also had significantly higher total blood levels of lead (1.42 vs. 1.13 mcg/L; P = .007 ) and cadmium (0.42 vs. 0.34; P = .03), and they had significantly higher urinary levels of total arsenic (15.2 vs. 8.4 mcg/L; P = .003). These significant differences persisted after researchers controlled for age, sex, race, and smoking status.
Additionally, among 101 individuals on GFDs who had no laboratory or clinical indication of celiac disease, blood levels of total mercury were significantly elevated, compared with individuals not on a GFD (1.40 vs. 0.93 mcg/L; P = .02), as were blood lead concentrations (1.44 vs. 1.13 mcg/L; P = .01) and urinary arsenic levels (14.7 vs. 8.3 mcg/L; P = .01). Blood cadmium levels also were increased (0.42 vs. 0.34 mcg/L), but this difference did not reach statistical significance (P = .06).
Individuals who reported eating fish or shellfish in the past month had higher blood mercury levels than those who did not, regardless of whether they were on a GFD. However, only two individuals in the study exceeded the toxicity threshold for mercury and neither was on a GFD, the researchers said. For most individuals on a GFD, levels of all heavy metals except urinary arsenic stayed under the recognized limits for toxicity, they noted.
The number of respondents following a GFD was small, but the investigators followed NHANES recommendations on sampling weights and sample design variables. Also, although the NHANES included only one question on GFDs, trained interviewers were used to help minimize bias. “Studies are needed to determine the long-term effects of accumulation of these elements in persons on a GFD,” the researchers concluded.
The Centers for Disease Control and Prevention provided partial funding. The researchers reported having no conflicts of interest.
SOURCE: Raehsler S et al. Clin Gastro Hepatol. 2018;(in press).
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: A gluten-free diet was associated with significantly increased bioaccumulation of several heavy metals.
Major finding: After accounting for demographic factors, blood or urinary levels of lead, cadmium, arsenic, and mercury were significantly higher in persons following a gluten-free diet, compared with those who did not follow a gluten-free diet.
Data source: A population-based, cross-sectional study of 11,354 respondents to NHANES 2009-2012, including 115 persons on a gluten-free diet.
Disclosures: The Centers for Disease Control and Prevention provided partial funding. The researchers reported having no conflicts of interest.
Source: Raehsler S et al. Clin Gastro Hepatol. 2018 (in press).
Study eyed natural history of branch-duct intraductal papillary mucinous neoplasms
Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) grew at a median annual rate of 0.8 mm in a retrospective study of 1,369 patients.
While most of these cysts were “indolent and dormant,” some grew rapidly and developed “other worrisome features,” Youngmin Han, MS, of Seoul (South Korea) National University reported with his associates in the February issue of Gastroenterology. Therefore, clinicians should plan follow-up surveillance based on initial cyst size and growth rate, they concluded.
Based on their findings, the researchers recommended surgery for young, fit, asymptomatic patients who have BD-IPMNs with a diameter of least 30 mm or with thickened cyst walls or those who have a main pancreatic duct measuring 5-9 mm. Surgery also should be considered when patients have lymphadenopathy, high tumor marker levels, or an abrupt change in pancreatic duct caliber with distal pancreatic atrophy or a rapidly growing cyst, they said.
For asymptomatic patients whose cysts are under 10 mm and who do not have worrisome features, they recommended follow-up with CT or MRI at 6 months and then every 2 years after that. Cysts of 10-20 mm should be imaged at 6 months, at 12 months, and then every 1.5-2 years after that, they said. Patients with cyst diameters greater than 20 mm “should undergo MRI or CT or EUS [endoscopic ultrasound] every 6 months for 1 year and then annually thereafter, until the cyst size and features become stable,” they added. Patients whose cysts have a diameter of 30 mm or greater “should be closely monitored with MRI or CT or EUS every 6 months. Surgical resection can be considered in younger patients or those with other combined worrisome features.”
To characterize the natural history of BD-IPMN, the investigators evaluated clinical and imaging data collected between 2001 and 2016 from patients with classical features of BD-IPMN. Each patient included in the study provided 3 or more years of CT, MRI, EUS, and endoscopic retrograde cholangiopancreatography data. The researchers used regression models to estimate changes in sizes of cysts and main pancreatic ducts.
Median follow-up time was 61 months (range, 36-189 months). Cyst diameter averaged 12.8 mm (standard deviation, 6.5 mm) at baseline and 17 mm (SD, 9.2 mm) at final measurement. Larger baseline diameter was associated with faster growth (P = .046): Cysts measuring less than 10 mm at baseline grew at a median annual rate of 0.8 mm (SD, 1.1 mm), while those measuring at least 30 mm grew at a median annual rate of 1.2 mm (SD, 2.1 mm).
Worrisome features were present in 59 patients at baseline and emerged in another 150 patients during follow-up. At baseline, only 2.3% of cysts exceeded 30 mm in diameter, but 8.0% did at final measurement. Cyst wall thickening was found in 0.5% of patients at baseline and 3.7% of patients at final measurement. Main pancreatic ducts measured 5-9 mm in 1.9% of patients at baseline and in 5.6% of patients at final measurement. Additionally, the prevalence of mural nodules rose from 0.4% at baseline to 3.1% at final measurement.
Main pancreatic ducts averaged 1.8 mm (SD, 1.0 mm) at baseline and 2.4 mm (SD, 1.8 mm) at final measurement. Compared with the values seen with smaller cysts, larger baseline cyst diameter correlated significantly with larger main pancreatic ducts, more cases of cyst wall thickening, and more cases with mural nodules (P less than .001 for all comparisons).
The study was funded by a grant from Korean Health Technology R&D Project of Ministry of Health and Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
SOURCE: Han Y et al. Gastroenterology. 2018. doi: 10.1053/j.gastro.2017.10.013.
The appropriate management of branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs), a precursor cystic lesion to pancreatic cancer, has been a controversial issue since their initial description in 1982. Current national and international guidelines are primarily based on surgical series with potential selection bias and on observational studies with short surveillance periods. Consequently, there is limited information on the natural history and, more importantly, the malignant potential of BD-IPMNs.
The study by Youngmin Han and colleagues represents a comprehensive analysis of over 1,000 patients, each with at least 3 years of follow-up for a suspected BD-IPMN. In addition, the authors identified an optimal screening method for patients based on cyst size. Their data largely validates prior reports and will undoubtedly serve as the basis for future pancreatic cyst guidelines.
However, as the authors note, limitations of their study include its retrospective design and validation of their screening protocol. Moreover, several lingering questions remain for patients with BD-IPMNs: What is the best method of measuring a BD-IPMN (for example, CT, MRI, or endoscopic ultrasound)? How long should surveillance continue? And what is the role for cytopathology and ancillary studies, such as carcinoembryonic antigen testing, molecular testing, and testing for other pancreatic cyst biomarkers? At the risk of enouncing a cliché, “further studies are needed” to identify an optimal treatment algorithm and, considering the increasingly frequent detection of pancreatic cysts, a cost-effective approach to the evaluation of patients with BD-IPMNs.
Aatur D. Singhi, MD, PhD, is in the division of anatomic pathology in the department of pathology at the University of Pittsburgh Medical Center. He has no conflicts of interest.
The appropriate management of branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs), a precursor cystic lesion to pancreatic cancer, has been a controversial issue since their initial description in 1982. Current national and international guidelines are primarily based on surgical series with potential selection bias and on observational studies with short surveillance periods. Consequently, there is limited information on the natural history and, more importantly, the malignant potential of BD-IPMNs.
The study by Youngmin Han and colleagues represents a comprehensive analysis of over 1,000 patients, each with at least 3 years of follow-up for a suspected BD-IPMN. In addition, the authors identified an optimal screening method for patients based on cyst size. Their data largely validates prior reports and will undoubtedly serve as the basis for future pancreatic cyst guidelines.
However, as the authors note, limitations of their study include its retrospective design and validation of their screening protocol. Moreover, several lingering questions remain for patients with BD-IPMNs: What is the best method of measuring a BD-IPMN (for example, CT, MRI, or endoscopic ultrasound)? How long should surveillance continue? And what is the role for cytopathology and ancillary studies, such as carcinoembryonic antigen testing, molecular testing, and testing for other pancreatic cyst biomarkers? At the risk of enouncing a cliché, “further studies are needed” to identify an optimal treatment algorithm and, considering the increasingly frequent detection of pancreatic cysts, a cost-effective approach to the evaluation of patients with BD-IPMNs.
Aatur D. Singhi, MD, PhD, is in the division of anatomic pathology in the department of pathology at the University of Pittsburgh Medical Center. He has no conflicts of interest.
The appropriate management of branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs), a precursor cystic lesion to pancreatic cancer, has been a controversial issue since their initial description in 1982. Current national and international guidelines are primarily based on surgical series with potential selection bias and on observational studies with short surveillance periods. Consequently, there is limited information on the natural history and, more importantly, the malignant potential of BD-IPMNs.
The study by Youngmin Han and colleagues represents a comprehensive analysis of over 1,000 patients, each with at least 3 years of follow-up for a suspected BD-IPMN. In addition, the authors identified an optimal screening method for patients based on cyst size. Their data largely validates prior reports and will undoubtedly serve as the basis for future pancreatic cyst guidelines.
However, as the authors note, limitations of their study include its retrospective design and validation of their screening protocol. Moreover, several lingering questions remain for patients with BD-IPMNs: What is the best method of measuring a BD-IPMN (for example, CT, MRI, or endoscopic ultrasound)? How long should surveillance continue? And what is the role for cytopathology and ancillary studies, such as carcinoembryonic antigen testing, molecular testing, and testing for other pancreatic cyst biomarkers? At the risk of enouncing a cliché, “further studies are needed” to identify an optimal treatment algorithm and, considering the increasingly frequent detection of pancreatic cysts, a cost-effective approach to the evaluation of patients with BD-IPMNs.
Aatur D. Singhi, MD, PhD, is in the division of anatomic pathology in the department of pathology at the University of Pittsburgh Medical Center. He has no conflicts of interest.
Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) grew at a median annual rate of 0.8 mm in a retrospective study of 1,369 patients.
While most of these cysts were “indolent and dormant,” some grew rapidly and developed “other worrisome features,” Youngmin Han, MS, of Seoul (South Korea) National University reported with his associates in the February issue of Gastroenterology. Therefore, clinicians should plan follow-up surveillance based on initial cyst size and growth rate, they concluded.
Based on their findings, the researchers recommended surgery for young, fit, asymptomatic patients who have BD-IPMNs with a diameter of least 30 mm or with thickened cyst walls or those who have a main pancreatic duct measuring 5-9 mm. Surgery also should be considered when patients have lymphadenopathy, high tumor marker levels, or an abrupt change in pancreatic duct caliber with distal pancreatic atrophy or a rapidly growing cyst, they said.
For asymptomatic patients whose cysts are under 10 mm and who do not have worrisome features, they recommended follow-up with CT or MRI at 6 months and then every 2 years after that. Cysts of 10-20 mm should be imaged at 6 months, at 12 months, and then every 1.5-2 years after that, they said. Patients with cyst diameters greater than 20 mm “should undergo MRI or CT or EUS [endoscopic ultrasound] every 6 months for 1 year and then annually thereafter, until the cyst size and features become stable,” they added. Patients whose cysts have a diameter of 30 mm or greater “should be closely monitored with MRI or CT or EUS every 6 months. Surgical resection can be considered in younger patients or those with other combined worrisome features.”
To characterize the natural history of BD-IPMN, the investigators evaluated clinical and imaging data collected between 2001 and 2016 from patients with classical features of BD-IPMN. Each patient included in the study provided 3 or more years of CT, MRI, EUS, and endoscopic retrograde cholangiopancreatography data. The researchers used regression models to estimate changes in sizes of cysts and main pancreatic ducts.
Median follow-up time was 61 months (range, 36-189 months). Cyst diameter averaged 12.8 mm (standard deviation, 6.5 mm) at baseline and 17 mm (SD, 9.2 mm) at final measurement. Larger baseline diameter was associated with faster growth (P = .046): Cysts measuring less than 10 mm at baseline grew at a median annual rate of 0.8 mm (SD, 1.1 mm), while those measuring at least 30 mm grew at a median annual rate of 1.2 mm (SD, 2.1 mm).
Worrisome features were present in 59 patients at baseline and emerged in another 150 patients during follow-up. At baseline, only 2.3% of cysts exceeded 30 mm in diameter, but 8.0% did at final measurement. Cyst wall thickening was found in 0.5% of patients at baseline and 3.7% of patients at final measurement. Main pancreatic ducts measured 5-9 mm in 1.9% of patients at baseline and in 5.6% of patients at final measurement. Additionally, the prevalence of mural nodules rose from 0.4% at baseline to 3.1% at final measurement.
Main pancreatic ducts averaged 1.8 mm (SD, 1.0 mm) at baseline and 2.4 mm (SD, 1.8 mm) at final measurement. Compared with the values seen with smaller cysts, larger baseline cyst diameter correlated significantly with larger main pancreatic ducts, more cases of cyst wall thickening, and more cases with mural nodules (P less than .001 for all comparisons).
The study was funded by a grant from Korean Health Technology R&D Project of Ministry of Health and Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
SOURCE: Han Y et al. Gastroenterology. 2018. doi: 10.1053/j.gastro.2017.10.013.
Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) grew at a median annual rate of 0.8 mm in a retrospective study of 1,369 patients.
While most of these cysts were “indolent and dormant,” some grew rapidly and developed “other worrisome features,” Youngmin Han, MS, of Seoul (South Korea) National University reported with his associates in the February issue of Gastroenterology. Therefore, clinicians should plan follow-up surveillance based on initial cyst size and growth rate, they concluded.
Based on their findings, the researchers recommended surgery for young, fit, asymptomatic patients who have BD-IPMNs with a diameter of least 30 mm or with thickened cyst walls or those who have a main pancreatic duct measuring 5-9 mm. Surgery also should be considered when patients have lymphadenopathy, high tumor marker levels, or an abrupt change in pancreatic duct caliber with distal pancreatic atrophy or a rapidly growing cyst, they said.
For asymptomatic patients whose cysts are under 10 mm and who do not have worrisome features, they recommended follow-up with CT or MRI at 6 months and then every 2 years after that. Cysts of 10-20 mm should be imaged at 6 months, at 12 months, and then every 1.5-2 years after that, they said. Patients with cyst diameters greater than 20 mm “should undergo MRI or CT or EUS [endoscopic ultrasound] every 6 months for 1 year and then annually thereafter, until the cyst size and features become stable,” they added. Patients whose cysts have a diameter of 30 mm or greater “should be closely monitored with MRI or CT or EUS every 6 months. Surgical resection can be considered in younger patients or those with other combined worrisome features.”
To characterize the natural history of BD-IPMN, the investigators evaluated clinical and imaging data collected between 2001 and 2016 from patients with classical features of BD-IPMN. Each patient included in the study provided 3 or more years of CT, MRI, EUS, and endoscopic retrograde cholangiopancreatography data. The researchers used regression models to estimate changes in sizes of cysts and main pancreatic ducts.
Median follow-up time was 61 months (range, 36-189 months). Cyst diameter averaged 12.8 mm (standard deviation, 6.5 mm) at baseline and 17 mm (SD, 9.2 mm) at final measurement. Larger baseline diameter was associated with faster growth (P = .046): Cysts measuring less than 10 mm at baseline grew at a median annual rate of 0.8 mm (SD, 1.1 mm), while those measuring at least 30 mm grew at a median annual rate of 1.2 mm (SD, 2.1 mm).
Worrisome features were present in 59 patients at baseline and emerged in another 150 patients during follow-up. At baseline, only 2.3% of cysts exceeded 30 mm in diameter, but 8.0% did at final measurement. Cyst wall thickening was found in 0.5% of patients at baseline and 3.7% of patients at final measurement. Main pancreatic ducts measured 5-9 mm in 1.9% of patients at baseline and in 5.6% of patients at final measurement. Additionally, the prevalence of mural nodules rose from 0.4% at baseline to 3.1% at final measurement.
Main pancreatic ducts averaged 1.8 mm (SD, 1.0 mm) at baseline and 2.4 mm (SD, 1.8 mm) at final measurement. Compared with the values seen with smaller cysts, larger baseline cyst diameter correlated significantly with larger main pancreatic ducts, more cases of cyst wall thickening, and more cases with mural nodules (P less than .001 for all comparisons).
The study was funded by a grant from Korean Health Technology R&D Project of Ministry of Health and Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
SOURCE: Han Y et al. Gastroenterology. 2018. doi: 10.1053/j.gastro.2017.10.013.
FROM GASTROENTEROLOGY
Key clinical point: Tailor the surveillance of BD-IPMNs based on initial diameter and the presence or absence of high-risk features.
Major finding: Median annual growth rate was 0.8 mm.
Data source: A retrospective study of 1,369 patients with BD-IPMNs.
Disclosures: The study was funded by a grant from the Korean Health Technology R&D Project of the Ministry of Health and Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
Source: Han Y et al. Gastroenterology. 2018. doi: 10.1053/j.gastro.2017.10.013.
One in five Crohn’s disease patients have major complications after infliximab withdrawal
About , according to research published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.09.061).
About 70% of patients remained free of both infliximab restart failure and major complications, said Catherine Reenaers, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium), and her associates. Significant predictors of major complications included upper gastrointestinal disease at the time of infliximab withdrawal, white blood cell count of at least 5.0 x 109 per L, and hemoglobin level under 12.5 g per dL. “Patients with at least two of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal,” the researchers reported.
Little is known about long-term outcomes after patients with Crohn’s disease withdraw from infliximab. Therefore, Dr. Reenaers and her associates retrospectively studied 102 patients with Crohn’s disease who had received infliximab and an antimetabolite (azathioprine, mercaptopurine, or methotrexate) for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and then withdrew from infliximab. Patients were recruited from 19 centers in Belgium and France and were originally part of a prospective cohort study of infliximab withdrawal in Crohn’s disease (Gastroenterology. 2012;142[1]:63-70.e5).
About half of patients relapsed and restarted infliximab within 12 months, which is in line with other studies, the researchers noted. Over a median follow-up of 83 months (interquartile range, 71-93 months), 21% (95% confidence interval, 13.1%-30.3%) of patients had no complications, did not restart infliximab, and started no other biologics. In all, 70.2% of patients (95% CI, 60.2%-80.1%) had no major complications and did not fail to respond after restarting infliximab.
Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: 14 who required surgery and 4 who developed new complex perianal lesions. In a multivariable model, the strongest independent predictor of major complications was leukocytosis (hazard ratio, 10.5; 95% CI, 1.3-83; P less than .002), followed by upper gastrointestinal disease (HR, 5.8; 95% CI, 1.5-22) and low hemoglobin level (HR, 4.1; 95% CI, 1.5-21.8; P less than .01). The 13 patients who lacked these risk factors had no major complications of infliximab withdrawal. Among 72 patients who had at least one risk factor, 16.3% (95% CI, 7%-25%) developed major complications over 7 years. Strikingly, among 17 with at least two risk factors, 43% (95% CI, 17%-69%) developed major complications over 7 years, the researchers noted.
Complications emerged a median of 50 months (interquartile range, 41-73 months) after patients received their last infliximab infusion, highlighting the need for close long-term monitoring even if patients show no signs of early clinical relapse after infliximab withdrawal, the investigators said. “One strength of this cohort was the homogeneity of the population,” they stressed. “Most studies of anti–tumor necrosis factor withdrawal after clinical remission were limited by heterogeneous populations, variable lengths of infliximab treatment before discontinuation, and variable use of immunomodulators and corticosteroids. In [our] cohort, the population was homogenous, infliximab withdrawal was standardized, and the disease characteristics at the time of stopping were collected prospectively.” Although follow-up times varied, less than 5% of patients were followed for less than 3 years, they noted.
The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.
SOURCE: Reenaers C et al. Clin Gastro Hepatol 2018 February (in press).
The option of stopping a biologic agent is an attractive prospect for most Crohn's disease (CD) patients in stable clinical remission. The STORI trial, published in 2012, was among the earliest and select few studies addressing withdrawal of biologic therapy in CD among patients in sustained clinical remission with combination therapy (infliximab and thiopurine/methotrexate) for at least 6 months. Almost 50% of patients experienced disease relapse within a year of stopping infliximab in the trial.
Reenaers et al. recently published long-term follow-up of the original STORI cohort. After a median follow-up time of 7 years; four out five patients previously in clinical remission with combination therapy experienced worsening disease activity following withdrawal of infliximab. While the majority (70%) were able to resume infliximab and recapture disease response without any untoward adverse effects; one in five patients experienced major disease-related complications such as complex perianal disease or need for abdominal surgery. Upper GI tract involvement, high white blood cell count, and low hemoglobin concentration were associated with increased likelihood of a major complication. Notably, median time to a major complication was almost 4 years.
These results are similar to long-term relapse rates reported in other studies of withdrawal of therapy in CD. While biomarkers such as C-reactive protein, fecal calprotectin, along with endoscopic disease activity are reliable predictors of short-term relapse; clinical factors such as family history of CD, disease extent, stricturing or penetrating disease, and cigarette smoking are more relevant predictors of long-term disease activity. It is important to consider both types of predictors when considering withdrawal of therapy in CD.
Lastly, while the majority of patients who relapse following withdrawal of a biologic agent will do so within a year or two, a subset may not experience disease-related complications for several years - underscoring the need for long-term follow-up.
Manreet Kaur, MD, is assistant professor in the division of gastroenterology and hepatology; medical director, Inflammatory Bowel Disease Center, and medical director, faculty group practice, Baylor College of Medicine, Houston.
The option of stopping a biologic agent is an attractive prospect for most Crohn's disease (CD) patients in stable clinical remission. The STORI trial, published in 2012, was among the earliest and select few studies addressing withdrawal of biologic therapy in CD among patients in sustained clinical remission with combination therapy (infliximab and thiopurine/methotrexate) for at least 6 months. Almost 50% of patients experienced disease relapse within a year of stopping infliximab in the trial.
Reenaers et al. recently published long-term follow-up of the original STORI cohort. After a median follow-up time of 7 years; four out five patients previously in clinical remission with combination therapy experienced worsening disease activity following withdrawal of infliximab. While the majority (70%) were able to resume infliximab and recapture disease response without any untoward adverse effects; one in five patients experienced major disease-related complications such as complex perianal disease or need for abdominal surgery. Upper GI tract involvement, high white blood cell count, and low hemoglobin concentration were associated with increased likelihood of a major complication. Notably, median time to a major complication was almost 4 years.
These results are similar to long-term relapse rates reported in other studies of withdrawal of therapy in CD. While biomarkers such as C-reactive protein, fecal calprotectin, along with endoscopic disease activity are reliable predictors of short-term relapse; clinical factors such as family history of CD, disease extent, stricturing or penetrating disease, and cigarette smoking are more relevant predictors of long-term disease activity. It is important to consider both types of predictors when considering withdrawal of therapy in CD.
Lastly, while the majority of patients who relapse following withdrawal of a biologic agent will do so within a year or two, a subset may not experience disease-related complications for several years - underscoring the need for long-term follow-up.
Manreet Kaur, MD, is assistant professor in the division of gastroenterology and hepatology; medical director, Inflammatory Bowel Disease Center, and medical director, faculty group practice, Baylor College of Medicine, Houston.
The option of stopping a biologic agent is an attractive prospect for most Crohn's disease (CD) patients in stable clinical remission. The STORI trial, published in 2012, was among the earliest and select few studies addressing withdrawal of biologic therapy in CD among patients in sustained clinical remission with combination therapy (infliximab and thiopurine/methotrexate) for at least 6 months. Almost 50% of patients experienced disease relapse within a year of stopping infliximab in the trial.
Reenaers et al. recently published long-term follow-up of the original STORI cohort. After a median follow-up time of 7 years; four out five patients previously in clinical remission with combination therapy experienced worsening disease activity following withdrawal of infliximab. While the majority (70%) were able to resume infliximab and recapture disease response without any untoward adverse effects; one in five patients experienced major disease-related complications such as complex perianal disease or need for abdominal surgery. Upper GI tract involvement, high white blood cell count, and low hemoglobin concentration were associated with increased likelihood of a major complication. Notably, median time to a major complication was almost 4 years.
These results are similar to long-term relapse rates reported in other studies of withdrawal of therapy in CD. While biomarkers such as C-reactive protein, fecal calprotectin, along with endoscopic disease activity are reliable predictors of short-term relapse; clinical factors such as family history of CD, disease extent, stricturing or penetrating disease, and cigarette smoking are more relevant predictors of long-term disease activity. It is important to consider both types of predictors when considering withdrawal of therapy in CD.
Lastly, while the majority of patients who relapse following withdrawal of a biologic agent will do so within a year or two, a subset may not experience disease-related complications for several years - underscoring the need for long-term follow-up.
Manreet Kaur, MD, is assistant professor in the division of gastroenterology and hepatology; medical director, Inflammatory Bowel Disease Center, and medical director, faculty group practice, Baylor College of Medicine, Houston.
About , according to research published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.09.061).
About 70% of patients remained free of both infliximab restart failure and major complications, said Catherine Reenaers, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium), and her associates. Significant predictors of major complications included upper gastrointestinal disease at the time of infliximab withdrawal, white blood cell count of at least 5.0 x 109 per L, and hemoglobin level under 12.5 g per dL. “Patients with at least two of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal,” the researchers reported.
Little is known about long-term outcomes after patients with Crohn’s disease withdraw from infliximab. Therefore, Dr. Reenaers and her associates retrospectively studied 102 patients with Crohn’s disease who had received infliximab and an antimetabolite (azathioprine, mercaptopurine, or methotrexate) for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and then withdrew from infliximab. Patients were recruited from 19 centers in Belgium and France and were originally part of a prospective cohort study of infliximab withdrawal in Crohn’s disease (Gastroenterology. 2012;142[1]:63-70.e5).
About half of patients relapsed and restarted infliximab within 12 months, which is in line with other studies, the researchers noted. Over a median follow-up of 83 months (interquartile range, 71-93 months), 21% (95% confidence interval, 13.1%-30.3%) of patients had no complications, did not restart infliximab, and started no other biologics. In all, 70.2% of patients (95% CI, 60.2%-80.1%) had no major complications and did not fail to respond after restarting infliximab.
Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: 14 who required surgery and 4 who developed new complex perianal lesions. In a multivariable model, the strongest independent predictor of major complications was leukocytosis (hazard ratio, 10.5; 95% CI, 1.3-83; P less than .002), followed by upper gastrointestinal disease (HR, 5.8; 95% CI, 1.5-22) and low hemoglobin level (HR, 4.1; 95% CI, 1.5-21.8; P less than .01). The 13 patients who lacked these risk factors had no major complications of infliximab withdrawal. Among 72 patients who had at least one risk factor, 16.3% (95% CI, 7%-25%) developed major complications over 7 years. Strikingly, among 17 with at least two risk factors, 43% (95% CI, 17%-69%) developed major complications over 7 years, the researchers noted.
Complications emerged a median of 50 months (interquartile range, 41-73 months) after patients received their last infliximab infusion, highlighting the need for close long-term monitoring even if patients show no signs of early clinical relapse after infliximab withdrawal, the investigators said. “One strength of this cohort was the homogeneity of the population,” they stressed. “Most studies of anti–tumor necrosis factor withdrawal after clinical remission were limited by heterogeneous populations, variable lengths of infliximab treatment before discontinuation, and variable use of immunomodulators and corticosteroids. In [our] cohort, the population was homogenous, infliximab withdrawal was standardized, and the disease characteristics at the time of stopping were collected prospectively.” Although follow-up times varied, less than 5% of patients were followed for less than 3 years, they noted.
The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.
SOURCE: Reenaers C et al. Clin Gastro Hepatol 2018 February (in press).
About , according to research published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.09.061).
About 70% of patients remained free of both infliximab restart failure and major complications, said Catherine Reenaers, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium), and her associates. Significant predictors of major complications included upper gastrointestinal disease at the time of infliximab withdrawal, white blood cell count of at least 5.0 x 109 per L, and hemoglobin level under 12.5 g per dL. “Patients with at least two of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal,” the researchers reported.
Little is known about long-term outcomes after patients with Crohn’s disease withdraw from infliximab. Therefore, Dr. Reenaers and her associates retrospectively studied 102 patients with Crohn’s disease who had received infliximab and an antimetabolite (azathioprine, mercaptopurine, or methotrexate) for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and then withdrew from infliximab. Patients were recruited from 19 centers in Belgium and France and were originally part of a prospective cohort study of infliximab withdrawal in Crohn’s disease (Gastroenterology. 2012;142[1]:63-70.e5).
About half of patients relapsed and restarted infliximab within 12 months, which is in line with other studies, the researchers noted. Over a median follow-up of 83 months (interquartile range, 71-93 months), 21% (95% confidence interval, 13.1%-30.3%) of patients had no complications, did not restart infliximab, and started no other biologics. In all, 70.2% of patients (95% CI, 60.2%-80.1%) had no major complications and did not fail to respond after restarting infliximab.
Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: 14 who required surgery and 4 who developed new complex perianal lesions. In a multivariable model, the strongest independent predictor of major complications was leukocytosis (hazard ratio, 10.5; 95% CI, 1.3-83; P less than .002), followed by upper gastrointestinal disease (HR, 5.8; 95% CI, 1.5-22) and low hemoglobin level (HR, 4.1; 95% CI, 1.5-21.8; P less than .01). The 13 patients who lacked these risk factors had no major complications of infliximab withdrawal. Among 72 patients who had at least one risk factor, 16.3% (95% CI, 7%-25%) developed major complications over 7 years. Strikingly, among 17 with at least two risk factors, 43% (95% CI, 17%-69%) developed major complications over 7 years, the researchers noted.
Complications emerged a median of 50 months (interquartile range, 41-73 months) after patients received their last infliximab infusion, highlighting the need for close long-term monitoring even if patients show no signs of early clinical relapse after infliximab withdrawal, the investigators said. “One strength of this cohort was the homogeneity of the population,” they stressed. “Most studies of anti–tumor necrosis factor withdrawal after clinical remission were limited by heterogeneous populations, variable lengths of infliximab treatment before discontinuation, and variable use of immunomodulators and corticosteroids. In [our] cohort, the population was homogenous, infliximab withdrawal was standardized, and the disease characteristics at the time of stopping were collected prospectively.” Although follow-up times varied, less than 5% of patients were followed for less than 3 years, they noted.
The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.
SOURCE: Reenaers C et al. Clin Gastro Hepatol 2018 February (in press).
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Over 7 years, about one in five patients with remitted Crohn’s disease developed a major complication after withdrawing from infliximab, despite remaining on an antimetabolite.
Major finding: Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: Fourteen needed surgery and four developed new complex perianal lesions.
Data source: A cohort study of 102 patients with Crohn’s disease who had received infliximab and an antimetabolite for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and who then withdrew from infliximab.
Disclosures: The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.
Source: Reenaers C et al. Clin Gastroenterol Hepatol. 2018 February (in press).
Eradicating HCV significantly improved liver stiffness in meta-analysis
Eradicating chronic hepatitis C virus (HCV) infection led to significant decreases in liver stiffness in a systematic review and meta-analysis of nearly 3,000 patients.
Mean liver stiffness fell by 4.1 kPa (kilopascals) (95% confidence interval, 3.3-4.9 kPa) 12 or more months after patients achieved sustained virologic response to treatment, but did not significantly change in patients who did not achieve SVR, reported Siddharth Singh, MD, of the University of San Diego, La Jolla, Calif., and his associates in the January issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.038). The results were especially striking among patients who received direct-acting antiviral agents (DAAs) or who had high baseline levels of inflammation, the investigators added.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Based on these findings, about 47% of patients with advanced fibrosis or cirrhosis at baseline will drop below 9.5 kPa after achieving SVR, they reported. “With this decline in liver stiffness, it is conceivable that risk of liver-related complications would decrease, particularly in patients without cirrhosis,” they added. “Future research is warranted on the impact of magnitude and kinetics of decline in liver stiffness on improvement in liver-related outcomes.”
Eradicating HCV infection was known to decrease liver stiffness, but the magnitude of decline was not well understood. Therefore, the reviewers searched the literature through October 2016 for studies of HCV-infected adults who underwent liver stiffness measurement by vibration-controlled transient elastography before and at least once after completing HCV treatment. All studies also included data on median liver stiffness among patients who did and did not achieve SVR. The search identified 23 observational studies and one post hoc analysis of a randomized controlled trial, for a total of 2,934 patients, of whom 2,214 achieved SVR.
Among patients who achieved SVR, mean liver stiffness dropped by 2.4 kPa at the end of treatment (95% CI, 1.7-3.0 kPa), by 3.1 kPa 1-6 months later (95% CI, 1.6-4.7 kPa), and by 3.2 kPa 6-12 months after completing treatment (90% CI, 2.6-3.9 kPa). A year or more after finishing treatment, patients who achieved SVR had a 28% median decrease in liver stiffness (interquartile range, 22%-35%). However, liver stiffness did not significantly change among patients who did not achieve SVR, the reviewers reported.
Mean liver stiffness declined significantly more among patients who received DAAs (4.5 kPa) than among recipients of interferon-based regimens (2.6 kPa; P = .03). However, studies of DAAs included patients with greater liver stiffness at baseline, which could at least partially explain this discrepancy, the investigators said. Baseline cirrhosis also was associated with a greater decline in liver stiffness (mean, 5.1 kPa, vs. 2.8 kPa in patients without cirrhosis; P = .02), as was high baseline alanine aminotransferase level (P less than .01). Among patients whose baseline liver stiffness measurement exceeded 9.5 kPa, 47% had their liver stiffness drop to less than 9.5 kPa after achieving SVR.
Coinfection with HIV did not significantly alter the magnitude of decline in liver stiffness 6-12 months after treatment in patients who achieved SVR, the reviewers noted. “[Follow-up] assessment after SVR was relatively short; hence, long-term evolution of liver stiffness after antiviral therapy and impact of decline in liver stiffness on patient clinical outcomes could not be ascertained,” they wrote. The studies also did not consistently assess potential confounders such as nonalcoholic fatty liver disease, diabetes, and alcohol consumption.
One reviewer disclosed funding from the National Institutes of Health/National Library of Medicine. None had conflicts of interest.
The current era of new-generation direct-acting antiviral agents have revolutionized the treatment landscape of chronic hepatitis C virus infection, providing short-duration, safe, and consistently effective regimens that achieve SVR or cure in nearly 100% of patients. While achieving SVR is important, even more important is the long-term impact of SVR and whether cure translates into outcomes such as improved mortality or a reduced risk of disease progression. Although improved mortality after SVR has been demonstrated, one of the main drivers of risk of disease progression is the severity of hepatic fibrosis.
Robert J. Wong, MD, MS, is with the department of medicine and is director of research and education, division of gastroenterology and hepatology, Alameda Health System – Highland Hospital, Oakland, Calif. He has received a 2017-2019 Clinical Translational Research Award from AASLD, has received research funding from Gilead and AbbVie, and is on the speakers bureau of Gilead, Salix, and Bayer. He has also done consulting for and been an advisory board member for Gilead.
The current era of new-generation direct-acting antiviral agents have revolutionized the treatment landscape of chronic hepatitis C virus infection, providing short-duration, safe, and consistently effective regimens that achieve SVR or cure in nearly 100% of patients. While achieving SVR is important, even more important is the long-term impact of SVR and whether cure translates into outcomes such as improved mortality or a reduced risk of disease progression. Although improved mortality after SVR has been demonstrated, one of the main drivers of risk of disease progression is the severity of hepatic fibrosis.
Robert J. Wong, MD, MS, is with the department of medicine and is director of research and education, division of gastroenterology and hepatology, Alameda Health System – Highland Hospital, Oakland, Calif. He has received a 2017-2019 Clinical Translational Research Award from AASLD, has received research funding from Gilead and AbbVie, and is on the speakers bureau of Gilead, Salix, and Bayer. He has also done consulting for and been an advisory board member for Gilead.
The current era of new-generation direct-acting antiviral agents have revolutionized the treatment landscape of chronic hepatitis C virus infection, providing short-duration, safe, and consistently effective regimens that achieve SVR or cure in nearly 100% of patients. While achieving SVR is important, even more important is the long-term impact of SVR and whether cure translates into outcomes such as improved mortality or a reduced risk of disease progression. Although improved mortality after SVR has been demonstrated, one of the main drivers of risk of disease progression is the severity of hepatic fibrosis.
Robert J. Wong, MD, MS, is with the department of medicine and is director of research and education, division of gastroenterology and hepatology, Alameda Health System – Highland Hospital, Oakland, Calif. He has received a 2017-2019 Clinical Translational Research Award from AASLD, has received research funding from Gilead and AbbVie, and is on the speakers bureau of Gilead, Salix, and Bayer. He has also done consulting for and been an advisory board member for Gilead.
Eradicating chronic hepatitis C virus (HCV) infection led to significant decreases in liver stiffness in a systematic review and meta-analysis of nearly 3,000 patients.
Mean liver stiffness fell by 4.1 kPa (kilopascals) (95% confidence interval, 3.3-4.9 kPa) 12 or more months after patients achieved sustained virologic response to treatment, but did not significantly change in patients who did not achieve SVR, reported Siddharth Singh, MD, of the University of San Diego, La Jolla, Calif., and his associates in the January issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.038). The results were especially striking among patients who received direct-acting antiviral agents (DAAs) or who had high baseline levels of inflammation, the investigators added.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Based on these findings, about 47% of patients with advanced fibrosis or cirrhosis at baseline will drop below 9.5 kPa after achieving SVR, they reported. “With this decline in liver stiffness, it is conceivable that risk of liver-related complications would decrease, particularly in patients without cirrhosis,” they added. “Future research is warranted on the impact of magnitude and kinetics of decline in liver stiffness on improvement in liver-related outcomes.”
Eradicating HCV infection was known to decrease liver stiffness, but the magnitude of decline was not well understood. Therefore, the reviewers searched the literature through October 2016 for studies of HCV-infected adults who underwent liver stiffness measurement by vibration-controlled transient elastography before and at least once after completing HCV treatment. All studies also included data on median liver stiffness among patients who did and did not achieve SVR. The search identified 23 observational studies and one post hoc analysis of a randomized controlled trial, for a total of 2,934 patients, of whom 2,214 achieved SVR.
Among patients who achieved SVR, mean liver stiffness dropped by 2.4 kPa at the end of treatment (95% CI, 1.7-3.0 kPa), by 3.1 kPa 1-6 months later (95% CI, 1.6-4.7 kPa), and by 3.2 kPa 6-12 months after completing treatment (90% CI, 2.6-3.9 kPa). A year or more after finishing treatment, patients who achieved SVR had a 28% median decrease in liver stiffness (interquartile range, 22%-35%). However, liver stiffness did not significantly change among patients who did not achieve SVR, the reviewers reported.
Mean liver stiffness declined significantly more among patients who received DAAs (4.5 kPa) than among recipients of interferon-based regimens (2.6 kPa; P = .03). However, studies of DAAs included patients with greater liver stiffness at baseline, which could at least partially explain this discrepancy, the investigators said. Baseline cirrhosis also was associated with a greater decline in liver stiffness (mean, 5.1 kPa, vs. 2.8 kPa in patients without cirrhosis; P = .02), as was high baseline alanine aminotransferase level (P less than .01). Among patients whose baseline liver stiffness measurement exceeded 9.5 kPa, 47% had their liver stiffness drop to less than 9.5 kPa after achieving SVR.
Coinfection with HIV did not significantly alter the magnitude of decline in liver stiffness 6-12 months after treatment in patients who achieved SVR, the reviewers noted. “[Follow-up] assessment after SVR was relatively short; hence, long-term evolution of liver stiffness after antiviral therapy and impact of decline in liver stiffness on patient clinical outcomes could not be ascertained,” they wrote. The studies also did not consistently assess potential confounders such as nonalcoholic fatty liver disease, diabetes, and alcohol consumption.
One reviewer disclosed funding from the National Institutes of Health/National Library of Medicine. None had conflicts of interest.
Eradicating chronic hepatitis C virus (HCV) infection led to significant decreases in liver stiffness in a systematic review and meta-analysis of nearly 3,000 patients.
Mean liver stiffness fell by 4.1 kPa (kilopascals) (95% confidence interval, 3.3-4.9 kPa) 12 or more months after patients achieved sustained virologic response to treatment, but did not significantly change in patients who did not achieve SVR, reported Siddharth Singh, MD, of the University of San Diego, La Jolla, Calif., and his associates in the January issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.038). The results were especially striking among patients who received direct-acting antiviral agents (DAAs) or who had high baseline levels of inflammation, the investigators added.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Based on these findings, about 47% of patients with advanced fibrosis or cirrhosis at baseline will drop below 9.5 kPa after achieving SVR, they reported. “With this decline in liver stiffness, it is conceivable that risk of liver-related complications would decrease, particularly in patients without cirrhosis,” they added. “Future research is warranted on the impact of magnitude and kinetics of decline in liver stiffness on improvement in liver-related outcomes.”
Eradicating HCV infection was known to decrease liver stiffness, but the magnitude of decline was not well understood. Therefore, the reviewers searched the literature through October 2016 for studies of HCV-infected adults who underwent liver stiffness measurement by vibration-controlled transient elastography before and at least once after completing HCV treatment. All studies also included data on median liver stiffness among patients who did and did not achieve SVR. The search identified 23 observational studies and one post hoc analysis of a randomized controlled trial, for a total of 2,934 patients, of whom 2,214 achieved SVR.
Among patients who achieved SVR, mean liver stiffness dropped by 2.4 kPa at the end of treatment (95% CI, 1.7-3.0 kPa), by 3.1 kPa 1-6 months later (95% CI, 1.6-4.7 kPa), and by 3.2 kPa 6-12 months after completing treatment (90% CI, 2.6-3.9 kPa). A year or more after finishing treatment, patients who achieved SVR had a 28% median decrease in liver stiffness (interquartile range, 22%-35%). However, liver stiffness did not significantly change among patients who did not achieve SVR, the reviewers reported.
Mean liver stiffness declined significantly more among patients who received DAAs (4.5 kPa) than among recipients of interferon-based regimens (2.6 kPa; P = .03). However, studies of DAAs included patients with greater liver stiffness at baseline, which could at least partially explain this discrepancy, the investigators said. Baseline cirrhosis also was associated with a greater decline in liver stiffness (mean, 5.1 kPa, vs. 2.8 kPa in patients without cirrhosis; P = .02), as was high baseline alanine aminotransferase level (P less than .01). Among patients whose baseline liver stiffness measurement exceeded 9.5 kPa, 47% had their liver stiffness drop to less than 9.5 kPa after achieving SVR.
Coinfection with HIV did not significantly alter the magnitude of decline in liver stiffness 6-12 months after treatment in patients who achieved SVR, the reviewers noted. “[Follow-up] assessment after SVR was relatively short; hence, long-term evolution of liver stiffness after antiviral therapy and impact of decline in liver stiffness on patient clinical outcomes could not be ascertained,” they wrote. The studies also did not consistently assess potential confounders such as nonalcoholic fatty liver disease, diabetes, and alcohol consumption.
One reviewer disclosed funding from the National Institutes of Health/National Library of Medicine. None had conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Eradicating chronic hepatitis C virus infection led to significant decreases in liver stiffness.
Major finding: Mean liver stiffness decreased by 4.1 kPa 12 or more months after patients achieved sustained virologic response to treatment, but did not significantly improve in patients who lacked SVR.
Data source: A systematic review and meta-analysis of 2,934 patients from 23 observational studies and one post hoc analysis of a randomized controlled trial.
Disclosures: One reviewer disclosed funding from the National Institutes of Health/National Library of Medicine. The reviewers reported having no conflicts of interest.
How to manage cytokine release syndrome
ATLANTA – Closely monitoring for cytokine release syndrome (CRS) and starting anticytokine therapy early can prevent life-threatening organ toxicities in recipients of chimeric antigen receptor (CAR) T-cell therapy, according to Daniel W. Lee III, MD.
There’s no evidence that early anticytokine therapy impairs antitumor response, he noted. “If you wait to give anticytokine therapy until a patient is intubated, it’s too late,” Dr. Lee said at the annual meeting of the American Society of Hematology. “If you wait until a patient has been hypotensive for days, it’s probably too late. If you intervene earlier, you can avoid intubation.”
Treating CRS is a clinical decision that shouldn’t hinge on cytokine levels, according to Dr. Lee. He and his colleagues base treatment on their revised severity grading assessment, which spans mild, moderate, severe, and life-threatening syndromes (Blood. 2014;124:188-95).
Using a consistent CRS severity grading system enables physicians to treat rationally across trials and CAR T-cell therapies, he said. His system defines grade 1 CRS as flu-like symptoms and fever up to 41.5 degrees Celsius. Patients with grade 1 CRS should receive antipyretics and analgesia as needed and should be monitored closely for infections and fluid imbalances, Dr. Lee said.
Hypotension signifies progression beyond grade 1 CRS. Affected patients should receive no more than two to three IV fluid boluses and then should “quickly move on to vasopressors,” such as norepinephrine, he emphasized.
His and his team implemented this important change after one of their patients, a 14-year-old boy with severe hypotensive grade 4 CRS, died of a cardiovascular event after receiving multiple IV fluid boluses. “We had not appreciated the extent of this patient’s ventricular strain,” Dr. Lee said. The patient was heavily pretreated and had an “extremely high disease burden” (more than 99% marrow involvement, hepatosplenomegaly, and pronounced blastic leukocytosis), which increased his risk of severe CRS, he noted. “Admittedly, we pushed the envelope a little bit, and we learned you should start anticytokine therapies much earlier. Earlier seems to be better, although we do not yet know if prophylactic tocilizumab or corticosteroids can prevent CRS symptoms before they start.”
For hypotensive patients on pressors, Dr. Lee recommends vigilant supportive care and daily echocardiograms to monitor ejection fraction and ventricular wall mobility. His system defines grade 2 CRS as hypotension responsive to one low-dose pressor or to fluid therapy and hypoxia responsive to less than 40% oxygen therapy. Patients with grade 2 CRS who also have comorbidities should receive tocilizumab – with or without corticosteroids – both of which “remain the standard of care for managing CRS,” he said. Severe CRS often stems from supraphysiologic release of interleukin 6, which induces not only classic IL-6 signaling but also proinflammatory trans-signaling across many cell types. Tocilizumab reverses this process by binding and blocking the IL-6 receptor, Dr. Lee noted.
Patients with grade 3 CRS have hypotension requiring multiple or high-dose pressors and hypoxia requiring at least 40% oxygen therapy. These patients have grade 3 organ toxicity and grade 4 transaminitis, Dr. Lee said. Even if they lack comorbidities, they need vigilant supportive care, tocilizumab, and possibly corticosteroids, he added. The ultimate goal is to avoid grade 4 CRS, he said, which involves grade 4 organ toxicity, requires mechanical ventilation, and yields a poor prognosis despite vigilant supportive care, tocilizumab, and corticosteroids.
Dr. Lee reported having no relevant conflicts of interest.
ATLANTA – Closely monitoring for cytokine release syndrome (CRS) and starting anticytokine therapy early can prevent life-threatening organ toxicities in recipients of chimeric antigen receptor (CAR) T-cell therapy, according to Daniel W. Lee III, MD.
There’s no evidence that early anticytokine therapy impairs antitumor response, he noted. “If you wait to give anticytokine therapy until a patient is intubated, it’s too late,” Dr. Lee said at the annual meeting of the American Society of Hematology. “If you wait until a patient has been hypotensive for days, it’s probably too late. If you intervene earlier, you can avoid intubation.”
Treating CRS is a clinical decision that shouldn’t hinge on cytokine levels, according to Dr. Lee. He and his colleagues base treatment on their revised severity grading assessment, which spans mild, moderate, severe, and life-threatening syndromes (Blood. 2014;124:188-95).
Using a consistent CRS severity grading system enables physicians to treat rationally across trials and CAR T-cell therapies, he said. His system defines grade 1 CRS as flu-like symptoms and fever up to 41.5 degrees Celsius. Patients with grade 1 CRS should receive antipyretics and analgesia as needed and should be monitored closely for infections and fluid imbalances, Dr. Lee said.
Hypotension signifies progression beyond grade 1 CRS. Affected patients should receive no more than two to three IV fluid boluses and then should “quickly move on to vasopressors,” such as norepinephrine, he emphasized.
His and his team implemented this important change after one of their patients, a 14-year-old boy with severe hypotensive grade 4 CRS, died of a cardiovascular event after receiving multiple IV fluid boluses. “We had not appreciated the extent of this patient’s ventricular strain,” Dr. Lee said. The patient was heavily pretreated and had an “extremely high disease burden” (more than 99% marrow involvement, hepatosplenomegaly, and pronounced blastic leukocytosis), which increased his risk of severe CRS, he noted. “Admittedly, we pushed the envelope a little bit, and we learned you should start anticytokine therapies much earlier. Earlier seems to be better, although we do not yet know if prophylactic tocilizumab or corticosteroids can prevent CRS symptoms before they start.”
For hypotensive patients on pressors, Dr. Lee recommends vigilant supportive care and daily echocardiograms to monitor ejection fraction and ventricular wall mobility. His system defines grade 2 CRS as hypotension responsive to one low-dose pressor or to fluid therapy and hypoxia responsive to less than 40% oxygen therapy. Patients with grade 2 CRS who also have comorbidities should receive tocilizumab – with or without corticosteroids – both of which “remain the standard of care for managing CRS,” he said. Severe CRS often stems from supraphysiologic release of interleukin 6, which induces not only classic IL-6 signaling but also proinflammatory trans-signaling across many cell types. Tocilizumab reverses this process by binding and blocking the IL-6 receptor, Dr. Lee noted.
Patients with grade 3 CRS have hypotension requiring multiple or high-dose pressors and hypoxia requiring at least 40% oxygen therapy. These patients have grade 3 organ toxicity and grade 4 transaminitis, Dr. Lee said. Even if they lack comorbidities, they need vigilant supportive care, tocilizumab, and possibly corticosteroids, he added. The ultimate goal is to avoid grade 4 CRS, he said, which involves grade 4 organ toxicity, requires mechanical ventilation, and yields a poor prognosis despite vigilant supportive care, tocilizumab, and corticosteroids.
Dr. Lee reported having no relevant conflicts of interest.
ATLANTA – Closely monitoring for cytokine release syndrome (CRS) and starting anticytokine therapy early can prevent life-threatening organ toxicities in recipients of chimeric antigen receptor (CAR) T-cell therapy, according to Daniel W. Lee III, MD.
There’s no evidence that early anticytokine therapy impairs antitumor response, he noted. “If you wait to give anticytokine therapy until a patient is intubated, it’s too late,” Dr. Lee said at the annual meeting of the American Society of Hematology. “If you wait until a patient has been hypotensive for days, it’s probably too late. If you intervene earlier, you can avoid intubation.”
Treating CRS is a clinical decision that shouldn’t hinge on cytokine levels, according to Dr. Lee. He and his colleagues base treatment on their revised severity grading assessment, which spans mild, moderate, severe, and life-threatening syndromes (Blood. 2014;124:188-95).
Using a consistent CRS severity grading system enables physicians to treat rationally across trials and CAR T-cell therapies, he said. His system defines grade 1 CRS as flu-like symptoms and fever up to 41.5 degrees Celsius. Patients with grade 1 CRS should receive antipyretics and analgesia as needed and should be monitored closely for infections and fluid imbalances, Dr. Lee said.
Hypotension signifies progression beyond grade 1 CRS. Affected patients should receive no more than two to three IV fluid boluses and then should “quickly move on to vasopressors,” such as norepinephrine, he emphasized.
His and his team implemented this important change after one of their patients, a 14-year-old boy with severe hypotensive grade 4 CRS, died of a cardiovascular event after receiving multiple IV fluid boluses. “We had not appreciated the extent of this patient’s ventricular strain,” Dr. Lee said. The patient was heavily pretreated and had an “extremely high disease burden” (more than 99% marrow involvement, hepatosplenomegaly, and pronounced blastic leukocytosis), which increased his risk of severe CRS, he noted. “Admittedly, we pushed the envelope a little bit, and we learned you should start anticytokine therapies much earlier. Earlier seems to be better, although we do not yet know if prophylactic tocilizumab or corticosteroids can prevent CRS symptoms before they start.”
For hypotensive patients on pressors, Dr. Lee recommends vigilant supportive care and daily echocardiograms to monitor ejection fraction and ventricular wall mobility. His system defines grade 2 CRS as hypotension responsive to one low-dose pressor or to fluid therapy and hypoxia responsive to less than 40% oxygen therapy. Patients with grade 2 CRS who also have comorbidities should receive tocilizumab – with or without corticosteroids – both of which “remain the standard of care for managing CRS,” he said. Severe CRS often stems from supraphysiologic release of interleukin 6, which induces not only classic IL-6 signaling but also proinflammatory trans-signaling across many cell types. Tocilizumab reverses this process by binding and blocking the IL-6 receptor, Dr. Lee noted.
Patients with grade 3 CRS have hypotension requiring multiple or high-dose pressors and hypoxia requiring at least 40% oxygen therapy. These patients have grade 3 organ toxicity and grade 4 transaminitis, Dr. Lee said. Even if they lack comorbidities, they need vigilant supportive care, tocilizumab, and possibly corticosteroids, he added. The ultimate goal is to avoid grade 4 CRS, he said, which involves grade 4 organ toxicity, requires mechanical ventilation, and yields a poor prognosis despite vigilant supportive care, tocilizumab, and corticosteroids.
Dr. Lee reported having no relevant conflicts of interest.
EXPERT ANALYSIS FROM ASH 2017
Daratumumab looks good in light chain amyloidosis
ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.
So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”
“Daratumumab also had a good safety profile characterized by nonsevere adverse events after initial infusion. There was only one drug-related serious adverse event, grade 3 lymphopenia,” she said.
In a second study, the risk for daratumumab infusion reactions was low when patients received a prophylactic regimen initiated about an hour before daratumumab infusion.
Daratumumab, a novel, fully humanized IgG1-kappa monoclonal antibody with high affinity for CD38, is approved for treating relapsed/refractory multiple myeloma. In AL amyloidosis, as in myeloma, monoclonal light chains nearly always originate from plasma cells that consistently express CD38.
Data from small studies indicate that daratumumab effectively treats AL amyloidosis. To further evaluate safety and efficacy, 36 adults with previously treated disease received 28-day cycles of daratumumab (16 mg/kg IV) weekly for two cycles and then every other week for four cycles. Most patients had received three prior lines of therapy, about two-thirds had cardiac involvement (median baseline NT-proBNP 1,118 ng/L; range, 60-6,825), and about 60% had renal involvement.
At data cutoff in mid-November 2017, fifteen patients had completed all six treatment cycles. Three stopped treatment because of progression. Two died, one of progressive cardiac amyloidosis and one of unrelated lung cancer.
Eleven patients had grade 1-2 infusion reactions at first injection. Among 17 grade 3 or higher adverse events, only lymphopenia was deemed treatment related.
At 6 months, 15 of 32 evaluable patients (44%) had a very good partial response (VGPR; at least a 40% drop in baseline difference in involved and uninvolved free light chains (dFLC). Another 16% had a partial response, and 41% did not respond.
Patients with durable responses tended to have about a 70% drop in dFLC after the first daratumumab dose. Baseline variables did not seem to predict durability of response, Dr. Roussel said. “Further studies in amyloidosis are warranted in relapsed or refractory patients and also in the frontline setting.”
The second trial focused on preventing infusion reactions to daratumumab. In early trials of daratumumab for relapsed/recalcitrant multiple myeloma, patients developed moderate to severe bronchospasm, laryngeal or pulmonary edema, hypoxia, and hypertension, noted Vaishali Sanchorawala, MD, of Boston Medical Center. Since those trials, prophylactic therapies have been used to reduce the risk of infusion reactions.
Dr. Sanchorawala’s study enrolled 12 patients with previously treated AL amyloidosis and cardiac biomarker stage II or stage III disease. About 60% of patients were refractory to their last treatment. Median NT-proBNP level was 1,357 pg/mL (range, 469-3,962), median urine protein excretion was 0.44 g (0-10.1), and median dFLC was 105 mg/dL (3.8-854).
Patients received 16 mg/kg daratumumab IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months. About an hour before infusion, they received acetaminophen, diphenhydramine, loratadine famotidine, montelukast, and methylprednisolone (100 mg for two infusions; 60 mg thereafter). Ondansetron also was added to control mild nausea and vomiting. Two hours into the infusion, patients received diphenhydramine, famotidine, and methylprednisolone (40 mg). They received methylprednisolone (20 mg) and montelukast 1-2 days after the first two infusions, after which montelukast was optional. All received prophylactic acyclovir.
At the Nov. 15, 2017 data cutoff, 11 patients remained on study and one left after disease progressed. This patient’s disease was refractory to many prior therapies and had a complete response to autologous stem cell transplant, said Dr. Sanchorawala.
There were no grade 3-4 infusion reactions. Nine evaluable patients at 3 months had two complete hematologic responses, six VGPRs (at least a 65% drop in dFLC), and one partial response. One-third had at least a 30% improvement in NT-proBNP at 3 months, as did three of four evaluable patients at 6 months. About half had least a 30% drop in urine protein excretion at 6 months.
First infusions lasted a median of 7 hours, making them doable during a clinic day if bloods are drawn beforehand, Dr. Sanchorawala said. Second and subsequent infusions took about 4 hours.
“Preliminary data suggest a rapid hematologic response after one dose of daratumumab and high rates of response at 3 and 6 months, ” she concluded. “Since the plasma cell clone is so low in amyloidosis, single-agent daratumumab has a very positive, strong effect. We may not need to combine other agents with this therapy.”
Both presentations sparked substantial interest during the discussion period after the presentations, especially because daratumumab was given as monotherapy. “This would be a new indication for daratumumab,” said session moderator Dan Vogl, MD, director of the Abramson Cancer Center Clinical Research Unit, University of Pennsylvania, Philadelphia.
Janssen makes daratumumab and provided partial funding for both studies. Dr. Sanchorawala had no conflicts of interest. Dr. Roussel disclosed honoraria and research funding from Janssen.
SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.
ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.
So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”
“Daratumumab also had a good safety profile characterized by nonsevere adverse events after initial infusion. There was only one drug-related serious adverse event, grade 3 lymphopenia,” she said.
In a second study, the risk for daratumumab infusion reactions was low when patients received a prophylactic regimen initiated about an hour before daratumumab infusion.
Daratumumab, a novel, fully humanized IgG1-kappa monoclonal antibody with high affinity for CD38, is approved for treating relapsed/refractory multiple myeloma. In AL amyloidosis, as in myeloma, monoclonal light chains nearly always originate from plasma cells that consistently express CD38.
Data from small studies indicate that daratumumab effectively treats AL amyloidosis. To further evaluate safety and efficacy, 36 adults with previously treated disease received 28-day cycles of daratumumab (16 mg/kg IV) weekly for two cycles and then every other week for four cycles. Most patients had received three prior lines of therapy, about two-thirds had cardiac involvement (median baseline NT-proBNP 1,118 ng/L; range, 60-6,825), and about 60% had renal involvement.
At data cutoff in mid-November 2017, fifteen patients had completed all six treatment cycles. Three stopped treatment because of progression. Two died, one of progressive cardiac amyloidosis and one of unrelated lung cancer.
Eleven patients had grade 1-2 infusion reactions at first injection. Among 17 grade 3 or higher adverse events, only lymphopenia was deemed treatment related.
At 6 months, 15 of 32 evaluable patients (44%) had a very good partial response (VGPR; at least a 40% drop in baseline difference in involved and uninvolved free light chains (dFLC). Another 16% had a partial response, and 41% did not respond.
Patients with durable responses tended to have about a 70% drop in dFLC after the first daratumumab dose. Baseline variables did not seem to predict durability of response, Dr. Roussel said. “Further studies in amyloidosis are warranted in relapsed or refractory patients and also in the frontline setting.”
The second trial focused on preventing infusion reactions to daratumumab. In early trials of daratumumab for relapsed/recalcitrant multiple myeloma, patients developed moderate to severe bronchospasm, laryngeal or pulmonary edema, hypoxia, and hypertension, noted Vaishali Sanchorawala, MD, of Boston Medical Center. Since those trials, prophylactic therapies have been used to reduce the risk of infusion reactions.
Dr. Sanchorawala’s study enrolled 12 patients with previously treated AL amyloidosis and cardiac biomarker stage II or stage III disease. About 60% of patients were refractory to their last treatment. Median NT-proBNP level was 1,357 pg/mL (range, 469-3,962), median urine protein excretion was 0.44 g (0-10.1), and median dFLC was 105 mg/dL (3.8-854).
Patients received 16 mg/kg daratumumab IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months. About an hour before infusion, they received acetaminophen, diphenhydramine, loratadine famotidine, montelukast, and methylprednisolone (100 mg for two infusions; 60 mg thereafter). Ondansetron also was added to control mild nausea and vomiting. Two hours into the infusion, patients received diphenhydramine, famotidine, and methylprednisolone (40 mg). They received methylprednisolone (20 mg) and montelukast 1-2 days after the first two infusions, after which montelukast was optional. All received prophylactic acyclovir.
At the Nov. 15, 2017 data cutoff, 11 patients remained on study and one left after disease progressed. This patient’s disease was refractory to many prior therapies and had a complete response to autologous stem cell transplant, said Dr. Sanchorawala.
There were no grade 3-4 infusion reactions. Nine evaluable patients at 3 months had two complete hematologic responses, six VGPRs (at least a 65% drop in dFLC), and one partial response. One-third had at least a 30% improvement in NT-proBNP at 3 months, as did three of four evaluable patients at 6 months. About half had least a 30% drop in urine protein excretion at 6 months.
First infusions lasted a median of 7 hours, making them doable during a clinic day if bloods are drawn beforehand, Dr. Sanchorawala said. Second and subsequent infusions took about 4 hours.
“Preliminary data suggest a rapid hematologic response after one dose of daratumumab and high rates of response at 3 and 6 months, ” she concluded. “Since the plasma cell clone is so low in amyloidosis, single-agent daratumumab has a very positive, strong effect. We may not need to combine other agents with this therapy.”
Both presentations sparked substantial interest during the discussion period after the presentations, especially because daratumumab was given as monotherapy. “This would be a new indication for daratumumab,” said session moderator Dan Vogl, MD, director of the Abramson Cancer Center Clinical Research Unit, University of Pennsylvania, Philadelphia.
Janssen makes daratumumab and provided partial funding for both studies. Dr. Sanchorawala had no conflicts of interest. Dr. Roussel disclosed honoraria and research funding from Janssen.
SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.
ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.
So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”
“Daratumumab also had a good safety profile characterized by nonsevere adverse events after initial infusion. There was only one drug-related serious adverse event, grade 3 lymphopenia,” she said.
In a second study, the risk for daratumumab infusion reactions was low when patients received a prophylactic regimen initiated about an hour before daratumumab infusion.
Daratumumab, a novel, fully humanized IgG1-kappa monoclonal antibody with high affinity for CD38, is approved for treating relapsed/refractory multiple myeloma. In AL amyloidosis, as in myeloma, monoclonal light chains nearly always originate from plasma cells that consistently express CD38.
Data from small studies indicate that daratumumab effectively treats AL amyloidosis. To further evaluate safety and efficacy, 36 adults with previously treated disease received 28-day cycles of daratumumab (16 mg/kg IV) weekly for two cycles and then every other week for four cycles. Most patients had received three prior lines of therapy, about two-thirds had cardiac involvement (median baseline NT-proBNP 1,118 ng/L; range, 60-6,825), and about 60% had renal involvement.
At data cutoff in mid-November 2017, fifteen patients had completed all six treatment cycles. Three stopped treatment because of progression. Two died, one of progressive cardiac amyloidosis and one of unrelated lung cancer.
Eleven patients had grade 1-2 infusion reactions at first injection. Among 17 grade 3 or higher adverse events, only lymphopenia was deemed treatment related.
At 6 months, 15 of 32 evaluable patients (44%) had a very good partial response (VGPR; at least a 40% drop in baseline difference in involved and uninvolved free light chains (dFLC). Another 16% had a partial response, and 41% did not respond.
Patients with durable responses tended to have about a 70% drop in dFLC after the first daratumumab dose. Baseline variables did not seem to predict durability of response, Dr. Roussel said. “Further studies in amyloidosis are warranted in relapsed or refractory patients and also in the frontline setting.”
The second trial focused on preventing infusion reactions to daratumumab. In early trials of daratumumab for relapsed/recalcitrant multiple myeloma, patients developed moderate to severe bronchospasm, laryngeal or pulmonary edema, hypoxia, and hypertension, noted Vaishali Sanchorawala, MD, of Boston Medical Center. Since those trials, prophylactic therapies have been used to reduce the risk of infusion reactions.
Dr. Sanchorawala’s study enrolled 12 patients with previously treated AL amyloidosis and cardiac biomarker stage II or stage III disease. About 60% of patients were refractory to their last treatment. Median NT-proBNP level was 1,357 pg/mL (range, 469-3,962), median urine protein excretion was 0.44 g (0-10.1), and median dFLC was 105 mg/dL (3.8-854).
Patients received 16 mg/kg daratumumab IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months. About an hour before infusion, they received acetaminophen, diphenhydramine, loratadine famotidine, montelukast, and methylprednisolone (100 mg for two infusions; 60 mg thereafter). Ondansetron also was added to control mild nausea and vomiting. Two hours into the infusion, patients received diphenhydramine, famotidine, and methylprednisolone (40 mg). They received methylprednisolone (20 mg) and montelukast 1-2 days after the first two infusions, after which montelukast was optional. All received prophylactic acyclovir.
At the Nov. 15, 2017 data cutoff, 11 patients remained on study and one left after disease progressed. This patient’s disease was refractory to many prior therapies and had a complete response to autologous stem cell transplant, said Dr. Sanchorawala.
There were no grade 3-4 infusion reactions. Nine evaluable patients at 3 months had two complete hematologic responses, six VGPRs (at least a 65% drop in dFLC), and one partial response. One-third had at least a 30% improvement in NT-proBNP at 3 months, as did three of four evaluable patients at 6 months. About half had least a 30% drop in urine protein excretion at 6 months.
First infusions lasted a median of 7 hours, making them doable during a clinic day if bloods are drawn beforehand, Dr. Sanchorawala said. Second and subsequent infusions took about 4 hours.
“Preliminary data suggest a rapid hematologic response after one dose of daratumumab and high rates of response at 3 and 6 months, ” she concluded. “Since the plasma cell clone is so low in amyloidosis, single-agent daratumumab has a very positive, strong effect. We may not need to combine other agents with this therapy.”
Both presentations sparked substantial interest during the discussion period after the presentations, especially because daratumumab was given as monotherapy. “This would be a new indication for daratumumab,” said session moderator Dan Vogl, MD, director of the Abramson Cancer Center Clinical Research Unit, University of Pennsylvania, Philadelphia.
Janssen makes daratumumab and provided partial funding for both studies. Dr. Sanchorawala had no conflicts of interest. Dr. Roussel disclosed honoraria and research funding from Janssen.
SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.
REPORTING FROM ASH 2017
Key clinical point: Major finding: Rates of very good partial response or complete response were 44% and 33%, respectively, at 6 months.
Data source: Two phase 2 trials of daratumumab monotherapy in patients with previously treated light chain amyloidosis (NCT02816476 [36 patients] and NCT02841033 [12 patients]).
Disclosures: Janssen makes daratumumab and provided partial funding for both studies. Dr. Roussel disclosed honoraria and research funding from Janssen. Dr. Sanchorawala had no conflicts of interest.
Sources: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.
Survival improvements lag for young Hispanic patients with myeloma
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
REPORTING FROM ASH 2017
Key clinical point: Recent improvements in multiple myeloma survival have left young Hispanics behind.
Major finding: Five-year and 10-year survival have improved significantly among young blacks and non-Hispanic whites with multiple myeloma (P less than .0001 for all comparisons) but not Hispanics (5-year survival P = .08; 10-year survival P = .13).
Data source: Surveillance Epidemiology and End Results (SEER) data for 1,460 adults up to 40 years old when diagnosed with multiple myeloma.
Disclosures: The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed funding from Pharmacyclics, Amgen, Novartis, and Takeda.
Source: Ailawadhi S et al. ASH Abstract 2149.
Single-agent daratumumab active in smoldering multiple myeloma
ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.
Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.
Current guidelines recommend monitoring smoldering multiple myeloma every 3-6 months and treating only after patients progress. However, some experts pursue earlier treatment in the premalignant setting.
In CENTAURUS, 123 adults with smoldering multiple myeloma were randomly assigned to receive daratumumab (16 mg/kg IV) in 8-week cycles according to a long, intermediate, or short/intense schedule. The long schedule consisted of treatment weekly for cycle 1, every other week for cycles 2-3, monthly for cycles 4-7, and once every 8 weeks for up to 13 more cycles. The intermediate schedule consisted of treatment weekly in cycle 1 and every 8 weeks for up to 20 cycles. The short, intense schedule consisted of weekly treatment for 8 weeks (one cycle). Patients were followed for up to 4 years or until they progressed to multiple myeloma based on International Myeloma Working Group guidelines.
Over a median follow-up period of 15.8 months (range, 0 to 24 months), rates of complete response were 2% in the long treatment arm, 5% in the intermediate treatment arm, and 0% in the short treatment arm. Rates of at least very good partial response were 29%, 24%, and 15%, respectively. Overall response rates were 56%, 54%, and 38%, respectively. Median PFS was not reached in any arm, exceeding 24 months.
Treatment was generally well tolerated, said Dr. Hofmeister. The most common treatment-related adverse effects were fatigue, cough, upper respiratory tract infection, headache, and insomnia. Hypertension and hyperglycemia were the most common grade 3-4 treatment-emergent adverse events, affecting up to 5% of patients per arm. Fewer than 10% of patients in any arm developed treatment-emergent hematologic adverse events, and fewer than 5% developed grade 3-4 pneumonia or sepsis. There were three cases of a second primary malignancy, including one case of breast cancer and two cases of melanoma.
Rates of infusion-related reactions did not correlate with treatment duration. Grade 3-4 infusion-related reactions affected 0% to 3% of patients per arm. The sole death in this trial resulted from disease progression in a patient from the short treatment arm. “Taken together, efficacy and safety data support long dosing compared to intermediate and short dosing,” Dr. Hofmeister said.
The three arms were demographically similar. Patients tended to be white, in their late 50s to 60s, and to have ECOG scores of 0 with at least two risk factors for progression. About 70% had IgG disease and nearly half had less than 20% plasma cells in bone marrow.
Janssen, the maker of daratumumab, sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.
ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.
Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.
Current guidelines recommend monitoring smoldering multiple myeloma every 3-6 months and treating only after patients progress. However, some experts pursue earlier treatment in the premalignant setting.
In CENTAURUS, 123 adults with smoldering multiple myeloma were randomly assigned to receive daratumumab (16 mg/kg IV) in 8-week cycles according to a long, intermediate, or short/intense schedule. The long schedule consisted of treatment weekly for cycle 1, every other week for cycles 2-3, monthly for cycles 4-7, and once every 8 weeks for up to 13 more cycles. The intermediate schedule consisted of treatment weekly in cycle 1 and every 8 weeks for up to 20 cycles. The short, intense schedule consisted of weekly treatment for 8 weeks (one cycle). Patients were followed for up to 4 years or until they progressed to multiple myeloma based on International Myeloma Working Group guidelines.
Over a median follow-up period of 15.8 months (range, 0 to 24 months), rates of complete response were 2% in the long treatment arm, 5% in the intermediate treatment arm, and 0% in the short treatment arm. Rates of at least very good partial response were 29%, 24%, and 15%, respectively. Overall response rates were 56%, 54%, and 38%, respectively. Median PFS was not reached in any arm, exceeding 24 months.
Treatment was generally well tolerated, said Dr. Hofmeister. The most common treatment-related adverse effects were fatigue, cough, upper respiratory tract infection, headache, and insomnia. Hypertension and hyperglycemia were the most common grade 3-4 treatment-emergent adverse events, affecting up to 5% of patients per arm. Fewer than 10% of patients in any arm developed treatment-emergent hematologic adverse events, and fewer than 5% developed grade 3-4 pneumonia or sepsis. There were three cases of a second primary malignancy, including one case of breast cancer and two cases of melanoma.
Rates of infusion-related reactions did not correlate with treatment duration. Grade 3-4 infusion-related reactions affected 0% to 3% of patients per arm. The sole death in this trial resulted from disease progression in a patient from the short treatment arm. “Taken together, efficacy and safety data support long dosing compared to intermediate and short dosing,” Dr. Hofmeister said.
The three arms were demographically similar. Patients tended to be white, in their late 50s to 60s, and to have ECOG scores of 0 with at least two risk factors for progression. About 70% had IgG disease and nearly half had less than 20% plasma cells in bone marrow.
Janssen, the maker of daratumumab, sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.
ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.
Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.
Current guidelines recommend monitoring smoldering multiple myeloma every 3-6 months and treating only after patients progress. However, some experts pursue earlier treatment in the premalignant setting.
In CENTAURUS, 123 adults with smoldering multiple myeloma were randomly assigned to receive daratumumab (16 mg/kg IV) in 8-week cycles according to a long, intermediate, or short/intense schedule. The long schedule consisted of treatment weekly for cycle 1, every other week for cycles 2-3, monthly for cycles 4-7, and once every 8 weeks for up to 13 more cycles. The intermediate schedule consisted of treatment weekly in cycle 1 and every 8 weeks for up to 20 cycles. The short, intense schedule consisted of weekly treatment for 8 weeks (one cycle). Patients were followed for up to 4 years or until they progressed to multiple myeloma based on International Myeloma Working Group guidelines.
Over a median follow-up period of 15.8 months (range, 0 to 24 months), rates of complete response were 2% in the long treatment arm, 5% in the intermediate treatment arm, and 0% in the short treatment arm. Rates of at least very good partial response were 29%, 24%, and 15%, respectively. Overall response rates were 56%, 54%, and 38%, respectively. Median PFS was not reached in any arm, exceeding 24 months.
Treatment was generally well tolerated, said Dr. Hofmeister. The most common treatment-related adverse effects were fatigue, cough, upper respiratory tract infection, headache, and insomnia. Hypertension and hyperglycemia were the most common grade 3-4 treatment-emergent adverse events, affecting up to 5% of patients per arm. Fewer than 10% of patients in any arm developed treatment-emergent hematologic adverse events, and fewer than 5% developed grade 3-4 pneumonia or sepsis. There were three cases of a second primary malignancy, including one case of breast cancer and two cases of melanoma.
Rates of infusion-related reactions did not correlate with treatment duration. Grade 3-4 infusion-related reactions affected 0% to 3% of patients per arm. The sole death in this trial resulted from disease progression in a patient from the short treatment arm. “Taken together, efficacy and safety data support long dosing compared to intermediate and short dosing,” Dr. Hofmeister said.
The three arms were demographically similar. Patients tended to be white, in their late 50s to 60s, and to have ECOG scores of 0 with at least two risk factors for progression. About 70% had IgG disease and nearly half had less than 20% plasma cells in bone marrow.
Janssen, the maker of daratumumab, sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.
REPORTING FROM ASH 2017
Key clinical point: Single-agent daratumumab therapy was active and its safety profile was acceptable in patients with smoldering multiple myeloma.
Major finding: Rates of at least very good partial response were 29%, 24%, and 15% among patients who received long, intermediate, and short/intense treatment schedules, respectively. Median progression-free survival exceeded 24 months in all three arms.
Data source: CENTAURUS, a phase II trial of 123 patients with smoldering multiple myeloma.
Disclosures: Janssen sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
Source: Hofmeister C et al, ASH 2017, Abstract 510.
Study identifies predictors of acquired von Willebrand disease
ATLANTA – Waldenström macroglobulinemia can present as acquired von Willebrand disease (VWD), and when it does, the finding strongly correlates with high serum IgM levels and the presence of CXCR4 mutations, according to the results of a large, single-center retrospective study.
Further, successfully treating Waldenström macroglobulinemia often resolves acquired VWD, and the depth of treatment response predicts the degree of improvement, Jorge J. Castillo, MD, and his associates wrote in a poster presented at the annual meeting of the American Society of Hematology.
Acquired VWD is an uncommon, poorly understood presentation of Waldenström macroglobulinemia. Because affected patients require treatment, better characterizing this subgroup is important, the investigators noted.
At the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute in Boston, the researchers retrospectively studied 320 individuals with newly diagnosed Waldenström macroglobulinemia and used logistic regression analysis to seek predictors of acquired VWD, which they evaluated by measuring levels of VW factor antigen, VW factor activity, and factor VIII. Levels under 30% were considered VWD and levels between 30% and 50% were considered low-level VWD.
In all, 49 individuals had acquired VWD while 271 patients did not. These two groups were similar in terms of age, sex, hemoglobin level, platelet count, and bone marrow involvement. However, 45% of patients with acquired VWD had serum IgM levels above 6,000 mg/dL versus 6% of patients without acquired VWD (P less than .001), and 47% of patients with acquired VWD had serum IgM levels between 3,000 and 5,999 versus 31% of patients without acquired VWD (P less than .001). Also, 77% of patients with acquired VWD tested positive for CXCR4 mutation versus 37% of patients without acquired VWD (P less than .001).
A significantly higher proportion of patients without acquired VWD had white blood cell concentrations above 6,000/mcL (29% vs. 50%; P = .006). This finding lost statistical significance in the logistic regression model, but all the other variables remained significantly associated. Serum IgM levels above 6,000 mg/dL conferred a 55-fold increase in the odds of having acquired VWD (95% confidence interval, 17-177; P less than .001), and serum IgM levels between 3,000 and 5,999 mg/dL led to an 11-fold increase in these odds (95% CI, 4-34). The presence of CXCR4 mutations was associated with a sixfold increased odds of acquired VWD (95% CI, 2-15). The P value for each of these three associations was at or below .001.
Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment. After treatment, 78% of patients with acquired VWD had levels of all three measures above 50% (versus 0% before treatment; P less than .001). Patients with acquired VWD with the best responses to treatment had about a 90% decrease in IgM levels, while those with a partial response had about a two-thirds decrease and patients with stable disease had about a 20% decrease. A linear regression model confirmed that depth of treatment response, based on change in IgM level, correlated with degree of improvement in VWD – that is, the extent of improvement in levels of VW factor antigen, VW factor activity, and factor VIII.
No external funding sources were reported. Dr. Castillo disclosed consulting ties and research funding from Pharmacyclics and Janssen, and research funding from Millenium and Abbvie.
SOURCE: Castillo J, et al. ASH 2017 Abstract 1088.
ATLANTA – Waldenström macroglobulinemia can present as acquired von Willebrand disease (VWD), and when it does, the finding strongly correlates with high serum IgM levels and the presence of CXCR4 mutations, according to the results of a large, single-center retrospective study.
Further, successfully treating Waldenström macroglobulinemia often resolves acquired VWD, and the depth of treatment response predicts the degree of improvement, Jorge J. Castillo, MD, and his associates wrote in a poster presented at the annual meeting of the American Society of Hematology.
Acquired VWD is an uncommon, poorly understood presentation of Waldenström macroglobulinemia. Because affected patients require treatment, better characterizing this subgroup is important, the investigators noted.
At the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute in Boston, the researchers retrospectively studied 320 individuals with newly diagnosed Waldenström macroglobulinemia and used logistic regression analysis to seek predictors of acquired VWD, which they evaluated by measuring levels of VW factor antigen, VW factor activity, and factor VIII. Levels under 30% were considered VWD and levels between 30% and 50% were considered low-level VWD.
In all, 49 individuals had acquired VWD while 271 patients did not. These two groups were similar in terms of age, sex, hemoglobin level, platelet count, and bone marrow involvement. However, 45% of patients with acquired VWD had serum IgM levels above 6,000 mg/dL versus 6% of patients without acquired VWD (P less than .001), and 47% of patients with acquired VWD had serum IgM levels between 3,000 and 5,999 versus 31% of patients without acquired VWD (P less than .001). Also, 77% of patients with acquired VWD tested positive for CXCR4 mutation versus 37% of patients without acquired VWD (P less than .001).
A significantly higher proportion of patients without acquired VWD had white blood cell concentrations above 6,000/mcL (29% vs. 50%; P = .006). This finding lost statistical significance in the logistic regression model, but all the other variables remained significantly associated. Serum IgM levels above 6,000 mg/dL conferred a 55-fold increase in the odds of having acquired VWD (95% confidence interval, 17-177; P less than .001), and serum IgM levels between 3,000 and 5,999 mg/dL led to an 11-fold increase in these odds (95% CI, 4-34). The presence of CXCR4 mutations was associated with a sixfold increased odds of acquired VWD (95% CI, 2-15). The P value for each of these three associations was at or below .001.
Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment. After treatment, 78% of patients with acquired VWD had levels of all three measures above 50% (versus 0% before treatment; P less than .001). Patients with acquired VWD with the best responses to treatment had about a 90% decrease in IgM levels, while those with a partial response had about a two-thirds decrease and patients with stable disease had about a 20% decrease. A linear regression model confirmed that depth of treatment response, based on change in IgM level, correlated with degree of improvement in VWD – that is, the extent of improvement in levels of VW factor antigen, VW factor activity, and factor VIII.
No external funding sources were reported. Dr. Castillo disclosed consulting ties and research funding from Pharmacyclics and Janssen, and research funding from Millenium and Abbvie.
SOURCE: Castillo J, et al. ASH 2017 Abstract 1088.
ATLANTA – Waldenström macroglobulinemia can present as acquired von Willebrand disease (VWD), and when it does, the finding strongly correlates with high serum IgM levels and the presence of CXCR4 mutations, according to the results of a large, single-center retrospective study.
Further, successfully treating Waldenström macroglobulinemia often resolves acquired VWD, and the depth of treatment response predicts the degree of improvement, Jorge J. Castillo, MD, and his associates wrote in a poster presented at the annual meeting of the American Society of Hematology.
Acquired VWD is an uncommon, poorly understood presentation of Waldenström macroglobulinemia. Because affected patients require treatment, better characterizing this subgroup is important, the investigators noted.
At the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute in Boston, the researchers retrospectively studied 320 individuals with newly diagnosed Waldenström macroglobulinemia and used logistic regression analysis to seek predictors of acquired VWD, which they evaluated by measuring levels of VW factor antigen, VW factor activity, and factor VIII. Levels under 30% were considered VWD and levels between 30% and 50% were considered low-level VWD.
In all, 49 individuals had acquired VWD while 271 patients did not. These two groups were similar in terms of age, sex, hemoglobin level, platelet count, and bone marrow involvement. However, 45% of patients with acquired VWD had serum IgM levels above 6,000 mg/dL versus 6% of patients without acquired VWD (P less than .001), and 47% of patients with acquired VWD had serum IgM levels between 3,000 and 5,999 versus 31% of patients without acquired VWD (P less than .001). Also, 77% of patients with acquired VWD tested positive for CXCR4 mutation versus 37% of patients without acquired VWD (P less than .001).
A significantly higher proportion of patients without acquired VWD had white blood cell concentrations above 6,000/mcL (29% vs. 50%; P = .006). This finding lost statistical significance in the logistic regression model, but all the other variables remained significantly associated. Serum IgM levels above 6,000 mg/dL conferred a 55-fold increase in the odds of having acquired VWD (95% confidence interval, 17-177; P less than .001), and serum IgM levels between 3,000 and 5,999 mg/dL led to an 11-fold increase in these odds (95% CI, 4-34). The presence of CXCR4 mutations was associated with a sixfold increased odds of acquired VWD (95% CI, 2-15). The P value for each of these three associations was at or below .001.
Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment. After treatment, 78% of patients with acquired VWD had levels of all three measures above 50% (versus 0% before treatment; P less than .001). Patients with acquired VWD with the best responses to treatment had about a 90% decrease in IgM levels, while those with a partial response had about a two-thirds decrease and patients with stable disease had about a 20% decrease. A linear regression model confirmed that depth of treatment response, based on change in IgM level, correlated with degree of improvement in VWD – that is, the extent of improvement in levels of VW factor antigen, VW factor activity, and factor VIII.
No external funding sources were reported. Dr. Castillo disclosed consulting ties and research funding from Pharmacyclics and Janssen, and research funding from Millenium and Abbvie.
SOURCE: Castillo J, et al. ASH 2017 Abstract 1088.
AT ASH 2017
Key clinical point: Successfully treating Waldenström macroglobulinemia often resolves acquired von Willebrand disease.
Major finding: Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment.
Data source: A single-center retrospective study of 320 patients with newly diagnosed Waldenström macroglobulinemia.
Disclosures: No external funding sources were reported. Dr. Castillo disclosed consultancy and research funding from Pharmacyclics and Janssen. He also disclosed research funding from Millenium and Abbvie.
Source: Castillo J, et al. ASH 2017 Abstract 1088.
HERCULES: Caplacizumab improved platelet response in aTTP
ATLANTA – Adding caplacizumab to standard therapy for acquired thrombotic thrombocytopenic purpura (aTTP) significantly improved platelet response and prevented recurrent episodes in an international, randomized, double-blind, phase 3 placebo-controlled trial.
“Patients were 55% more likely to achieve normalization of platelet count in the caplacizumab group, and this was highly significant,” Marie Scully, MD, said during a late-breaking presentation at the annual meeting of the American Society of Hematology.
“So far, phase 2 and phase 3 studies confirm no deaths in patients treated with caplacizumab,” said Dr. Scully of University College London Hospitals NHS Trust.
Acquired TTP is an acute, life-threatening thrombotic microangiopathy that occurs when inhibitory autoantibodies cause a deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor (vWF). Inadequate levels of ADAMTS13 activity lead to the formation of ultra-large vWF multimers, platelet strings, and microthrombi. Caplacizumab is a humanized immunoglobulin that helps stop this process by binding the A1 domain of vWF.
“Caplacizumab addresses the pathophysiological platelet aggregation that leads to the formation of microthrombi,” Dr. Scully said.
In this phase 3 trial (HERCULES), 145 patients who had received plasma exchange (PE) at least once for an acute episode of aTTP were randomly assigned to receive caplacizumab or placebo injections plus daily PE and corticosteroids. Caplacizumab (10-mg) therapy consisted of one IV bolus followed by subcutaneous treatment for 30 days. Patients whose ADAMTS13 activity remained below 10% were able to continue treatment for another 28 days, after which all patients were followed for another 28 days without treatment.
At any given time, platelet normalization was 55% more likely with caplacizumab (10 mg) than placebo (platelet normalization rate ratio, 1.55; 95% confidence interval, 1.10-2.20; P less than .01).
Rates of a key combined secondary endpoint – aTTP-related death/recurrence/major thrombotic events – were 12.7% with caplacizumab and 49.3% with placebo (P less than .0001).
Rates of major thrombotic events were 8% in each arm, and deaths were rare overall, meaning that the difference in rates of recurrence drove most of the effect on the combined secondary endpoint. However, patients who received caplacizumab also received 41% less plasma and had 38% fewer days of PE, 65% fewer days in the intensive care unit, and 31% fewer days in the hospital than patients in the placebo arm.
Refractory aTTP affected 4.2% of placebo patients and no caplacizumab patients, which trended toward statistical significance (P = .057). Caplacizumab therapy also led to a faster normalization of several markers of organ damage, including lactate dehydrogenase, cardiac troponin 1, and serum creatinine.
Safety findings reflected earlier-phase studies and caplacizumab’s mechanism of action, Dr. Scully said. Nearly all trial participants experienced at least one treatment-emergent adverse event. Such events led 7% of patients to stop caplacizumab and 12% to stop placebo. Caplacizumab was associated with a range of bleeding-related events, most commonly epistaxis (23.9 vs. 1.4% with placebo), gingival bleeding (11.3% vs. 0%), bruising (7.0% vs. 4.1%), and hematuria (5.6% vs. 1.4%).
Patients in both arms tended to be in their 40s and two-thirds were female. At baseline, about 85% had less than 10% ADAMTS13 activity, and about 40% had severe aTTP (French severity scores of at least 3 or severe neurologic or cardiac involvement).
“Most [66%] patients in the caplacizumab group presented with de novo aTTP, and this is relevant because patients who are in their first episode are much harder to treat,” Dr. Scully said. About half of placebo patients had de novo disease.
In July 2017, caplacizumab received a fast-track designation from the Food and Drug Administration for aTTP after a phase 2 trial showed that platelet counts normalized 39% faster with caplacizumab versus placebo plus standard of care (P = .005). Of eight patients in that study who relapsed within a month of stopping caplacizumab, seven still had less than 10% ADAMTS13 activity, “suggesting unresolved autoimmune activity,” the investigators wrote at the time in the New England Journal of Medicine (2016;374:511-22).
Dr. Scully reported similar findings in the phase 3 HERCULES trial, noting that all patients had ADAMTS13 levels less than 5% on stopping caplacizumab.
Ablynx provided funding for the study. Dr. Scully reported financial relationships with Ablynx, Shire, Novartis, and Alexion.
SOURCE: Scully M et al., ASH 2017 Abstract LBA-1.
ATLANTA – Adding caplacizumab to standard therapy for acquired thrombotic thrombocytopenic purpura (aTTP) significantly improved platelet response and prevented recurrent episodes in an international, randomized, double-blind, phase 3 placebo-controlled trial.
“Patients were 55% more likely to achieve normalization of platelet count in the caplacizumab group, and this was highly significant,” Marie Scully, MD, said during a late-breaking presentation at the annual meeting of the American Society of Hematology.
“So far, phase 2 and phase 3 studies confirm no deaths in patients treated with caplacizumab,” said Dr. Scully of University College London Hospitals NHS Trust.
Acquired TTP is an acute, life-threatening thrombotic microangiopathy that occurs when inhibitory autoantibodies cause a deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor (vWF). Inadequate levels of ADAMTS13 activity lead to the formation of ultra-large vWF multimers, platelet strings, and microthrombi. Caplacizumab is a humanized immunoglobulin that helps stop this process by binding the A1 domain of vWF.
“Caplacizumab addresses the pathophysiological platelet aggregation that leads to the formation of microthrombi,” Dr. Scully said.
In this phase 3 trial (HERCULES), 145 patients who had received plasma exchange (PE) at least once for an acute episode of aTTP were randomly assigned to receive caplacizumab or placebo injections plus daily PE and corticosteroids. Caplacizumab (10-mg) therapy consisted of one IV bolus followed by subcutaneous treatment for 30 days. Patients whose ADAMTS13 activity remained below 10% were able to continue treatment for another 28 days, after which all patients were followed for another 28 days without treatment.
At any given time, platelet normalization was 55% more likely with caplacizumab (10 mg) than placebo (platelet normalization rate ratio, 1.55; 95% confidence interval, 1.10-2.20; P less than .01).
Rates of a key combined secondary endpoint – aTTP-related death/recurrence/major thrombotic events – were 12.7% with caplacizumab and 49.3% with placebo (P less than .0001).
Rates of major thrombotic events were 8% in each arm, and deaths were rare overall, meaning that the difference in rates of recurrence drove most of the effect on the combined secondary endpoint. However, patients who received caplacizumab also received 41% less plasma and had 38% fewer days of PE, 65% fewer days in the intensive care unit, and 31% fewer days in the hospital than patients in the placebo arm.
Refractory aTTP affected 4.2% of placebo patients and no caplacizumab patients, which trended toward statistical significance (P = .057). Caplacizumab therapy also led to a faster normalization of several markers of organ damage, including lactate dehydrogenase, cardiac troponin 1, and serum creatinine.
Safety findings reflected earlier-phase studies and caplacizumab’s mechanism of action, Dr. Scully said. Nearly all trial participants experienced at least one treatment-emergent adverse event. Such events led 7% of patients to stop caplacizumab and 12% to stop placebo. Caplacizumab was associated with a range of bleeding-related events, most commonly epistaxis (23.9 vs. 1.4% with placebo), gingival bleeding (11.3% vs. 0%), bruising (7.0% vs. 4.1%), and hematuria (5.6% vs. 1.4%).
Patients in both arms tended to be in their 40s and two-thirds were female. At baseline, about 85% had less than 10% ADAMTS13 activity, and about 40% had severe aTTP (French severity scores of at least 3 or severe neurologic or cardiac involvement).
“Most [66%] patients in the caplacizumab group presented with de novo aTTP, and this is relevant because patients who are in their first episode are much harder to treat,” Dr. Scully said. About half of placebo patients had de novo disease.
In July 2017, caplacizumab received a fast-track designation from the Food and Drug Administration for aTTP after a phase 2 trial showed that platelet counts normalized 39% faster with caplacizumab versus placebo plus standard of care (P = .005). Of eight patients in that study who relapsed within a month of stopping caplacizumab, seven still had less than 10% ADAMTS13 activity, “suggesting unresolved autoimmune activity,” the investigators wrote at the time in the New England Journal of Medicine (2016;374:511-22).
Dr. Scully reported similar findings in the phase 3 HERCULES trial, noting that all patients had ADAMTS13 levels less than 5% on stopping caplacizumab.
Ablynx provided funding for the study. Dr. Scully reported financial relationships with Ablynx, Shire, Novartis, and Alexion.
SOURCE: Scully M et al., ASH 2017 Abstract LBA-1.
ATLANTA – Adding caplacizumab to standard therapy for acquired thrombotic thrombocytopenic purpura (aTTP) significantly improved platelet response and prevented recurrent episodes in an international, randomized, double-blind, phase 3 placebo-controlled trial.
“Patients were 55% more likely to achieve normalization of platelet count in the caplacizumab group, and this was highly significant,” Marie Scully, MD, said during a late-breaking presentation at the annual meeting of the American Society of Hematology.
“So far, phase 2 and phase 3 studies confirm no deaths in patients treated with caplacizumab,” said Dr. Scully of University College London Hospitals NHS Trust.
Acquired TTP is an acute, life-threatening thrombotic microangiopathy that occurs when inhibitory autoantibodies cause a deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor (vWF). Inadequate levels of ADAMTS13 activity lead to the formation of ultra-large vWF multimers, platelet strings, and microthrombi. Caplacizumab is a humanized immunoglobulin that helps stop this process by binding the A1 domain of vWF.
“Caplacizumab addresses the pathophysiological platelet aggregation that leads to the formation of microthrombi,” Dr. Scully said.
In this phase 3 trial (HERCULES), 145 patients who had received plasma exchange (PE) at least once for an acute episode of aTTP were randomly assigned to receive caplacizumab or placebo injections plus daily PE and corticosteroids. Caplacizumab (10-mg) therapy consisted of one IV bolus followed by subcutaneous treatment for 30 days. Patients whose ADAMTS13 activity remained below 10% were able to continue treatment for another 28 days, after which all patients were followed for another 28 days without treatment.
At any given time, platelet normalization was 55% more likely with caplacizumab (10 mg) than placebo (platelet normalization rate ratio, 1.55; 95% confidence interval, 1.10-2.20; P less than .01).
Rates of a key combined secondary endpoint – aTTP-related death/recurrence/major thrombotic events – were 12.7% with caplacizumab and 49.3% with placebo (P less than .0001).
Rates of major thrombotic events were 8% in each arm, and deaths were rare overall, meaning that the difference in rates of recurrence drove most of the effect on the combined secondary endpoint. However, patients who received caplacizumab also received 41% less plasma and had 38% fewer days of PE, 65% fewer days in the intensive care unit, and 31% fewer days in the hospital than patients in the placebo arm.
Refractory aTTP affected 4.2% of placebo patients and no caplacizumab patients, which trended toward statistical significance (P = .057). Caplacizumab therapy also led to a faster normalization of several markers of organ damage, including lactate dehydrogenase, cardiac troponin 1, and serum creatinine.
Safety findings reflected earlier-phase studies and caplacizumab’s mechanism of action, Dr. Scully said. Nearly all trial participants experienced at least one treatment-emergent adverse event. Such events led 7% of patients to stop caplacizumab and 12% to stop placebo. Caplacizumab was associated with a range of bleeding-related events, most commonly epistaxis (23.9 vs. 1.4% with placebo), gingival bleeding (11.3% vs. 0%), bruising (7.0% vs. 4.1%), and hematuria (5.6% vs. 1.4%).
Patients in both arms tended to be in their 40s and two-thirds were female. At baseline, about 85% had less than 10% ADAMTS13 activity, and about 40% had severe aTTP (French severity scores of at least 3 or severe neurologic or cardiac involvement).
“Most [66%] patients in the caplacizumab group presented with de novo aTTP, and this is relevant because patients who are in their first episode are much harder to treat,” Dr. Scully said. About half of placebo patients had de novo disease.
In July 2017, caplacizumab received a fast-track designation from the Food and Drug Administration for aTTP after a phase 2 trial showed that platelet counts normalized 39% faster with caplacizumab versus placebo plus standard of care (P = .005). Of eight patients in that study who relapsed within a month of stopping caplacizumab, seven still had less than 10% ADAMTS13 activity, “suggesting unresolved autoimmune activity,” the investigators wrote at the time in the New England Journal of Medicine (2016;374:511-22).
Dr. Scully reported similar findings in the phase 3 HERCULES trial, noting that all patients had ADAMTS13 levels less than 5% on stopping caplacizumab.
Ablynx provided funding for the study. Dr. Scully reported financial relationships with Ablynx, Shire, Novartis, and Alexion.
SOURCE: Scully M et al., ASH 2017 Abstract LBA-1.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The rate of platelet normalization was 55% faster for caplacizumab vs. placebo plus standard of care (platelet normalization rate ratio, 1.55; P less than .01).
Study details: A randomized double-blind phase 3 trial of 145 patients.
Disclosures: Ablynx provided funding for the study. Dr. Scully reported financial relationships with Ablynx, Shire, Novartis, and Alexion.
Source: Scully M et al. ASH 2017 Abstract LBA-1.