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CGRP Monoclonal Antibodies May Be Beneficial for Migraine Prevention
BOSTON—A new class of drugs for the prevention of chronic and episodic migraine demonstrated promising results in recent phase II and phase III trials. Data for four humanized calcitonin gene–related peptide (CGRP) monoclonal antibodies—eptinezumab, erenumab, fremanezumab, and galcanezumab—were presented at the 59th Annual Scientific Meeting of the American Headache Society. Previous research has long implicated CGRP (which is elevated in jugular vein blood during acute migraine and cluster headaches) in disease pathophysiology. Recent advances in molecular neuroscience have helped shed further light on the pathogenic mechanisms and possible targets for treatment.
Eptinezumab
In a phase II study, a single infusion of eptinezumab (which Alder BioPharmaceuticals is developing under the name ALD403) reduced the number of migraine days per month, as well as the number of migraines classified as severe, in patients with chronic migraine. Of the four drugs presented at the meeting, eptinezumab was the only one to have an IV mode of delivery.
“We used International Classification of Headache Disorders 3 criteria to define chronic migraine, which is at least 15 headache days per month, of which eight must be migraine-like,” said Jeffrey T. L. Smith, MD, Senior Vice President of Translational Medicine at Alder BioPharmaceuticals in Bothell, Washington. “Patients also had to have a history of migraine for a year or more.”
On average, the patients included in this multisite study were slightly younger than 40. Most patients were women, and the average number of migraine days was between 16.2 and 16.5. After a one-month run-in period, patients were randomized to receive placebo or one of four doses of eptinezumab (ie, 300 mg, 100 mg, 30 mg, or 10 mg).
Reporting 12-week data from the 48-week trial, Dr. Smith and colleagues found that significantly more patients taking the 300-mg (33%) and 100-mg (31%) doses of eptinezumab reached the primary end point of a 75% reduction from baseline in migraine days, compared with patients who received placebo (21%). Differences in patients taking the 30-mg and 10-mg doses (28% and 27%, respectively) were not statistically significant. “Overall, approximately half of patients treated with eptinezumab experienced a 50% reduction in migraine days versus 41% of patients on placebo,” Dr. Smith added. Eptinezumab was well tolerated, and no serious adverse events were reported.
Post hoc analyses indicated that of the migraines that were not eliminated as a result of treatment, the percentage classified as severe was significantly reduced from baseline in each of the eptinezumab groups, compared with placebo. Also, fewer patients in the eptinezumab groups than in the placebo group experienced a migraine within the first 24 to 48 hours after infusion. “Although the post hoc results are exploratory, these findings are important as well,” said Dr. Smith. “Other things are happening besides the reduction in migraine frequency that may be of benefit.”
Erenumab
A registration, pivotal study on erenumab for chronic migraine prevention was reported at the meeting. “Unlike eptinezumab, fremanezumab, and galcanezumab, which are monoclonal antibodies against the CGRP ligand, erenumab is an anti-CGRP receptor monoclonal antibody,” said Stewart J. Tepper, MD, Professor of Neurology at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire. Amgen is developing this antibody.
In the 12-week randomized controlled trial, patients were enrolled in the US and around the world, Dr. Tepper noted. He and his colleagues included patients who had 15 or more headache days per month with at least eight days of migraine per month. Patients were excluded if they had experienced treatment failure with more than three classes of preventive agents. Mean age was 40, about 80% of patients were women, and roughly half of patients had previously experienced treatment failure with at least two preventive agents.
A total of 667 patients were randomized 3:2:2 to placebo, erenumab (70 mg), or erenumab (140 mg). Treatment was given monthly via subcutaneous injection. The primary end point was change from baseline in monthly migraine days (MMD). Secondary end points included at least a 50% reduction in MMD, change from baseline in acute migraine-specific medication days, and cumulative headache hours.
In both erenumab groups, patients experienced a mean 6.6-day reduction in MMD from a baseline of 18.0 days, which was significantly different, compared with the 4.2-day reduction seen in the placebo group. Furthermore, a significantly greater proportion of patients in the 70-mg and 140-mg groups (40% and 41%, respectively) experienced at least a 50% reduction in MMD, compared with the placebo group (23%). For the secondary end points, both erenumab groups had significantly greater reductions in acute migraine-specific medication days versus placebo. However, the difference in the reduction of cumulative headache hours did not reach statistical significance. “We speculated that this was because headache hours is a relatively variable end point, and it is collected in differing ways, with wide confidence intervals,” Dr. Tepper said.
The safety profile for both erenumab groups and the placebo group was similar. “No serious adverse events were reported by more than one patient in any treatment arm, and no serious adverse events were considered related to treatment,” he said.
Another erenumab trial enrolled patients with episodic migraine. Randomization was stratified by region and current and prior migraine preventive medication, said Daniel Mikol, MD, PhD, Executive Medical Director of Neuroscience Development at Amgen in Thousand Oaks, California. Patients included in the phase III study could be taking a single concomitant migraine preventive therapy. “Patients could have also failed previous preventive therapies due to poor tolerability or lack of efficacy,” he said. “There was no limit regarding the number of previous failures due to poor tolerability. With regard to lack of efficacy, patients could have no therapeutic response to two or fewer preventive therapies.”
Adults with episodic migraine (n = 955) were randomized 1:1:1 to monthly subcutaneous injections of placebo, erenumab (70 mg), or erenumab (140 mg) for 24 weeks. The primary end point was change from baseline in MMD from weeks 13 to 24. Secondary end points included achievement of 50% or more reduction in MMD, change in mean acute migraine-specific medication days, and changes in mean physical impairment and impact on everyday activity scores, as measured by the Migraine Physical Function Impact Diary, a novel patient-reported instrument, Dr. Mikol explained.
Subjects had a mean of 8.3 MMD at baseline. This measurement was reduced by 3.2, 3.7, and 1.8 days in the 70-mg, 140-mg, and placebo groups, respectively—a statistically significant difference in favor of the erenumab groups. Statistically superior results for erenumab 70 mg and 140 mg over placebo also were seen in the secondary end points of > 50% response (43%, 50%, and 27%, respectively), reduction from baseline in monthly acute migraine-specific medication days (1.1, 1.6, and 0.2), improved physical impairment score from baseline (4.2, 4.8, and 2.5), and improved everyday activity scores from baseline (5.5, 5.9, and 3.3).
“The safety profiles for erenumab were similar to that of placebo,” Dr. Mikol said. “Specifically, 63% of patients on placebo had adverse events, compared with 56% to 57% of patients in the erenumab groups. Serious adverse events and adverse events leading to treatment discontinuation were low in frequency and balanced across the groups.”
Galcanezumab
The efficacy, tolerability, and safety of galcanezumab, an investigational drug for the treatment of episodic migraine, was assessed in a six-month phase III study called EVOLVE-2. In this study, patients with episodic migraine experienced four to 14 migraine headache days per month with or without aura. “Our patient population had a mean age of about 40, and most [participants] were Caucasian women,” said Robert Conley, MD, Distinguished Lilly Scholar of Neuroscience at Eli Lilly and Company (the developer of galcanezumab) in Indianapolis.
“Half of our subjects were from North America, a quarter from Europe, and a quarter from the rest of the world.” Subjects had a 20-year migraine history on average and a mean of nine headache days per month at baseline, he noted. “In addition, two-thirds had been on prior preventive treatment, and they had relatively severe levels of disease.”
After screening 1,700 patients for the study, Dr. Conley and colleagues randomized 914 patients 1:1:2 to subcutaneous injection of galcanezumab (120 mg/month), galcanezumab (240 mg/month), or placebo. “There was about an 87% completion rate for the galcanezumab groups and an 83% completion rate in the placebo group. The higher number of dropouts in the placebo group was due to lack of efficacy,” said Dr. Conley. The primary end point was change from baseline in MMD at the end of six months. Secondary end points were percentages of patients with 50%, 75%, and 100% response rates; reduction in MMD requiring acute migraine medication; change in function score on the Migraine-Specific Quality of Life Questionnaire (MSQ); and change in the Patient Global Impression of Severity (PGI-S) rating.
After adjusting for multiplicity, the investigators found statistically significant differences between placebo and the galcanezumab arms in the primary end point. Mean reductions in headache days were 4.29 in the 120-mg group and 4.18 in the 240-mg group. Patients in the placebo group experienced a reduction of 2.28 days. “We looked at the early effects of treatment and found statistically significant improvements within a few days of injection that persisted over time,” Dr. Conley said.
In addition, statistically significant differences between galcanezumab and placebo were observed for all secondary end points. “In the 120-mg and 240-mg treatment groups, 59.3% and 56.5%, respectively, had at least a 50% reduction in monthly headache days, which was significantly different from placebo, but not different from each other,” said Dr. Conley. “We also saw that approximately one-third of patients in the galcanezumab arms experienced 75% response rates, which is double that seen in the placebo group. The 100% response rate was 11.5% to 13.8% in the treated groups—again, not a significant difference between them, but significantly different from placebo.” The change in the MSQ function score and the PGI-S rating averaged for months 4, 5, and 6 were significantly improved in the galcanezumab arms, compared with the placebo arm.
For most of the safety parameters, there were no significant differences between either dose of galcanezumab and placebo. However, the rates of injection-site reactions and pruritus were significantly higher for both drug doses, compared with placebo. Injection-site erythema was significantly higher in the 240-mg dose only.
Fremanezumab
“The phase III trial for fremanezumab in chronic migraine investigated a flexible dose for a quarterly and a monthly regimen,” said Ernesto Aycardi, MD, Vice President and Therapeutic Area Head for Migraine and Headache at Teva Pharmaceuticals
The primary end point of this multicenter trial was the mean change from baseline in monthly days of headache of at least moderate severity. The four main secondary end points were the proportion of patients with at least a 50% reduction in headache days, mean change in the number of days using acute headache medication at the end of the 12-week period of the trial, mean change from baseline in the days of at least moderate severity in the first four weeks of the trial, and change in disability scale (HIT-6) score from baseline. In this trial, patients treated with fremanezumab experienced significant improvement, compared with placebo on all primary and secondary end points for both monthly and quarterly dosing regimens.
“The average age of the study population was 41, with an average history of migraine of about 20 years,” Dr. Aycardi said. “All demographic characteristics, including weight, height, and ethnicity, were well balanced between the groups.”
Patients on the monthly regimen had a mean reduction of 4.6 headache days of at least moderate severity, and patients on the quarterly regimen had a reduction of 4.3 headache days of at least moderate severity, which was significantly different from the placebo group (2.5 headache days). Researchers also observed significant differences for each of the four secondary end points in favor of the monthly and quarterly regimens.
“Fremanezumab was well tolerated, compared with placebo,” Dr. Aycardi said. “The most commonly reported adverse event in the study was injection-site pain, with similar rates in the placebo and active groups.”
Dr. Aycardi highlighted how phase II results validated that target in chronic migraine. “With these phase III results, this is confirmed, bringing hope for patients with this disabling condition.”
—Adriene Marshall
Suggested Reading
Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006;46(Suppl 1):S3–S8.
Reuter U. Anti-CGRP antibodies: a new approach to migraine prevention. Lancet Neurol. 2014;13(9):857-859.
Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434.
BOSTON—A new class of drugs for the prevention of chronic and episodic migraine demonstrated promising results in recent phase II and phase III trials. Data for four humanized calcitonin gene–related peptide (CGRP) monoclonal antibodies—eptinezumab, erenumab, fremanezumab, and galcanezumab—were presented at the 59th Annual Scientific Meeting of the American Headache Society. Previous research has long implicated CGRP (which is elevated in jugular vein blood during acute migraine and cluster headaches) in disease pathophysiology. Recent advances in molecular neuroscience have helped shed further light on the pathogenic mechanisms and possible targets for treatment.
Eptinezumab
In a phase II study, a single infusion of eptinezumab (which Alder BioPharmaceuticals is developing under the name ALD403) reduced the number of migraine days per month, as well as the number of migraines classified as severe, in patients with chronic migraine. Of the four drugs presented at the meeting, eptinezumab was the only one to have an IV mode of delivery.
“We used International Classification of Headache Disorders 3 criteria to define chronic migraine, which is at least 15 headache days per month, of which eight must be migraine-like,” said Jeffrey T. L. Smith, MD, Senior Vice President of Translational Medicine at Alder BioPharmaceuticals in Bothell, Washington. “Patients also had to have a history of migraine for a year or more.”
On average, the patients included in this multisite study were slightly younger than 40. Most patients were women, and the average number of migraine days was between 16.2 and 16.5. After a one-month run-in period, patients were randomized to receive placebo or one of four doses of eptinezumab (ie, 300 mg, 100 mg, 30 mg, or 10 mg).
Reporting 12-week data from the 48-week trial, Dr. Smith and colleagues found that significantly more patients taking the 300-mg (33%) and 100-mg (31%) doses of eptinezumab reached the primary end point of a 75% reduction from baseline in migraine days, compared with patients who received placebo (21%). Differences in patients taking the 30-mg and 10-mg doses (28% and 27%, respectively) were not statistically significant. “Overall, approximately half of patients treated with eptinezumab experienced a 50% reduction in migraine days versus 41% of patients on placebo,” Dr. Smith added. Eptinezumab was well tolerated, and no serious adverse events were reported.
Post hoc analyses indicated that of the migraines that were not eliminated as a result of treatment, the percentage classified as severe was significantly reduced from baseline in each of the eptinezumab groups, compared with placebo. Also, fewer patients in the eptinezumab groups than in the placebo group experienced a migraine within the first 24 to 48 hours after infusion. “Although the post hoc results are exploratory, these findings are important as well,” said Dr. Smith. “Other things are happening besides the reduction in migraine frequency that may be of benefit.”
Erenumab
A registration, pivotal study on erenumab for chronic migraine prevention was reported at the meeting. “Unlike eptinezumab, fremanezumab, and galcanezumab, which are monoclonal antibodies against the CGRP ligand, erenumab is an anti-CGRP receptor monoclonal antibody,” said Stewart J. Tepper, MD, Professor of Neurology at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire. Amgen is developing this antibody.
In the 12-week randomized controlled trial, patients were enrolled in the US and around the world, Dr. Tepper noted. He and his colleagues included patients who had 15 or more headache days per month with at least eight days of migraine per month. Patients were excluded if they had experienced treatment failure with more than three classes of preventive agents. Mean age was 40, about 80% of patients were women, and roughly half of patients had previously experienced treatment failure with at least two preventive agents.
A total of 667 patients were randomized 3:2:2 to placebo, erenumab (70 mg), or erenumab (140 mg). Treatment was given monthly via subcutaneous injection. The primary end point was change from baseline in monthly migraine days (MMD). Secondary end points included at least a 50% reduction in MMD, change from baseline in acute migraine-specific medication days, and cumulative headache hours.
In both erenumab groups, patients experienced a mean 6.6-day reduction in MMD from a baseline of 18.0 days, which was significantly different, compared with the 4.2-day reduction seen in the placebo group. Furthermore, a significantly greater proportion of patients in the 70-mg and 140-mg groups (40% and 41%, respectively) experienced at least a 50% reduction in MMD, compared with the placebo group (23%). For the secondary end points, both erenumab groups had significantly greater reductions in acute migraine-specific medication days versus placebo. However, the difference in the reduction of cumulative headache hours did not reach statistical significance. “We speculated that this was because headache hours is a relatively variable end point, and it is collected in differing ways, with wide confidence intervals,” Dr. Tepper said.
The safety profile for both erenumab groups and the placebo group was similar. “No serious adverse events were reported by more than one patient in any treatment arm, and no serious adverse events were considered related to treatment,” he said.
Another erenumab trial enrolled patients with episodic migraine. Randomization was stratified by region and current and prior migraine preventive medication, said Daniel Mikol, MD, PhD, Executive Medical Director of Neuroscience Development at Amgen in Thousand Oaks, California. Patients included in the phase III study could be taking a single concomitant migraine preventive therapy. “Patients could have also failed previous preventive therapies due to poor tolerability or lack of efficacy,” he said. “There was no limit regarding the number of previous failures due to poor tolerability. With regard to lack of efficacy, patients could have no therapeutic response to two or fewer preventive therapies.”
Adults with episodic migraine (n = 955) were randomized 1:1:1 to monthly subcutaneous injections of placebo, erenumab (70 mg), or erenumab (140 mg) for 24 weeks. The primary end point was change from baseline in MMD from weeks 13 to 24. Secondary end points included achievement of 50% or more reduction in MMD, change in mean acute migraine-specific medication days, and changes in mean physical impairment and impact on everyday activity scores, as measured by the Migraine Physical Function Impact Diary, a novel patient-reported instrument, Dr. Mikol explained.
Subjects had a mean of 8.3 MMD at baseline. This measurement was reduced by 3.2, 3.7, and 1.8 days in the 70-mg, 140-mg, and placebo groups, respectively—a statistically significant difference in favor of the erenumab groups. Statistically superior results for erenumab 70 mg and 140 mg over placebo also were seen in the secondary end points of > 50% response (43%, 50%, and 27%, respectively), reduction from baseline in monthly acute migraine-specific medication days (1.1, 1.6, and 0.2), improved physical impairment score from baseline (4.2, 4.8, and 2.5), and improved everyday activity scores from baseline (5.5, 5.9, and 3.3).
“The safety profiles for erenumab were similar to that of placebo,” Dr. Mikol said. “Specifically, 63% of patients on placebo had adverse events, compared with 56% to 57% of patients in the erenumab groups. Serious adverse events and adverse events leading to treatment discontinuation were low in frequency and balanced across the groups.”
Galcanezumab
The efficacy, tolerability, and safety of galcanezumab, an investigational drug for the treatment of episodic migraine, was assessed in a six-month phase III study called EVOLVE-2. In this study, patients with episodic migraine experienced four to 14 migraine headache days per month with or without aura. “Our patient population had a mean age of about 40, and most [participants] were Caucasian women,” said Robert Conley, MD, Distinguished Lilly Scholar of Neuroscience at Eli Lilly and Company (the developer of galcanezumab) in Indianapolis.
“Half of our subjects were from North America, a quarter from Europe, and a quarter from the rest of the world.” Subjects had a 20-year migraine history on average and a mean of nine headache days per month at baseline, he noted. “In addition, two-thirds had been on prior preventive treatment, and they had relatively severe levels of disease.”
After screening 1,700 patients for the study, Dr. Conley and colleagues randomized 914 patients 1:1:2 to subcutaneous injection of galcanezumab (120 mg/month), galcanezumab (240 mg/month), or placebo. “There was about an 87% completion rate for the galcanezumab groups and an 83% completion rate in the placebo group. The higher number of dropouts in the placebo group was due to lack of efficacy,” said Dr. Conley. The primary end point was change from baseline in MMD at the end of six months. Secondary end points were percentages of patients with 50%, 75%, and 100% response rates; reduction in MMD requiring acute migraine medication; change in function score on the Migraine-Specific Quality of Life Questionnaire (MSQ); and change in the Patient Global Impression of Severity (PGI-S) rating.
After adjusting for multiplicity, the investigators found statistically significant differences between placebo and the galcanezumab arms in the primary end point. Mean reductions in headache days were 4.29 in the 120-mg group and 4.18 in the 240-mg group. Patients in the placebo group experienced a reduction of 2.28 days. “We looked at the early effects of treatment and found statistically significant improvements within a few days of injection that persisted over time,” Dr. Conley said.
In addition, statistically significant differences between galcanezumab and placebo were observed for all secondary end points. “In the 120-mg and 240-mg treatment groups, 59.3% and 56.5%, respectively, had at least a 50% reduction in monthly headache days, which was significantly different from placebo, but not different from each other,” said Dr. Conley. “We also saw that approximately one-third of patients in the galcanezumab arms experienced 75% response rates, which is double that seen in the placebo group. The 100% response rate was 11.5% to 13.8% in the treated groups—again, not a significant difference between them, but significantly different from placebo.” The change in the MSQ function score and the PGI-S rating averaged for months 4, 5, and 6 were significantly improved in the galcanezumab arms, compared with the placebo arm.
For most of the safety parameters, there were no significant differences between either dose of galcanezumab and placebo. However, the rates of injection-site reactions and pruritus were significantly higher for both drug doses, compared with placebo. Injection-site erythema was significantly higher in the 240-mg dose only.
Fremanezumab
“The phase III trial for fremanezumab in chronic migraine investigated a flexible dose for a quarterly and a monthly regimen,” said Ernesto Aycardi, MD, Vice President and Therapeutic Area Head for Migraine and Headache at Teva Pharmaceuticals
The primary end point of this multicenter trial was the mean change from baseline in monthly days of headache of at least moderate severity. The four main secondary end points were the proportion of patients with at least a 50% reduction in headache days, mean change in the number of days using acute headache medication at the end of the 12-week period of the trial, mean change from baseline in the days of at least moderate severity in the first four weeks of the trial, and change in disability scale (HIT-6) score from baseline. In this trial, patients treated with fremanezumab experienced significant improvement, compared with placebo on all primary and secondary end points for both monthly and quarterly dosing regimens.
“The average age of the study population was 41, with an average history of migraine of about 20 years,” Dr. Aycardi said. “All demographic characteristics, including weight, height, and ethnicity, were well balanced between the groups.”
Patients on the monthly regimen had a mean reduction of 4.6 headache days of at least moderate severity, and patients on the quarterly regimen had a reduction of 4.3 headache days of at least moderate severity, which was significantly different from the placebo group (2.5 headache days). Researchers also observed significant differences for each of the four secondary end points in favor of the monthly and quarterly regimens.
“Fremanezumab was well tolerated, compared with placebo,” Dr. Aycardi said. “The most commonly reported adverse event in the study was injection-site pain, with similar rates in the placebo and active groups.”
Dr. Aycardi highlighted how phase II results validated that target in chronic migraine. “With these phase III results, this is confirmed, bringing hope for patients with this disabling condition.”
—Adriene Marshall
Suggested Reading
Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006;46(Suppl 1):S3–S8.
Reuter U. Anti-CGRP antibodies: a new approach to migraine prevention. Lancet Neurol. 2014;13(9):857-859.
Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434.
BOSTON—A new class of drugs for the prevention of chronic and episodic migraine demonstrated promising results in recent phase II and phase III trials. Data for four humanized calcitonin gene–related peptide (CGRP) monoclonal antibodies—eptinezumab, erenumab, fremanezumab, and galcanezumab—were presented at the 59th Annual Scientific Meeting of the American Headache Society. Previous research has long implicated CGRP (which is elevated in jugular vein blood during acute migraine and cluster headaches) in disease pathophysiology. Recent advances in molecular neuroscience have helped shed further light on the pathogenic mechanisms and possible targets for treatment.
Eptinezumab
In a phase II study, a single infusion of eptinezumab (which Alder BioPharmaceuticals is developing under the name ALD403) reduced the number of migraine days per month, as well as the number of migraines classified as severe, in patients with chronic migraine. Of the four drugs presented at the meeting, eptinezumab was the only one to have an IV mode of delivery.
“We used International Classification of Headache Disorders 3 criteria to define chronic migraine, which is at least 15 headache days per month, of which eight must be migraine-like,” said Jeffrey T. L. Smith, MD, Senior Vice President of Translational Medicine at Alder BioPharmaceuticals in Bothell, Washington. “Patients also had to have a history of migraine for a year or more.”
On average, the patients included in this multisite study were slightly younger than 40. Most patients were women, and the average number of migraine days was between 16.2 and 16.5. After a one-month run-in period, patients were randomized to receive placebo or one of four doses of eptinezumab (ie, 300 mg, 100 mg, 30 mg, or 10 mg).
Reporting 12-week data from the 48-week trial, Dr. Smith and colleagues found that significantly more patients taking the 300-mg (33%) and 100-mg (31%) doses of eptinezumab reached the primary end point of a 75% reduction from baseline in migraine days, compared with patients who received placebo (21%). Differences in patients taking the 30-mg and 10-mg doses (28% and 27%, respectively) were not statistically significant. “Overall, approximately half of patients treated with eptinezumab experienced a 50% reduction in migraine days versus 41% of patients on placebo,” Dr. Smith added. Eptinezumab was well tolerated, and no serious adverse events were reported.
Post hoc analyses indicated that of the migraines that were not eliminated as a result of treatment, the percentage classified as severe was significantly reduced from baseline in each of the eptinezumab groups, compared with placebo. Also, fewer patients in the eptinezumab groups than in the placebo group experienced a migraine within the first 24 to 48 hours after infusion. “Although the post hoc results are exploratory, these findings are important as well,” said Dr. Smith. “Other things are happening besides the reduction in migraine frequency that may be of benefit.”
Erenumab
A registration, pivotal study on erenumab for chronic migraine prevention was reported at the meeting. “Unlike eptinezumab, fremanezumab, and galcanezumab, which are monoclonal antibodies against the CGRP ligand, erenumab is an anti-CGRP receptor monoclonal antibody,” said Stewart J. Tepper, MD, Professor of Neurology at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire. Amgen is developing this antibody.
In the 12-week randomized controlled trial, patients were enrolled in the US and around the world, Dr. Tepper noted. He and his colleagues included patients who had 15 or more headache days per month with at least eight days of migraine per month. Patients were excluded if they had experienced treatment failure with more than three classes of preventive agents. Mean age was 40, about 80% of patients were women, and roughly half of patients had previously experienced treatment failure with at least two preventive agents.
A total of 667 patients were randomized 3:2:2 to placebo, erenumab (70 mg), or erenumab (140 mg). Treatment was given monthly via subcutaneous injection. The primary end point was change from baseline in monthly migraine days (MMD). Secondary end points included at least a 50% reduction in MMD, change from baseline in acute migraine-specific medication days, and cumulative headache hours.
In both erenumab groups, patients experienced a mean 6.6-day reduction in MMD from a baseline of 18.0 days, which was significantly different, compared with the 4.2-day reduction seen in the placebo group. Furthermore, a significantly greater proportion of patients in the 70-mg and 140-mg groups (40% and 41%, respectively) experienced at least a 50% reduction in MMD, compared with the placebo group (23%). For the secondary end points, both erenumab groups had significantly greater reductions in acute migraine-specific medication days versus placebo. However, the difference in the reduction of cumulative headache hours did not reach statistical significance. “We speculated that this was because headache hours is a relatively variable end point, and it is collected in differing ways, with wide confidence intervals,” Dr. Tepper said.
The safety profile for both erenumab groups and the placebo group was similar. “No serious adverse events were reported by more than one patient in any treatment arm, and no serious adverse events were considered related to treatment,” he said.
Another erenumab trial enrolled patients with episodic migraine. Randomization was stratified by region and current and prior migraine preventive medication, said Daniel Mikol, MD, PhD, Executive Medical Director of Neuroscience Development at Amgen in Thousand Oaks, California. Patients included in the phase III study could be taking a single concomitant migraine preventive therapy. “Patients could have also failed previous preventive therapies due to poor tolerability or lack of efficacy,” he said. “There was no limit regarding the number of previous failures due to poor tolerability. With regard to lack of efficacy, patients could have no therapeutic response to two or fewer preventive therapies.”
Adults with episodic migraine (n = 955) were randomized 1:1:1 to monthly subcutaneous injections of placebo, erenumab (70 mg), or erenumab (140 mg) for 24 weeks. The primary end point was change from baseline in MMD from weeks 13 to 24. Secondary end points included achievement of 50% or more reduction in MMD, change in mean acute migraine-specific medication days, and changes in mean physical impairment and impact on everyday activity scores, as measured by the Migraine Physical Function Impact Diary, a novel patient-reported instrument, Dr. Mikol explained.
Subjects had a mean of 8.3 MMD at baseline. This measurement was reduced by 3.2, 3.7, and 1.8 days in the 70-mg, 140-mg, and placebo groups, respectively—a statistically significant difference in favor of the erenumab groups. Statistically superior results for erenumab 70 mg and 140 mg over placebo also were seen in the secondary end points of > 50% response (43%, 50%, and 27%, respectively), reduction from baseline in monthly acute migraine-specific medication days (1.1, 1.6, and 0.2), improved physical impairment score from baseline (4.2, 4.8, and 2.5), and improved everyday activity scores from baseline (5.5, 5.9, and 3.3).
“The safety profiles for erenumab were similar to that of placebo,” Dr. Mikol said. “Specifically, 63% of patients on placebo had adverse events, compared with 56% to 57% of patients in the erenumab groups. Serious adverse events and adverse events leading to treatment discontinuation were low in frequency and balanced across the groups.”
Galcanezumab
The efficacy, tolerability, and safety of galcanezumab, an investigational drug for the treatment of episodic migraine, was assessed in a six-month phase III study called EVOLVE-2. In this study, patients with episodic migraine experienced four to 14 migraine headache days per month with or without aura. “Our patient population had a mean age of about 40, and most [participants] were Caucasian women,” said Robert Conley, MD, Distinguished Lilly Scholar of Neuroscience at Eli Lilly and Company (the developer of galcanezumab) in Indianapolis.
“Half of our subjects were from North America, a quarter from Europe, and a quarter from the rest of the world.” Subjects had a 20-year migraine history on average and a mean of nine headache days per month at baseline, he noted. “In addition, two-thirds had been on prior preventive treatment, and they had relatively severe levels of disease.”
After screening 1,700 patients for the study, Dr. Conley and colleagues randomized 914 patients 1:1:2 to subcutaneous injection of galcanezumab (120 mg/month), galcanezumab (240 mg/month), or placebo. “There was about an 87% completion rate for the galcanezumab groups and an 83% completion rate in the placebo group. The higher number of dropouts in the placebo group was due to lack of efficacy,” said Dr. Conley. The primary end point was change from baseline in MMD at the end of six months. Secondary end points were percentages of patients with 50%, 75%, and 100% response rates; reduction in MMD requiring acute migraine medication; change in function score on the Migraine-Specific Quality of Life Questionnaire (MSQ); and change in the Patient Global Impression of Severity (PGI-S) rating.
After adjusting for multiplicity, the investigators found statistically significant differences between placebo and the galcanezumab arms in the primary end point. Mean reductions in headache days were 4.29 in the 120-mg group and 4.18 in the 240-mg group. Patients in the placebo group experienced a reduction of 2.28 days. “We looked at the early effects of treatment and found statistically significant improvements within a few days of injection that persisted over time,” Dr. Conley said.
In addition, statistically significant differences between galcanezumab and placebo were observed for all secondary end points. “In the 120-mg and 240-mg treatment groups, 59.3% and 56.5%, respectively, had at least a 50% reduction in monthly headache days, which was significantly different from placebo, but not different from each other,” said Dr. Conley. “We also saw that approximately one-third of patients in the galcanezumab arms experienced 75% response rates, which is double that seen in the placebo group. The 100% response rate was 11.5% to 13.8% in the treated groups—again, not a significant difference between them, but significantly different from placebo.” The change in the MSQ function score and the PGI-S rating averaged for months 4, 5, and 6 were significantly improved in the galcanezumab arms, compared with the placebo arm.
For most of the safety parameters, there were no significant differences between either dose of galcanezumab and placebo. However, the rates of injection-site reactions and pruritus were significantly higher for both drug doses, compared with placebo. Injection-site erythema was significantly higher in the 240-mg dose only.
Fremanezumab
“The phase III trial for fremanezumab in chronic migraine investigated a flexible dose for a quarterly and a monthly regimen,” said Ernesto Aycardi, MD, Vice President and Therapeutic Area Head for Migraine and Headache at Teva Pharmaceuticals
The primary end point of this multicenter trial was the mean change from baseline in monthly days of headache of at least moderate severity. The four main secondary end points were the proportion of patients with at least a 50% reduction in headache days, mean change in the number of days using acute headache medication at the end of the 12-week period of the trial, mean change from baseline in the days of at least moderate severity in the first four weeks of the trial, and change in disability scale (HIT-6) score from baseline. In this trial, patients treated with fremanezumab experienced significant improvement, compared with placebo on all primary and secondary end points for both monthly and quarterly dosing regimens.
“The average age of the study population was 41, with an average history of migraine of about 20 years,” Dr. Aycardi said. “All demographic characteristics, including weight, height, and ethnicity, were well balanced between the groups.”
Patients on the monthly regimen had a mean reduction of 4.6 headache days of at least moderate severity, and patients on the quarterly regimen had a reduction of 4.3 headache days of at least moderate severity, which was significantly different from the placebo group (2.5 headache days). Researchers also observed significant differences for each of the four secondary end points in favor of the monthly and quarterly regimens.
“Fremanezumab was well tolerated, compared with placebo,” Dr. Aycardi said. “The most commonly reported adverse event in the study was injection-site pain, with similar rates in the placebo and active groups.”
Dr. Aycardi highlighted how phase II results validated that target in chronic migraine. “With these phase III results, this is confirmed, bringing hope for patients with this disabling condition.”
—Adriene Marshall
Suggested Reading
Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006;46(Suppl 1):S3–S8.
Reuter U. Anti-CGRP antibodies: a new approach to migraine prevention. Lancet Neurol. 2014;13(9):857-859.
Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434.
Hidden CABG costs will disrupt bundled payment systems
COLORADO SPRINGS – With bundled payment models for coronary artery bypass graft surgery looming ahead, it’s vital that cardiac surgeons take a hard look at the procedure’s hidden costs – namely, the steep price tag for postoperative complications, James H. Mehaffey, MD, said at the annual meeting of the Western Thoracic Surgical Association.
He presented a retrospective study of the 30-day hospital costs for all 36,588 patients who underwent isolated CABG during 2006-2015 at the 19 Virginia centers where the surgery is performed. This was a typical CABG population, with an average predicted risk of mortality of 1.9%. The actual 30-day mortality was 0.6%, so the surgical performance was better than expected.
“The population of patients experiencing one or more major comorbidities demonstrated a significant and dramatic increase in total hospital costs. It was an exponential increase with each additional major morbidity,” reported Dr. Mehaffey of the University of Virginia, Charlottesville.
Indeed, the average cost jumped from $36,580 for uncomplicated surgery to $64,542 with one major complication, $111,239 with two, and $194,043 with three.
The two most frequent major complications were postoperative atrial fibrillation, which occurred in 18.4% of patients, and prolonged ventilation for longer than 24 hours, which occurred in 9%. Over the course of the decade-long study period, the 19 medical centers in the Virginia Cardiac Surgery Quality Initiative collectively spent roughly $59 million on prolonged ventilation and $27 million for postoperative atrial fibrillation.
The cost of CABG during the study years outpaced the CMS health care–specific inflation rate, and this escalating cost was driven primarily by postoperative complications.
For the Virginia cardiac surgery collaborative, these data on the cost of postoperative complications will be utilized to prioritize quality improvement projects.
For example, during the past decade, the Virginia collaborative made reduction in the rate of postoperative atrial fibrillation a priority. Toward that end, the collaborative developed a protocol for routine perioperative prophylactic amiodarone therapy.
“At the beginning of the study decade we had postoperative atrial fibrillation rates above 25%. The average for the entire decade was just over 18%, and in the last couple years we’ve been in the 15%-16% range. So I think we are moving the needle on this. We are making a meaningful impact,” Dr. Mehaffey said.
“We’ve already used the complication cost data to do a cost-effectiveness analysis of our prophylactic amiodarone innovation. We showed we saved an average of $250 per patient, even though we’re treating a bunch of patients who’d never get that complication,” he continued.
This sort of data on the cost of adverse events is also critical to accurately risk-adjust bundled payment models.
Discussant Richard J. Shemin, MD, asked if there was much variability in postoperative complication costs between the CABG centers in the Virginia collaborative.
The variability is enormous, Dr. Mehaffey replied. Investigators recently plugged the last 5 years worth of hospital cost and complication rate data into a proposed CABG bundled payment model and extrapolated what that would mean over the next 5 years.
“There were some institutions that would be positive by a couple million dollars from this payment system and some that were losing more than $20 million, just because of the cost variability,” said Dr. Mehaffey.
Dr. Shemin also noted that the Virginia collaborative was able to collect 30-day outcome data only through the STS database, yet the bundled payment programs are based on the 90-day postoperative experience.
“How do we capture the costs in that full 90 days that we’ll be responsible for?” asked Dr. Shemin, professor of surgery and codirector of the UCLA Cardiovascular Center.
Dr. Mehaffey said that’s indeed an important question, since a major complication such as stroke or deep sternal wound infection typically entails considerable long-term costs and repeated hospital admissions beyond the 30-day window. In Virginia, the cardiac surgery collaborative is working with payers to gain access to the 90 days worth of patient data.
He reported having no financial conflicts regarding his study.
COLORADO SPRINGS – With bundled payment models for coronary artery bypass graft surgery looming ahead, it’s vital that cardiac surgeons take a hard look at the procedure’s hidden costs – namely, the steep price tag for postoperative complications, James H. Mehaffey, MD, said at the annual meeting of the Western Thoracic Surgical Association.
He presented a retrospective study of the 30-day hospital costs for all 36,588 patients who underwent isolated CABG during 2006-2015 at the 19 Virginia centers where the surgery is performed. This was a typical CABG population, with an average predicted risk of mortality of 1.9%. The actual 30-day mortality was 0.6%, so the surgical performance was better than expected.
“The population of patients experiencing one or more major comorbidities demonstrated a significant and dramatic increase in total hospital costs. It was an exponential increase with each additional major morbidity,” reported Dr. Mehaffey of the University of Virginia, Charlottesville.
Indeed, the average cost jumped from $36,580 for uncomplicated surgery to $64,542 with one major complication, $111,239 with two, and $194,043 with three.
The two most frequent major complications were postoperative atrial fibrillation, which occurred in 18.4% of patients, and prolonged ventilation for longer than 24 hours, which occurred in 9%. Over the course of the decade-long study period, the 19 medical centers in the Virginia Cardiac Surgery Quality Initiative collectively spent roughly $59 million on prolonged ventilation and $27 million for postoperative atrial fibrillation.
The cost of CABG during the study years outpaced the CMS health care–specific inflation rate, and this escalating cost was driven primarily by postoperative complications.
For the Virginia cardiac surgery collaborative, these data on the cost of postoperative complications will be utilized to prioritize quality improvement projects.
For example, during the past decade, the Virginia collaborative made reduction in the rate of postoperative atrial fibrillation a priority. Toward that end, the collaborative developed a protocol for routine perioperative prophylactic amiodarone therapy.
“At the beginning of the study decade we had postoperative atrial fibrillation rates above 25%. The average for the entire decade was just over 18%, and in the last couple years we’ve been in the 15%-16% range. So I think we are moving the needle on this. We are making a meaningful impact,” Dr. Mehaffey said.
“We’ve already used the complication cost data to do a cost-effectiveness analysis of our prophylactic amiodarone innovation. We showed we saved an average of $250 per patient, even though we’re treating a bunch of patients who’d never get that complication,” he continued.
This sort of data on the cost of adverse events is also critical to accurately risk-adjust bundled payment models.
Discussant Richard J. Shemin, MD, asked if there was much variability in postoperative complication costs between the CABG centers in the Virginia collaborative.
The variability is enormous, Dr. Mehaffey replied. Investigators recently plugged the last 5 years worth of hospital cost and complication rate data into a proposed CABG bundled payment model and extrapolated what that would mean over the next 5 years.
“There were some institutions that would be positive by a couple million dollars from this payment system and some that were losing more than $20 million, just because of the cost variability,” said Dr. Mehaffey.
Dr. Shemin also noted that the Virginia collaborative was able to collect 30-day outcome data only through the STS database, yet the bundled payment programs are based on the 90-day postoperative experience.
“How do we capture the costs in that full 90 days that we’ll be responsible for?” asked Dr. Shemin, professor of surgery and codirector of the UCLA Cardiovascular Center.
Dr. Mehaffey said that’s indeed an important question, since a major complication such as stroke or deep sternal wound infection typically entails considerable long-term costs and repeated hospital admissions beyond the 30-day window. In Virginia, the cardiac surgery collaborative is working with payers to gain access to the 90 days worth of patient data.
He reported having no financial conflicts regarding his study.
COLORADO SPRINGS – With bundled payment models for coronary artery bypass graft surgery looming ahead, it’s vital that cardiac surgeons take a hard look at the procedure’s hidden costs – namely, the steep price tag for postoperative complications, James H. Mehaffey, MD, said at the annual meeting of the Western Thoracic Surgical Association.
He presented a retrospective study of the 30-day hospital costs for all 36,588 patients who underwent isolated CABG during 2006-2015 at the 19 Virginia centers where the surgery is performed. This was a typical CABG population, with an average predicted risk of mortality of 1.9%. The actual 30-day mortality was 0.6%, so the surgical performance was better than expected.
“The population of patients experiencing one or more major comorbidities demonstrated a significant and dramatic increase in total hospital costs. It was an exponential increase with each additional major morbidity,” reported Dr. Mehaffey of the University of Virginia, Charlottesville.
Indeed, the average cost jumped from $36,580 for uncomplicated surgery to $64,542 with one major complication, $111,239 with two, and $194,043 with three.
The two most frequent major complications were postoperative atrial fibrillation, which occurred in 18.4% of patients, and prolonged ventilation for longer than 24 hours, which occurred in 9%. Over the course of the decade-long study period, the 19 medical centers in the Virginia Cardiac Surgery Quality Initiative collectively spent roughly $59 million on prolonged ventilation and $27 million for postoperative atrial fibrillation.
The cost of CABG during the study years outpaced the CMS health care–specific inflation rate, and this escalating cost was driven primarily by postoperative complications.
For the Virginia cardiac surgery collaborative, these data on the cost of postoperative complications will be utilized to prioritize quality improvement projects.
For example, during the past decade, the Virginia collaborative made reduction in the rate of postoperative atrial fibrillation a priority. Toward that end, the collaborative developed a protocol for routine perioperative prophylactic amiodarone therapy.
“At the beginning of the study decade we had postoperative atrial fibrillation rates above 25%. The average for the entire decade was just over 18%, and in the last couple years we’ve been in the 15%-16% range. So I think we are moving the needle on this. We are making a meaningful impact,” Dr. Mehaffey said.
“We’ve already used the complication cost data to do a cost-effectiveness analysis of our prophylactic amiodarone innovation. We showed we saved an average of $250 per patient, even though we’re treating a bunch of patients who’d never get that complication,” he continued.
This sort of data on the cost of adverse events is also critical to accurately risk-adjust bundled payment models.
Discussant Richard J. Shemin, MD, asked if there was much variability in postoperative complication costs between the CABG centers in the Virginia collaborative.
The variability is enormous, Dr. Mehaffey replied. Investigators recently plugged the last 5 years worth of hospital cost and complication rate data into a proposed CABG bundled payment model and extrapolated what that would mean over the next 5 years.
“There were some institutions that would be positive by a couple million dollars from this payment system and some that were losing more than $20 million, just because of the cost variability,” said Dr. Mehaffey.
Dr. Shemin also noted that the Virginia collaborative was able to collect 30-day outcome data only through the STS database, yet the bundled payment programs are based on the 90-day postoperative experience.
“How do we capture the costs in that full 90 days that we’ll be responsible for?” asked Dr. Shemin, professor of surgery and codirector of the UCLA Cardiovascular Center.
Dr. Mehaffey said that’s indeed an important question, since a major complication such as stroke or deep sternal wound infection typically entails considerable long-term costs and repeated hospital admissions beyond the 30-day window. In Virginia, the cardiac surgery collaborative is working with payers to gain access to the 90 days worth of patient data.
He reported having no financial conflicts regarding his study.
AT THE WTSA ANNUAL MEETING
Key clinical point:
Major finding: The average 30-day total hospital cost of an isolated CABG procedure during 2006-2015 in Virginia was $36,580 if there were no postoperative complications, jumping to $64,542 with one major complication and $111,239 with two.
Data source: A retrospective study of the 30-day total hospital costs for all isolated CABG procedures performed in Virginia during 2006-2015.
Disclosures: The study presenter reported having no financial conflicts.
Medicare Part D premiums dip as drug costs continue to rise
As insurance premiums in other sectors of the health care industry continue to soar, seniors enrolled in the Medicare Part D prescription drug plan will see a slight decrease in the average premium for their drug coverage.
The Centers for Medicare & Medicaid Services announced Aug. 2 that the average basic premium for drug coverage is projected to drop to $33.50 per month in 2018, down $1.20 from 2017’s average monthly premium of $34.70.
Average premiums are falling despite the rise in drug spending, according to the 2017 Medicare Trustees report, which details the solvency of the Medicare program.
The report notes, however, that drug costs are lower than previous reports due to higher manufacturer rebates and decreased use of direct acting antiviral therapies for hepatitis C virus. Overall, Medicare Part D expenditures per enrollee are estimated to increase by an average of 4.7% annually from 2017 through 2026.
As insurance premiums in other sectors of the health care industry continue to soar, seniors enrolled in the Medicare Part D prescription drug plan will see a slight decrease in the average premium for their drug coverage.
The Centers for Medicare & Medicaid Services announced Aug. 2 that the average basic premium for drug coverage is projected to drop to $33.50 per month in 2018, down $1.20 from 2017’s average monthly premium of $34.70.
Average premiums are falling despite the rise in drug spending, according to the 2017 Medicare Trustees report, which details the solvency of the Medicare program.
The report notes, however, that drug costs are lower than previous reports due to higher manufacturer rebates and decreased use of direct acting antiviral therapies for hepatitis C virus. Overall, Medicare Part D expenditures per enrollee are estimated to increase by an average of 4.7% annually from 2017 through 2026.
As insurance premiums in other sectors of the health care industry continue to soar, seniors enrolled in the Medicare Part D prescription drug plan will see a slight decrease in the average premium for their drug coverage.
The Centers for Medicare & Medicaid Services announced Aug. 2 that the average basic premium for drug coverage is projected to drop to $33.50 per month in 2018, down $1.20 from 2017’s average monthly premium of $34.70.
Average premiums are falling despite the rise in drug spending, according to the 2017 Medicare Trustees report, which details the solvency of the Medicare program.
The report notes, however, that drug costs are lower than previous reports due to higher manufacturer rebates and decreased use of direct acting antiviral therapies for hepatitis C virus. Overall, Medicare Part D expenditures per enrollee are estimated to increase by an average of 4.7% annually from 2017 through 2026.
How to Keep Pace With Genetic Advances in Movement Disorders
VANCOUVER—Researchers’ understanding of genetic causes of movement disorders is advancing rapidly. “The ability to generate data has almost surpassed our ability to understand and use it in the clinic,” said Buz Jinnah, MD, PhD, at the 21st International Congress of Parkinson’s Disease and Movement Disorders.
A recent study underscores the swift evolution of the field. Investigators compared the diagnostic ability of a dystonia gene panel with that of experts who formulated a diagnostic workup without the use of gene panel analysis. In a cohort of 61 patients, the gene panel led to more genetic diagnoses and did so faster and at less cost on average, compared with experts using traditional methods.
Neurologists face practical questions, such as which patients need genetic testing, which tests they should perform, and how the results influence clinical management, said Dr. Jinnah, Professor of Neurology, Human Genetics, and Pediatrics at Emory University School of Medicine in Atlanta. Neurologists once considered Wilson’s disease to have the only genetic cause of movement disorders that significantly changed treatment. Now, researchers have identified more than 30 genetic movement disorders with specific, effective treatments.
Does a Patient Need Genetic Testing?
Not all patients need genetic testing. In some cases, the need for genetic testing is obvious, but in other cases, it is not so clear, Dr. Jinnah said. Certain features increase suspicion for a genetic disorder, such as family history, unusually young age of onset, and combinations of features that fit a recognized syndrome.
Genetic testing also may be warranted in presumed acquired cases. “Methodical studies of these so-called acquired cases reveal a high proportion of genetic explanation for them,” he said. “We typically think of cerebral palsy as an acquired disorder…. But the studies are now showing that about a third of these cases have a genetic explanation.”
Single-gene sequencing, chromosomal microarray, and tests for deletions or insertions are available, as well as next-generation sequencing methods with broader reach. Next-generation techniques include gene panels that can test hundreds of genes associated with a disease, whole-exome sequencing, and whole-genome sequencing.
Choosing a Test
Experts tend to use one of three strategies to select which genetic test to perform. One approach entails identifying red flags—“telltale clinical features that point to a specific diagnosis or group of diagnoses,” said Dr. Jinnah.
Another approach involves pattern recognition. Syndromic combinations may lead a neurologist “straight to a single gene test to confirm the diagnosis” if a patient has a classic presentation of a genetic disease.
The third approach uses diagnostic algorithms. “Depending on the presence or absence of various clinical features … [an algorithm] tells you which gene or collection of genes you need to test for,” he said.
Each strategy has limitations, however. It is difficult to remember all of the red flags and syndromic patterns, and many disorders lack red flags. Atypical syndromes can be misleading, and atypical presentations that have been reported in the literature for decades “continue to surprise us,” Dr. Jinnah said. Researchers have published various diagnostic algorithms for dystonia, parkinsonism, and ataxia, and none of them is perfect.
Several studies have shown the potential of next-generation genetic testing. A report from the NIH’s Undiagnosed Diseases Program found that 25% of patients in the program reached a diagnosis within a few weeks using whole-exome sequencing. “Their conclusion was that these agnostic methods need to be used earlier in the diagnostic process,” he said.
A similar study in Canada evaluated the use of whole-exome sequencing in 362 children with disorders that experts had not been able to diagnose. About 30% of the patients received a definitive diagnosis using whole-exome sequencing.
Clinical Implications
Genetic testing may be important for patient counseling. For instance, if a patient has a family history of Huntington’s disease and develops symptoms suggestive of Huntington’s disease, a normal test result is therapeutic, Dr. Jinnah said. Normal results may be false negatives, however. For example, next-generation sequencing methods are not suitable for detecting certain problems like large insertions, duplications, triplet disorders, and certain genes, and neurologists should consider whether other tests may be useful.
If a genetic test yields a pathologic result, it can inform prognosis and guide family counseling and planning. Furthermore, some inherited disorders have life-altering treatments.
Neurologists are familiar with typical and atypical presentations of Wilson’s disease because the disorder has highly effective treatments. But recent studies have identified lesser-known disorders that may be equally important to recognize. “How many of us are routinely testing these same cases for disorders of manganese transporters?” Dr. Jinnah asked. “It is relatively new information, but the clinical scenario is virtually identical.”
The International Parkinson and Movement Disorder Society’s Rare Movement Disorders Task Force sought to determine how many treatable genetic movement disorders have been identified. The task force found more than 30 disorders with specific treatments—including vitamins, dietary interventions, trigger avoidance, and drugs—that can have “a dramatic impact on the patient’s clinical course,” Dr. Jinnah said. “All of them are quite rare, but we do not want to miss them, because they are treatable.” Investigators identify more treatable disorders each year.
Interpreting Ambiguous Results
Another practical concern for neurologists is the interpretation of variants of unknown significance (VOUS) in genetic test results. “It means that a change or variant in the normal gene was discovered by the laboratory, but the change has never been described in association with the disease that you are interested in,” Dr. Jinnah said. “As a result, the laboratory cannot tell you whether it is relevant or not.”
Neurologists might be inclined to tell a patient that they “found something weird in their DNA,” but this approach “consolidates the patient’s concern that they have some mysterious disorder that none of the doctors can figure out, even the experts,” he said. Nor should neurologists tell a patient that the VOUS is not significant, because that is not what VOUS means.
A VOUS is comparable to a radiology report that says, “Clinical correlation is advised.” That phrase leads neurologists to compare neuroimaging to the clinical phenotype and ask whether the imaging findings make sense. “A VOUS is no different from this,” he said. Neurologists cannot explain all genetic variants, just as neurologists cannot explain all of the spots on a brain scan. “We have to get comfortable with the fact that we do not have answers for everything and that there will be some ambiguities when we are done.”
Genetics is logical and straightforward, and educational sessions are available at conferences for neurologists who are interested in learning more about genetic testing, Dr. Jinnah said. Neurologists also can refer patients to experts. “This referral must be a collaboration,” he said. “People in human genetics are not trained in movement disorders, and many of them have no formal training in neurology. They need your careful phenotypic exam to point them in th
Genetic testing often is expensive, not readily available, and not covered by insurance, but this situation may change, Dr. Jinnah said. He likened the situation of genetic testing today to that of MRI in the 1980s. “Only a few centers in the world had [MRI]. It was extremely expensive. Now, MRI scanners are everywhere, and everybody uses it because it is so valuable in clinical medicine,” he said. “I suspect that in a few years, we will see the same with genetic tests.”
—Jake Remaly
Suggested Reading
Charlesworth G, Bhatia KP, Wood NW. The genetics of dystonia: new twists in an old tale. Brain. 2013;136(Pt 7):2017-2037.
Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011;305(18):1904-1905.
Olgiati S, Quadri M, Bonifati V. Genetics of movement disorders in the next-generation sequencing era. Mov Disord. 2016;31(4):458-470.
Sawyer SL, Hartley T, Dyment DA, et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet. 2016;89(3):275-284.
van Egmond ME, Lugtenberg CHA, Brouwer OF, et al. A post hoc study on gene panel analysis for the diagnosis of dystonia. Mov Disord. 2017;32(4):569-575.
VANCOUVER—Researchers’ understanding of genetic causes of movement disorders is advancing rapidly. “The ability to generate data has almost surpassed our ability to understand and use it in the clinic,” said Buz Jinnah, MD, PhD, at the 21st International Congress of Parkinson’s Disease and Movement Disorders.
A recent study underscores the swift evolution of the field. Investigators compared the diagnostic ability of a dystonia gene panel with that of experts who formulated a diagnostic workup without the use of gene panel analysis. In a cohort of 61 patients, the gene panel led to more genetic diagnoses and did so faster and at less cost on average, compared with experts using traditional methods.
Neurologists face practical questions, such as which patients need genetic testing, which tests they should perform, and how the results influence clinical management, said Dr. Jinnah, Professor of Neurology, Human Genetics, and Pediatrics at Emory University School of Medicine in Atlanta. Neurologists once considered Wilson’s disease to have the only genetic cause of movement disorders that significantly changed treatment. Now, researchers have identified more than 30 genetic movement disorders with specific, effective treatments.
Does a Patient Need Genetic Testing?
Not all patients need genetic testing. In some cases, the need for genetic testing is obvious, but in other cases, it is not so clear, Dr. Jinnah said. Certain features increase suspicion for a genetic disorder, such as family history, unusually young age of onset, and combinations of features that fit a recognized syndrome.
Genetic testing also may be warranted in presumed acquired cases. “Methodical studies of these so-called acquired cases reveal a high proportion of genetic explanation for them,” he said. “We typically think of cerebral palsy as an acquired disorder…. But the studies are now showing that about a third of these cases have a genetic explanation.”
Single-gene sequencing, chromosomal microarray, and tests for deletions or insertions are available, as well as next-generation sequencing methods with broader reach. Next-generation techniques include gene panels that can test hundreds of genes associated with a disease, whole-exome sequencing, and whole-genome sequencing.
Choosing a Test
Experts tend to use one of three strategies to select which genetic test to perform. One approach entails identifying red flags—“telltale clinical features that point to a specific diagnosis or group of diagnoses,” said Dr. Jinnah.
Another approach involves pattern recognition. Syndromic combinations may lead a neurologist “straight to a single gene test to confirm the diagnosis” if a patient has a classic presentation of a genetic disease.
The third approach uses diagnostic algorithms. “Depending on the presence or absence of various clinical features … [an algorithm] tells you which gene or collection of genes you need to test for,” he said.
Each strategy has limitations, however. It is difficult to remember all of the red flags and syndromic patterns, and many disorders lack red flags. Atypical syndromes can be misleading, and atypical presentations that have been reported in the literature for decades “continue to surprise us,” Dr. Jinnah said. Researchers have published various diagnostic algorithms for dystonia, parkinsonism, and ataxia, and none of them is perfect.
Several studies have shown the potential of next-generation genetic testing. A report from the NIH’s Undiagnosed Diseases Program found that 25% of patients in the program reached a diagnosis within a few weeks using whole-exome sequencing. “Their conclusion was that these agnostic methods need to be used earlier in the diagnostic process,” he said.
A similar study in Canada evaluated the use of whole-exome sequencing in 362 children with disorders that experts had not been able to diagnose. About 30% of the patients received a definitive diagnosis using whole-exome sequencing.
Clinical Implications
Genetic testing may be important for patient counseling. For instance, if a patient has a family history of Huntington’s disease and develops symptoms suggestive of Huntington’s disease, a normal test result is therapeutic, Dr. Jinnah said. Normal results may be false negatives, however. For example, next-generation sequencing methods are not suitable for detecting certain problems like large insertions, duplications, triplet disorders, and certain genes, and neurologists should consider whether other tests may be useful.
If a genetic test yields a pathologic result, it can inform prognosis and guide family counseling and planning. Furthermore, some inherited disorders have life-altering treatments.
Neurologists are familiar with typical and atypical presentations of Wilson’s disease because the disorder has highly effective treatments. But recent studies have identified lesser-known disorders that may be equally important to recognize. “How many of us are routinely testing these same cases for disorders of manganese transporters?” Dr. Jinnah asked. “It is relatively new information, but the clinical scenario is virtually identical.”
The International Parkinson and Movement Disorder Society’s Rare Movement Disorders Task Force sought to determine how many treatable genetic movement disorders have been identified. The task force found more than 30 disorders with specific treatments—including vitamins, dietary interventions, trigger avoidance, and drugs—that can have “a dramatic impact on the patient’s clinical course,” Dr. Jinnah said. “All of them are quite rare, but we do not want to miss them, because they are treatable.” Investigators identify more treatable disorders each year.
Interpreting Ambiguous Results
Another practical concern for neurologists is the interpretation of variants of unknown significance (VOUS) in genetic test results. “It means that a change or variant in the normal gene was discovered by the laboratory, but the change has never been described in association with the disease that you are interested in,” Dr. Jinnah said. “As a result, the laboratory cannot tell you whether it is relevant or not.”
Neurologists might be inclined to tell a patient that they “found something weird in their DNA,” but this approach “consolidates the patient’s concern that they have some mysterious disorder that none of the doctors can figure out, even the experts,” he said. Nor should neurologists tell a patient that the VOUS is not significant, because that is not what VOUS means.
A VOUS is comparable to a radiology report that says, “Clinical correlation is advised.” That phrase leads neurologists to compare neuroimaging to the clinical phenotype and ask whether the imaging findings make sense. “A VOUS is no different from this,” he said. Neurologists cannot explain all genetic variants, just as neurologists cannot explain all of the spots on a brain scan. “We have to get comfortable with the fact that we do not have answers for everything and that there will be some ambiguities when we are done.”
Genetics is logical and straightforward, and educational sessions are available at conferences for neurologists who are interested in learning more about genetic testing, Dr. Jinnah said. Neurologists also can refer patients to experts. “This referral must be a collaboration,” he said. “People in human genetics are not trained in movement disorders, and many of them have no formal training in neurology. They need your careful phenotypic exam to point them in th
Genetic testing often is expensive, not readily available, and not covered by insurance, but this situation may change, Dr. Jinnah said. He likened the situation of genetic testing today to that of MRI in the 1980s. “Only a few centers in the world had [MRI]. It was extremely expensive. Now, MRI scanners are everywhere, and everybody uses it because it is so valuable in clinical medicine,” he said. “I suspect that in a few years, we will see the same with genetic tests.”
—Jake Remaly
Suggested Reading
Charlesworth G, Bhatia KP, Wood NW. The genetics of dystonia: new twists in an old tale. Brain. 2013;136(Pt 7):2017-2037.
Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011;305(18):1904-1905.
Olgiati S, Quadri M, Bonifati V. Genetics of movement disorders in the next-generation sequencing era. Mov Disord. 2016;31(4):458-470.
Sawyer SL, Hartley T, Dyment DA, et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet. 2016;89(3):275-284.
van Egmond ME, Lugtenberg CHA, Brouwer OF, et al. A post hoc study on gene panel analysis for the diagnosis of dystonia. Mov Disord. 2017;32(4):569-575.
VANCOUVER—Researchers’ understanding of genetic causes of movement disorders is advancing rapidly. “The ability to generate data has almost surpassed our ability to understand and use it in the clinic,” said Buz Jinnah, MD, PhD, at the 21st International Congress of Parkinson’s Disease and Movement Disorders.
A recent study underscores the swift evolution of the field. Investigators compared the diagnostic ability of a dystonia gene panel with that of experts who formulated a diagnostic workup without the use of gene panel analysis. In a cohort of 61 patients, the gene panel led to more genetic diagnoses and did so faster and at less cost on average, compared with experts using traditional methods.
Neurologists face practical questions, such as which patients need genetic testing, which tests they should perform, and how the results influence clinical management, said Dr. Jinnah, Professor of Neurology, Human Genetics, and Pediatrics at Emory University School of Medicine in Atlanta. Neurologists once considered Wilson’s disease to have the only genetic cause of movement disorders that significantly changed treatment. Now, researchers have identified more than 30 genetic movement disorders with specific, effective treatments.
Does a Patient Need Genetic Testing?
Not all patients need genetic testing. In some cases, the need for genetic testing is obvious, but in other cases, it is not so clear, Dr. Jinnah said. Certain features increase suspicion for a genetic disorder, such as family history, unusually young age of onset, and combinations of features that fit a recognized syndrome.
Genetic testing also may be warranted in presumed acquired cases. “Methodical studies of these so-called acquired cases reveal a high proportion of genetic explanation for them,” he said. “We typically think of cerebral palsy as an acquired disorder…. But the studies are now showing that about a third of these cases have a genetic explanation.”
Single-gene sequencing, chromosomal microarray, and tests for deletions or insertions are available, as well as next-generation sequencing methods with broader reach. Next-generation techniques include gene panels that can test hundreds of genes associated with a disease, whole-exome sequencing, and whole-genome sequencing.
Choosing a Test
Experts tend to use one of three strategies to select which genetic test to perform. One approach entails identifying red flags—“telltale clinical features that point to a specific diagnosis or group of diagnoses,” said Dr. Jinnah.
Another approach involves pattern recognition. Syndromic combinations may lead a neurologist “straight to a single gene test to confirm the diagnosis” if a patient has a classic presentation of a genetic disease.
The third approach uses diagnostic algorithms. “Depending on the presence or absence of various clinical features … [an algorithm] tells you which gene or collection of genes you need to test for,” he said.
Each strategy has limitations, however. It is difficult to remember all of the red flags and syndromic patterns, and many disorders lack red flags. Atypical syndromes can be misleading, and atypical presentations that have been reported in the literature for decades “continue to surprise us,” Dr. Jinnah said. Researchers have published various diagnostic algorithms for dystonia, parkinsonism, and ataxia, and none of them is perfect.
Several studies have shown the potential of next-generation genetic testing. A report from the NIH’s Undiagnosed Diseases Program found that 25% of patients in the program reached a diagnosis within a few weeks using whole-exome sequencing. “Their conclusion was that these agnostic methods need to be used earlier in the diagnostic process,” he said.
A similar study in Canada evaluated the use of whole-exome sequencing in 362 children with disorders that experts had not been able to diagnose. About 30% of the patients received a definitive diagnosis using whole-exome sequencing.
Clinical Implications
Genetic testing may be important for patient counseling. For instance, if a patient has a family history of Huntington’s disease and develops symptoms suggestive of Huntington’s disease, a normal test result is therapeutic, Dr. Jinnah said. Normal results may be false negatives, however. For example, next-generation sequencing methods are not suitable for detecting certain problems like large insertions, duplications, triplet disorders, and certain genes, and neurologists should consider whether other tests may be useful.
If a genetic test yields a pathologic result, it can inform prognosis and guide family counseling and planning. Furthermore, some inherited disorders have life-altering treatments.
Neurologists are familiar with typical and atypical presentations of Wilson’s disease because the disorder has highly effective treatments. But recent studies have identified lesser-known disorders that may be equally important to recognize. “How many of us are routinely testing these same cases for disorders of manganese transporters?” Dr. Jinnah asked. “It is relatively new information, but the clinical scenario is virtually identical.”
The International Parkinson and Movement Disorder Society’s Rare Movement Disorders Task Force sought to determine how many treatable genetic movement disorders have been identified. The task force found more than 30 disorders with specific treatments—including vitamins, dietary interventions, trigger avoidance, and drugs—that can have “a dramatic impact on the patient’s clinical course,” Dr. Jinnah said. “All of them are quite rare, but we do not want to miss them, because they are treatable.” Investigators identify more treatable disorders each year.
Interpreting Ambiguous Results
Another practical concern for neurologists is the interpretation of variants of unknown significance (VOUS) in genetic test results. “It means that a change or variant in the normal gene was discovered by the laboratory, but the change has never been described in association with the disease that you are interested in,” Dr. Jinnah said. “As a result, the laboratory cannot tell you whether it is relevant or not.”
Neurologists might be inclined to tell a patient that they “found something weird in their DNA,” but this approach “consolidates the patient’s concern that they have some mysterious disorder that none of the doctors can figure out, even the experts,” he said. Nor should neurologists tell a patient that the VOUS is not significant, because that is not what VOUS means.
A VOUS is comparable to a radiology report that says, “Clinical correlation is advised.” That phrase leads neurologists to compare neuroimaging to the clinical phenotype and ask whether the imaging findings make sense. “A VOUS is no different from this,” he said. Neurologists cannot explain all genetic variants, just as neurologists cannot explain all of the spots on a brain scan. “We have to get comfortable with the fact that we do not have answers for everything and that there will be some ambiguities when we are done.”
Genetics is logical and straightforward, and educational sessions are available at conferences for neurologists who are interested in learning more about genetic testing, Dr. Jinnah said. Neurologists also can refer patients to experts. “This referral must be a collaboration,” he said. “People in human genetics are not trained in movement disorders, and many of them have no formal training in neurology. They need your careful phenotypic exam to point them in th
Genetic testing often is expensive, not readily available, and not covered by insurance, but this situation may change, Dr. Jinnah said. He likened the situation of genetic testing today to that of MRI in the 1980s. “Only a few centers in the world had [MRI]. It was extremely expensive. Now, MRI scanners are everywhere, and everybody uses it because it is so valuable in clinical medicine,” he said. “I suspect that in a few years, we will see the same with genetic tests.”
—Jake Remaly
Suggested Reading
Charlesworth G, Bhatia KP, Wood NW. The genetics of dystonia: new twists in an old tale. Brain. 2013;136(Pt 7):2017-2037.
Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011;305(18):1904-1905.
Olgiati S, Quadri M, Bonifati V. Genetics of movement disorders in the next-generation sequencing era. Mov Disord. 2016;31(4):458-470.
Sawyer SL, Hartley T, Dyment DA, et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet. 2016;89(3):275-284.
van Egmond ME, Lugtenberg CHA, Brouwer OF, et al. A post hoc study on gene panel analysis for the diagnosis of dystonia. Mov Disord. 2017;32(4):569-575.
Liposomal daunorubicin and cytarabine approved for t-AML, AML-MRC
, the Food and Drug Administration announced on Aug. 3.
Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.
“Vyxeos is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes,” Jeffrey E. Lancet, MD, an investigator in the clinical trials of Vyxeos and chair of the department of malignant hematology at the H. Lee Moffitt Cancer Center in Tampa, Fla., said in a press release.
Vyxeos was associated with a median overall survival of 9.6 months and a standard combination of cytarabine and daunorubicin (7+3) was associated with a median survival of 5.9 months in a randomized, multicenter, open-label trial of 309 patients aged 60-75 years with newly-diagnosed t-AML or AML-MRC. Data from the study, which is NCT01696084, was the basis for the drug’s approval.
Vyxeos is a fixed-dose combination with each Vyxeos vial containing 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes. As dosing is based on the daunorubicin component, the corresponding cytarabine dose does not need to be calculated. Daunorubicin dosing is calculated on the basis of body surface area (mg/m2).
For the first induction cycle, the recommended Vyxeos dose is daunorubicin 44 mg/m2 (cytarabine 100 mg/m2) infused intravenously over 90 minutes on days 1, 3, and 5. If a second induction cycle is needed, the same dose is administered on days 1 and 3. The recommended dose of Vyxeos for each cycle of consolidation therapy is daunorubicin 29 mg/m2 (cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.
Adverse reactions occurring in at least 25% of treated patients in the clinical trial included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The prescribing information includes a boxed warning not to substitute Vyxeos with other daunorubicin- or cytarabine-containing products. Full prescribing information is available at: www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf
The maker of Vyxeos is Jazz Pharmaceuticals.
mdales@frontlinemedcom.com
On Twitter @maryjodales
, the Food and Drug Administration announced on Aug. 3.
Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.
“Vyxeos is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes,” Jeffrey E. Lancet, MD, an investigator in the clinical trials of Vyxeos and chair of the department of malignant hematology at the H. Lee Moffitt Cancer Center in Tampa, Fla., said in a press release.
Vyxeos was associated with a median overall survival of 9.6 months and a standard combination of cytarabine and daunorubicin (7+3) was associated with a median survival of 5.9 months in a randomized, multicenter, open-label trial of 309 patients aged 60-75 years with newly-diagnosed t-AML or AML-MRC. Data from the study, which is NCT01696084, was the basis for the drug’s approval.
Vyxeos is a fixed-dose combination with each Vyxeos vial containing 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes. As dosing is based on the daunorubicin component, the corresponding cytarabine dose does not need to be calculated. Daunorubicin dosing is calculated on the basis of body surface area (mg/m2).
For the first induction cycle, the recommended Vyxeos dose is daunorubicin 44 mg/m2 (cytarabine 100 mg/m2) infused intravenously over 90 minutes on days 1, 3, and 5. If a second induction cycle is needed, the same dose is administered on days 1 and 3. The recommended dose of Vyxeos for each cycle of consolidation therapy is daunorubicin 29 mg/m2 (cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.
Adverse reactions occurring in at least 25% of treated patients in the clinical trial included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The prescribing information includes a boxed warning not to substitute Vyxeos with other daunorubicin- or cytarabine-containing products. Full prescribing information is available at: www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf
The maker of Vyxeos is Jazz Pharmaceuticals.
mdales@frontlinemedcom.com
On Twitter @maryjodales
, the Food and Drug Administration announced on Aug. 3.
Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.
“Vyxeos is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes,” Jeffrey E. Lancet, MD, an investigator in the clinical trials of Vyxeos and chair of the department of malignant hematology at the H. Lee Moffitt Cancer Center in Tampa, Fla., said in a press release.
Vyxeos was associated with a median overall survival of 9.6 months and a standard combination of cytarabine and daunorubicin (7+3) was associated with a median survival of 5.9 months in a randomized, multicenter, open-label trial of 309 patients aged 60-75 years with newly-diagnosed t-AML or AML-MRC. Data from the study, which is NCT01696084, was the basis for the drug’s approval.
Vyxeos is a fixed-dose combination with each Vyxeos vial containing 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes. As dosing is based on the daunorubicin component, the corresponding cytarabine dose does not need to be calculated. Daunorubicin dosing is calculated on the basis of body surface area (mg/m2).
For the first induction cycle, the recommended Vyxeos dose is daunorubicin 44 mg/m2 (cytarabine 100 mg/m2) infused intravenously over 90 minutes on days 1, 3, and 5. If a second induction cycle is needed, the same dose is administered on days 1 and 3. The recommended dose of Vyxeos for each cycle of consolidation therapy is daunorubicin 29 mg/m2 (cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.
Adverse reactions occurring in at least 25% of treated patients in the clinical trial included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The prescribing information includes a boxed warning not to substitute Vyxeos with other daunorubicin- or cytarabine-containing products. Full prescribing information is available at: www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf
The maker of Vyxeos is Jazz Pharmaceuticals.
mdales@frontlinemedcom.com
On Twitter @maryjodales
PHM17 session summary: Tools for engaging learners of all levels
NASHVILLE, TENN. – Various instructional tools and techniques can help hospitalists teach medical learners at a variety of levels, according to experts who spoke at Pediatric Hospital Medicine 2017, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Session
Tools for Engaging Learners of All Levels: Multilevel Teaching Techniques & Cognitive Apprenticeship
Presenters
Session summary
Hospitalists are commonly charged with teaching learners at a variety of levels. There are various tools that can be used to accomplish this including multilevel teaching and cognitive apprenticeship.
Multilevel teaching is defined as teaching multiple levels of learners simultaneously. The goal is to maintain engagement without being boring or teaching over any learner’s head. Examples include:
1. Broadening: Change the case to make it more challenging or interesting such as asking what to do if the patient was a different age or had a comorbid condition.
2. Targeting: Target questions at specific team members depending on difficulty such as asking students common causes of bacterial meningitis and asking residents about admission criteria.
3. Novelty: Provide new data such as a recent journal article.
4. Up the Ladder: Ask the same question to all team members, starting with the most junior.
5. Student as Teacher: Ask a senior learner to teach a junior learner.
6. Multi-Answer: Seek multiple answers to one question such as asking each learner to contribute an item to a differential diagnosis.
7. No Right Answer: Ask questions that do not have a single correct answer such as how to approach a difficult conversation.
8. Teaching to the Top: Teach to the level of the most senior learner.
9. Extreme Challenge: Teach at a level above all learners on the team.
Laura Certain, MD, PhD, et al1 found that most trainees feel Targeting, Up the Ladder, Student as Teacher, and Multi-Answer are most effective. No Right Answer, Teaching to the Top, and Extreme Challenge were felt to be least effective.
Another concept for engaging learners at all levels is cognitive apprenticeship, which is an instructional model whereby teachers make explicit their generally tacit cognitive processes. Examples include:
1. Modeling: Actively demonstrate skills such as performing a procedure while verbalizing the steps and thought processes.
2. Couching: Observe learners and provide feedback on their performance.
3. Scaffolding: Inquire about past experiences and provide opportunity for independent activities, while also providing help for activities that are difficult for learners.
4. Articulation: Ask learners to explain their thought processes.
5. Reflection: Prompt students to deliberately consider their strengths and weaknesses.
6. Exploration: Encourage students to set personal learning goals.
Coaching and articulation have been found to be more useful for novice learners. Reflection and exploration are more useful for advanced learners.
Key takeaways for Pediatric HM
• Multilevel teaching can be used to engage a variety of learners simultaneously. Targeting, Up the Ladder, Student as Teacher, and Multi-Answer are effective methods to achieve this goal.
• Cognitive apprenticeship can be used in clinical teaching to make a tacit cognitive process explicit. Methods such as coaching and articulation have been found to be more useful for novice learners. Reflection and exploration are more useful for advanced learners.
• Regardless of the method used, teachers should demonstrate interest in the learners’ education and treat them with respect.
Dr. Rogers is assistant professor of pediatrics and Section of Hospital Medicine associate program director, Pediatric Residency Program, at the Medical College of Wisconsin, Milwaukee.
References
1. Certain LK, Guarino AJ, Greenwald JL. Effective multilevel teaching techniques on attending rounds: a pilot survey and systematic review of the literature. Med Teach. 2011;33(12),e644-650. doi: 10.3109/0142159X.2011.610844.
NASHVILLE, TENN. – Various instructional tools and techniques can help hospitalists teach medical learners at a variety of levels, according to experts who spoke at Pediatric Hospital Medicine 2017, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Session
Tools for Engaging Learners of All Levels: Multilevel Teaching Techniques & Cognitive Apprenticeship
Presenters
Session summary
Hospitalists are commonly charged with teaching learners at a variety of levels. There are various tools that can be used to accomplish this including multilevel teaching and cognitive apprenticeship.
Multilevel teaching is defined as teaching multiple levels of learners simultaneously. The goal is to maintain engagement without being boring or teaching over any learner’s head. Examples include:
1. Broadening: Change the case to make it more challenging or interesting such as asking what to do if the patient was a different age or had a comorbid condition.
2. Targeting: Target questions at specific team members depending on difficulty such as asking students common causes of bacterial meningitis and asking residents about admission criteria.
3. Novelty: Provide new data such as a recent journal article.
4. Up the Ladder: Ask the same question to all team members, starting with the most junior.
5. Student as Teacher: Ask a senior learner to teach a junior learner.
6. Multi-Answer: Seek multiple answers to one question such as asking each learner to contribute an item to a differential diagnosis.
7. No Right Answer: Ask questions that do not have a single correct answer such as how to approach a difficult conversation.
8. Teaching to the Top: Teach to the level of the most senior learner.
9. Extreme Challenge: Teach at a level above all learners on the team.
Laura Certain, MD, PhD, et al1 found that most trainees feel Targeting, Up the Ladder, Student as Teacher, and Multi-Answer are most effective. No Right Answer, Teaching to the Top, and Extreme Challenge were felt to be least effective.
Another concept for engaging learners at all levels is cognitive apprenticeship, which is an instructional model whereby teachers make explicit their generally tacit cognitive processes. Examples include:
1. Modeling: Actively demonstrate skills such as performing a procedure while verbalizing the steps and thought processes.
2. Couching: Observe learners and provide feedback on their performance.
3. Scaffolding: Inquire about past experiences and provide opportunity for independent activities, while also providing help for activities that are difficult for learners.
4. Articulation: Ask learners to explain their thought processes.
5. Reflection: Prompt students to deliberately consider their strengths and weaknesses.
6. Exploration: Encourage students to set personal learning goals.
Coaching and articulation have been found to be more useful for novice learners. Reflection and exploration are more useful for advanced learners.
Key takeaways for Pediatric HM
• Multilevel teaching can be used to engage a variety of learners simultaneously. Targeting, Up the Ladder, Student as Teacher, and Multi-Answer are effective methods to achieve this goal.
• Cognitive apprenticeship can be used in clinical teaching to make a tacit cognitive process explicit. Methods such as coaching and articulation have been found to be more useful for novice learners. Reflection and exploration are more useful for advanced learners.
• Regardless of the method used, teachers should demonstrate interest in the learners’ education and treat them with respect.
Dr. Rogers is assistant professor of pediatrics and Section of Hospital Medicine associate program director, Pediatric Residency Program, at the Medical College of Wisconsin, Milwaukee.
References
1. Certain LK, Guarino AJ, Greenwald JL. Effective multilevel teaching techniques on attending rounds: a pilot survey and systematic review of the literature. Med Teach. 2011;33(12),e644-650. doi: 10.3109/0142159X.2011.610844.
NASHVILLE, TENN. – Various instructional tools and techniques can help hospitalists teach medical learners at a variety of levels, according to experts who spoke at Pediatric Hospital Medicine 2017, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Session
Tools for Engaging Learners of All Levels: Multilevel Teaching Techniques & Cognitive Apprenticeship
Presenters
Session summary
Hospitalists are commonly charged with teaching learners at a variety of levels. There are various tools that can be used to accomplish this including multilevel teaching and cognitive apprenticeship.
Multilevel teaching is defined as teaching multiple levels of learners simultaneously. The goal is to maintain engagement without being boring or teaching over any learner’s head. Examples include:
1. Broadening: Change the case to make it more challenging or interesting such as asking what to do if the patient was a different age or had a comorbid condition.
2. Targeting: Target questions at specific team members depending on difficulty such as asking students common causes of bacterial meningitis and asking residents about admission criteria.
3. Novelty: Provide new data such as a recent journal article.
4. Up the Ladder: Ask the same question to all team members, starting with the most junior.
5. Student as Teacher: Ask a senior learner to teach a junior learner.
6. Multi-Answer: Seek multiple answers to one question such as asking each learner to contribute an item to a differential diagnosis.
7. No Right Answer: Ask questions that do not have a single correct answer such as how to approach a difficult conversation.
8. Teaching to the Top: Teach to the level of the most senior learner.
9. Extreme Challenge: Teach at a level above all learners on the team.
Laura Certain, MD, PhD, et al1 found that most trainees feel Targeting, Up the Ladder, Student as Teacher, and Multi-Answer are most effective. No Right Answer, Teaching to the Top, and Extreme Challenge were felt to be least effective.
Another concept for engaging learners at all levels is cognitive apprenticeship, which is an instructional model whereby teachers make explicit their generally tacit cognitive processes. Examples include:
1. Modeling: Actively demonstrate skills such as performing a procedure while verbalizing the steps and thought processes.
2. Couching: Observe learners and provide feedback on their performance.
3. Scaffolding: Inquire about past experiences and provide opportunity for independent activities, while also providing help for activities that are difficult for learners.
4. Articulation: Ask learners to explain their thought processes.
5. Reflection: Prompt students to deliberately consider their strengths and weaknesses.
6. Exploration: Encourage students to set personal learning goals.
Coaching and articulation have been found to be more useful for novice learners. Reflection and exploration are more useful for advanced learners.
Key takeaways for Pediatric HM
• Multilevel teaching can be used to engage a variety of learners simultaneously. Targeting, Up the Ladder, Student as Teacher, and Multi-Answer are effective methods to achieve this goal.
• Cognitive apprenticeship can be used in clinical teaching to make a tacit cognitive process explicit. Methods such as coaching and articulation have been found to be more useful for novice learners. Reflection and exploration are more useful for advanced learners.
• Regardless of the method used, teachers should demonstrate interest in the learners’ education and treat them with respect.
Dr. Rogers is assistant professor of pediatrics and Section of Hospital Medicine associate program director, Pediatric Residency Program, at the Medical College of Wisconsin, Milwaukee.
References
1. Certain LK, Guarino AJ, Greenwald JL. Effective multilevel teaching techniques on attending rounds: a pilot survey and systematic review of the literature. Med Teach. 2011;33(12),e644-650. doi: 10.3109/0142159X.2011.610844.
At PHM 2017
VIDEO: Study highlights risks of postponing cholecystectomy
Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy (CCY) within the next 60 days according to the results of a large, retrospective cohort study reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.048).
“Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of a recurrent biliary event while waiting for a delayed CCY, compared with patients who underwent early CCY,” wrote Robert J. Huang, MD, and his associates of Stanford (Calif.) University Medical Center. Delayed CCY is cost effective, but that benefit must be weighed against the risk of loss to follow-up, especially if patients have “little or no health insurance,” they said.
Source: American Gastroenterological Association
Gallstone disease affects up to 15% of adults in developed societies, including about 20-25 million Americans. Yearly costs of treatment tally at more than $6.2 billion and have risen by more than 20% in 3 decades, according to multiple studies. Approximately 20% of patients with gallstone disease have choledocholithiasis, mainly because gallstones can pass from the gallbladder into the common bile duct. After undergoing ERCP, such patients are typically referred for CCY, but there are no “societal guidelines” on timing the referral, the researchers said. Practice patterns remain “largely institution based and may be subject to the vagaries of surgeon availability and other institutional resource constraints.” One prior study linked a median 7-week wait time for CCY with a 20% rate of recurrent biliary events. To evaluate large-scale practice patterns, the researchers studied 4,516 patients who had undergone ERCP for choledocholithiasis in California (during 2009-2011), New York (during 2011-2013), and Florida (during 2012-2014) and calculated timing and rates of subsequent CCY, recurrent biliary events, and deaths. Patients were followed for up to 365 days after ERCP.
Of the 4,516 patients studied, 1,859 (41.2%) patients underwent CCY during their index hospital admission (early CCY). Of the 2,657 (58.8%) patients who were discharged without CCY, only 491 (18%) had a planned CCY within 60 days (delayed CCY), 350 (71.3%) of which were done in an outpatient setting. Of the patients in the study, 2,168 (48.0%) did not have a CCY (no CCY) during their index visit or within 60 days. Over 365 days of follow-up, 10% of patients who did not have a CCY had recurrent biliary events, compared with 1.3% of patients who underwent early or delayed CCY. The risk of recurrent biliary events for patients who underwent early or delayed CCY was about 88% lower than if they had had no CCY within 60 days of ERCP (P less than .001 for each comparison). Performing CCY during index admission cut the risk of recurrent biliary events occurring within 60 days by 92%, compared with delayed or no CCY (P less than .001).
In all, 15 (0.7%) patients who did not undergo CCY died after subsequent hospitalization for a recurrent biliary event, compared with 1 patient who underwent early CCY (0.1%; P less than .001). There were no deaths associated with recurrent biliary events in the delayed-CCY group. Rates of all-cause mortality over 365 days were 3.1% in the no-CCY group, 0.6% in the early-CCY group, and 0% in the delayed-CCY group. Thus, cumulative death rates were about seven times higher among patients who did not undergo CCY compared with those who did (P less than .001).
Patients who did not undergo CCY tended to be older than delayed- and early-CCY patients (mean ages 66 years, 58 years, and 52 years, respectively). No-CCY patients also tended to have more comorbidities. Nonetheless, having an early CCY retained a “robust” protective effect against recurrent biliary events after accounting for age, sex, comorbidities, stent placement, facility volume, and state of residence. Even after researchers adjusted for those factors, the protective effect of early CCY dropped by less than 5% (from 92% to about 87%), the investigators said.
They also noted that the overall cohort averaged 60 years of age and that 64% were female, which is consistent with the epidemiology of biliary stone disease. Just over half were non-Hispanic whites. Medicare was the single largest primary payer (46%), followed by private insurance (28%) and Medicaid (16%).
“A strategy of delayed CCY performed on an outpatient basis was least costly,” the researchers said. “Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY.”
Funders included a seed grant from the Stanford division of gastroenterology and hepatology and the National Institutes of Health. The investigators had no conflicts of interest.
Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy (CCY) within the next 60 days according to the results of a large, retrospective cohort study reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.048).
“Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of a recurrent biliary event while waiting for a delayed CCY, compared with patients who underwent early CCY,” wrote Robert J. Huang, MD, and his associates of Stanford (Calif.) University Medical Center. Delayed CCY is cost effective, but that benefit must be weighed against the risk of loss to follow-up, especially if patients have “little or no health insurance,” they said.
Source: American Gastroenterological Association
Gallstone disease affects up to 15% of adults in developed societies, including about 20-25 million Americans. Yearly costs of treatment tally at more than $6.2 billion and have risen by more than 20% in 3 decades, according to multiple studies. Approximately 20% of patients with gallstone disease have choledocholithiasis, mainly because gallstones can pass from the gallbladder into the common bile duct. After undergoing ERCP, such patients are typically referred for CCY, but there are no “societal guidelines” on timing the referral, the researchers said. Practice patterns remain “largely institution based and may be subject to the vagaries of surgeon availability and other institutional resource constraints.” One prior study linked a median 7-week wait time for CCY with a 20% rate of recurrent biliary events. To evaluate large-scale practice patterns, the researchers studied 4,516 patients who had undergone ERCP for choledocholithiasis in California (during 2009-2011), New York (during 2011-2013), and Florida (during 2012-2014) and calculated timing and rates of subsequent CCY, recurrent biliary events, and deaths. Patients were followed for up to 365 days after ERCP.
Of the 4,516 patients studied, 1,859 (41.2%) patients underwent CCY during their index hospital admission (early CCY). Of the 2,657 (58.8%) patients who were discharged without CCY, only 491 (18%) had a planned CCY within 60 days (delayed CCY), 350 (71.3%) of which were done in an outpatient setting. Of the patients in the study, 2,168 (48.0%) did not have a CCY (no CCY) during their index visit or within 60 days. Over 365 days of follow-up, 10% of patients who did not have a CCY had recurrent biliary events, compared with 1.3% of patients who underwent early or delayed CCY. The risk of recurrent biliary events for patients who underwent early or delayed CCY was about 88% lower than if they had had no CCY within 60 days of ERCP (P less than .001 for each comparison). Performing CCY during index admission cut the risk of recurrent biliary events occurring within 60 days by 92%, compared with delayed or no CCY (P less than .001).
In all, 15 (0.7%) patients who did not undergo CCY died after subsequent hospitalization for a recurrent biliary event, compared with 1 patient who underwent early CCY (0.1%; P less than .001). There were no deaths associated with recurrent biliary events in the delayed-CCY group. Rates of all-cause mortality over 365 days were 3.1% in the no-CCY group, 0.6% in the early-CCY group, and 0% in the delayed-CCY group. Thus, cumulative death rates were about seven times higher among patients who did not undergo CCY compared with those who did (P less than .001).
Patients who did not undergo CCY tended to be older than delayed- and early-CCY patients (mean ages 66 years, 58 years, and 52 years, respectively). No-CCY patients also tended to have more comorbidities. Nonetheless, having an early CCY retained a “robust” protective effect against recurrent biliary events after accounting for age, sex, comorbidities, stent placement, facility volume, and state of residence. Even after researchers adjusted for those factors, the protective effect of early CCY dropped by less than 5% (from 92% to about 87%), the investigators said.
They also noted that the overall cohort averaged 60 years of age and that 64% were female, which is consistent with the epidemiology of biliary stone disease. Just over half were non-Hispanic whites. Medicare was the single largest primary payer (46%), followed by private insurance (28%) and Medicaid (16%).
“A strategy of delayed CCY performed on an outpatient basis was least costly,” the researchers said. “Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY.”
Funders included a seed grant from the Stanford division of gastroenterology and hepatology and the National Institutes of Health. The investigators had no conflicts of interest.
Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy (CCY) within the next 60 days according to the results of a large, retrospective cohort study reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.048).
“Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of a recurrent biliary event while waiting for a delayed CCY, compared with patients who underwent early CCY,” wrote Robert J. Huang, MD, and his associates of Stanford (Calif.) University Medical Center. Delayed CCY is cost effective, but that benefit must be weighed against the risk of loss to follow-up, especially if patients have “little or no health insurance,” they said.
Source: American Gastroenterological Association
Gallstone disease affects up to 15% of adults in developed societies, including about 20-25 million Americans. Yearly costs of treatment tally at more than $6.2 billion and have risen by more than 20% in 3 decades, according to multiple studies. Approximately 20% of patients with gallstone disease have choledocholithiasis, mainly because gallstones can pass from the gallbladder into the common bile duct. After undergoing ERCP, such patients are typically referred for CCY, but there are no “societal guidelines” on timing the referral, the researchers said. Practice patterns remain “largely institution based and may be subject to the vagaries of surgeon availability and other institutional resource constraints.” One prior study linked a median 7-week wait time for CCY with a 20% rate of recurrent biliary events. To evaluate large-scale practice patterns, the researchers studied 4,516 patients who had undergone ERCP for choledocholithiasis in California (during 2009-2011), New York (during 2011-2013), and Florida (during 2012-2014) and calculated timing and rates of subsequent CCY, recurrent biliary events, and deaths. Patients were followed for up to 365 days after ERCP.
Of the 4,516 patients studied, 1,859 (41.2%) patients underwent CCY during their index hospital admission (early CCY). Of the 2,657 (58.8%) patients who were discharged without CCY, only 491 (18%) had a planned CCY within 60 days (delayed CCY), 350 (71.3%) of which were done in an outpatient setting. Of the patients in the study, 2,168 (48.0%) did not have a CCY (no CCY) during their index visit or within 60 days. Over 365 days of follow-up, 10% of patients who did not have a CCY had recurrent biliary events, compared with 1.3% of patients who underwent early or delayed CCY. The risk of recurrent biliary events for patients who underwent early or delayed CCY was about 88% lower than if they had had no CCY within 60 days of ERCP (P less than .001 for each comparison). Performing CCY during index admission cut the risk of recurrent biliary events occurring within 60 days by 92%, compared with delayed or no CCY (P less than .001).
In all, 15 (0.7%) patients who did not undergo CCY died after subsequent hospitalization for a recurrent biliary event, compared with 1 patient who underwent early CCY (0.1%; P less than .001). There were no deaths associated with recurrent biliary events in the delayed-CCY group. Rates of all-cause mortality over 365 days were 3.1% in the no-CCY group, 0.6% in the early-CCY group, and 0% in the delayed-CCY group. Thus, cumulative death rates were about seven times higher among patients who did not undergo CCY compared with those who did (P less than .001).
Patients who did not undergo CCY tended to be older than delayed- and early-CCY patients (mean ages 66 years, 58 years, and 52 years, respectively). No-CCY patients also tended to have more comorbidities. Nonetheless, having an early CCY retained a “robust” protective effect against recurrent biliary events after accounting for age, sex, comorbidities, stent placement, facility volume, and state of residence. Even after researchers adjusted for those factors, the protective effect of early CCY dropped by less than 5% (from 92% to about 87%), the investigators said.
They also noted that the overall cohort averaged 60 years of age and that 64% were female, which is consistent with the epidemiology of biliary stone disease. Just over half were non-Hispanic whites. Medicare was the single largest primary payer (46%), followed by private insurance (28%) and Medicaid (16%).
“A strategy of delayed CCY performed on an outpatient basis was least costly,” the researchers said. “Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY.”
Funders included a seed grant from the Stanford division of gastroenterology and hepatology and the National Institutes of Health. The investigators had no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy within 60 days.
Major finding: A total of 48% had no cholecystectomy within 60 days. Performing cholecystectomy during index admission cut the risk of recurrent biliary events within 60 days by 92%, compared with delayed or no cholecystectomy (P less than .001).
Data source: A multistate, retrospective study of 4,516 patients hospitalized with choledocholithiasis.
Disclosures: Funders included a Stanford division of gastroenterology and hepatology divisional seed grant and the National Institutes of Health. The investigators had no conflicts of interest.
South African child has suppressed HIV without ART since infancy
A 9-year-old South African child treated with antiretroviral therapy (ART) for HIV infection for 40 weeks as an infant has been living with an undetectable level of the virus ever since without ART, researchers reported on July 24.
“To our knowledge, this is the first reported case of sustained control of HIV in a child enrolled in a randomized trial of ART interruption following treatment early in infancy,” said Avy Violari, MD, at the International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris.
Starting with a high viral load at 9 weeks of age, the child’s treatment brought the viral load to undetectable levels and was halted after 40 weeks. Follow-up examinations and blood sampling over the next 8.5 years showed the child in good health, with only a small reservoir of virus in a tiny portion of immune cells, but a completely undetectable viral load by standard assays. The child’s immune system is healthy, and there are no symptoms of HIV infection.
“Further study is needed to learn how to induce long-term HIV remission in infected babies,” Anthony S. Fauci, MD, director of NIAID, said in an NIH news release about the case. “However, this new case strengthens our hope that by treating HIV-infected children for a brief period beginning in infancy, we may be able to spare them the burden of lifelong therapy and the health consequences of long-term immune activation typically associated with HIV disease.”
A 9-year-old South African child treated with antiretroviral therapy (ART) for HIV infection for 40 weeks as an infant has been living with an undetectable level of the virus ever since without ART, researchers reported on July 24.
“To our knowledge, this is the first reported case of sustained control of HIV in a child enrolled in a randomized trial of ART interruption following treatment early in infancy,” said Avy Violari, MD, at the International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris.
Starting with a high viral load at 9 weeks of age, the child’s treatment brought the viral load to undetectable levels and was halted after 40 weeks. Follow-up examinations and blood sampling over the next 8.5 years showed the child in good health, with only a small reservoir of virus in a tiny portion of immune cells, but a completely undetectable viral load by standard assays. The child’s immune system is healthy, and there are no symptoms of HIV infection.
“Further study is needed to learn how to induce long-term HIV remission in infected babies,” Anthony S. Fauci, MD, director of NIAID, said in an NIH news release about the case. “However, this new case strengthens our hope that by treating HIV-infected children for a brief period beginning in infancy, we may be able to spare them the burden of lifelong therapy and the health consequences of long-term immune activation typically associated with HIV disease.”
A 9-year-old South African child treated with antiretroviral therapy (ART) for HIV infection for 40 weeks as an infant has been living with an undetectable level of the virus ever since without ART, researchers reported on July 24.
“To our knowledge, this is the first reported case of sustained control of HIV in a child enrolled in a randomized trial of ART interruption following treatment early in infancy,” said Avy Violari, MD, at the International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris.
Starting with a high viral load at 9 weeks of age, the child’s treatment brought the viral load to undetectable levels and was halted after 40 weeks. Follow-up examinations and blood sampling over the next 8.5 years showed the child in good health, with only a small reservoir of virus in a tiny portion of immune cells, but a completely undetectable viral load by standard assays. The child’s immune system is healthy, and there are no symptoms of HIV infection.
“Further study is needed to learn how to induce long-term HIV remission in infected babies,” Anthony S. Fauci, MD, director of NIAID, said in an NIH news release about the case. “However, this new case strengthens our hope that by treating HIV-infected children for a brief period beginning in infancy, we may be able to spare them the burden of lifelong therapy and the health consequences of long-term immune activation typically associated with HIV disease.”
FROM IAS 2017
Solid organ transplantation contributes significantly to incidence of NHL among children and adolescents
Solid organ transplant recipients contribute a disproportionate fraction of pediatric non-Hodgkin lymphoma (NHL) cases, especially diffuse large B-cell lymphoma cases (DLBCL), according to an analysis of data drawn from transplant and cancer registries.
Investigators calculated that the incidence of NHL for the pediatric transplant population was 257 times higher than the general population, after analysis from the U.S. transplant registry and 16 cancer registries from around the country between 1990 and 2012. The incidence of NHL for the pediatric transplant population was 306 cases per 100,000 person-years (95% CI, 271-344), compared to 1.19 cases per 100,000 person-years (95% CI, 1.12-1.27) in the general population. Furthermore, transplant recipients made up a much larger proportion of general population DLBCL cases (7.62%; 95% CI, 6.35%-8.88%).
In the general population, the most common subtypes were DLBCL (25% of cases), Burkitt lymphoma (24%), and precursor cell lymphoblastic lymphoma (20%). Among NHLs diagnosed in transplant recipients, 65% were DLBCL, and 9% were Burkitt lymphoma, whereas there were no cases of precursor cell lymphoblastic lymphoma, reported Elizabeth L. Yanik, PhD, of Washington University, St. Louis, and her associates (Cancer. 2017 Jul 31. doi: 10.1002/cncr.30923).
The increased risk of NHL and other cancers for organ transplant recipients is primarily the result of the immunosuppressant medications administered after transplantation, leading to an increased risk of infection-related cancers, the authors said.
“NHL cases are largely attributable to EBV [Epstein-Barr virus] infections that occur while recipients are immunosuppressed, as evidenced by the high prevalence of EBV detectable in NHL tumors and particularly in cases diagnosed during the heavily immunosuppressed period early after transplantation,” wrote Dr. Yanik and her colleagues. “Patients who experience a primary EBV infection after transplantation are particularly susceptible because transplant recipients have a higher NHL risk if they are seronegative for EBV before transplantation.”
Among those at risk, Dr. Yanik and fellow investigators found transplant patients younger than 5 years were the most susceptible to NHL, making up 19.79% of those diagnosed with DLBCL.
The proportion of NHL in solid organ transplant recipients within the entire pediatric NHL population has risen over time, from 1.66% of the NHL population during 1990-1994 to 3.73% during 2010-2012.
“This trend is driven by the rising prevalence of transplant recipients in the general population and not by increases in NHL risk among transplant recipients,” noted Dr. Yanik and her coauthors. “The proportion of NHL diagnoses attributable to transplant recipients has grown over time, and it is likely that this population will be an important source of pediatric NHL cases in the future.”
This study was partially funded by the National Cancer Institute. One coauthor reported being an employee at GRAIL Inc. No other relevant financial disclosures were reported.
ezimmerman@fronlinemedcom.com
On Twitter @eaztweets
Solid organ transplant recipients contribute a disproportionate fraction of pediatric non-Hodgkin lymphoma (NHL) cases, especially diffuse large B-cell lymphoma cases (DLBCL), according to an analysis of data drawn from transplant and cancer registries.
Investigators calculated that the incidence of NHL for the pediatric transplant population was 257 times higher than the general population, after analysis from the U.S. transplant registry and 16 cancer registries from around the country between 1990 and 2012. The incidence of NHL for the pediatric transplant population was 306 cases per 100,000 person-years (95% CI, 271-344), compared to 1.19 cases per 100,000 person-years (95% CI, 1.12-1.27) in the general population. Furthermore, transplant recipients made up a much larger proportion of general population DLBCL cases (7.62%; 95% CI, 6.35%-8.88%).
In the general population, the most common subtypes were DLBCL (25% of cases), Burkitt lymphoma (24%), and precursor cell lymphoblastic lymphoma (20%). Among NHLs diagnosed in transplant recipients, 65% were DLBCL, and 9% were Burkitt lymphoma, whereas there were no cases of precursor cell lymphoblastic lymphoma, reported Elizabeth L. Yanik, PhD, of Washington University, St. Louis, and her associates (Cancer. 2017 Jul 31. doi: 10.1002/cncr.30923).
The increased risk of NHL and other cancers for organ transplant recipients is primarily the result of the immunosuppressant medications administered after transplantation, leading to an increased risk of infection-related cancers, the authors said.
“NHL cases are largely attributable to EBV [Epstein-Barr virus] infections that occur while recipients are immunosuppressed, as evidenced by the high prevalence of EBV detectable in NHL tumors and particularly in cases diagnosed during the heavily immunosuppressed period early after transplantation,” wrote Dr. Yanik and her colleagues. “Patients who experience a primary EBV infection after transplantation are particularly susceptible because transplant recipients have a higher NHL risk if they are seronegative for EBV before transplantation.”
Among those at risk, Dr. Yanik and fellow investigators found transplant patients younger than 5 years were the most susceptible to NHL, making up 19.79% of those diagnosed with DLBCL.
The proportion of NHL in solid organ transplant recipients within the entire pediatric NHL population has risen over time, from 1.66% of the NHL population during 1990-1994 to 3.73% during 2010-2012.
“This trend is driven by the rising prevalence of transplant recipients in the general population and not by increases in NHL risk among transplant recipients,” noted Dr. Yanik and her coauthors. “The proportion of NHL diagnoses attributable to transplant recipients has grown over time, and it is likely that this population will be an important source of pediatric NHL cases in the future.”
This study was partially funded by the National Cancer Institute. One coauthor reported being an employee at GRAIL Inc. No other relevant financial disclosures were reported.
ezimmerman@fronlinemedcom.com
On Twitter @eaztweets
Solid organ transplant recipients contribute a disproportionate fraction of pediatric non-Hodgkin lymphoma (NHL) cases, especially diffuse large B-cell lymphoma cases (DLBCL), according to an analysis of data drawn from transplant and cancer registries.
Investigators calculated that the incidence of NHL for the pediatric transplant population was 257 times higher than the general population, after analysis from the U.S. transplant registry and 16 cancer registries from around the country between 1990 and 2012. The incidence of NHL for the pediatric transplant population was 306 cases per 100,000 person-years (95% CI, 271-344), compared to 1.19 cases per 100,000 person-years (95% CI, 1.12-1.27) in the general population. Furthermore, transplant recipients made up a much larger proportion of general population DLBCL cases (7.62%; 95% CI, 6.35%-8.88%).
In the general population, the most common subtypes were DLBCL (25% of cases), Burkitt lymphoma (24%), and precursor cell lymphoblastic lymphoma (20%). Among NHLs diagnosed in transplant recipients, 65% were DLBCL, and 9% were Burkitt lymphoma, whereas there were no cases of precursor cell lymphoblastic lymphoma, reported Elizabeth L. Yanik, PhD, of Washington University, St. Louis, and her associates (Cancer. 2017 Jul 31. doi: 10.1002/cncr.30923).
The increased risk of NHL and other cancers for organ transplant recipients is primarily the result of the immunosuppressant medications administered after transplantation, leading to an increased risk of infection-related cancers, the authors said.
“NHL cases are largely attributable to EBV [Epstein-Barr virus] infections that occur while recipients are immunosuppressed, as evidenced by the high prevalence of EBV detectable in NHL tumors and particularly in cases diagnosed during the heavily immunosuppressed period early after transplantation,” wrote Dr. Yanik and her colleagues. “Patients who experience a primary EBV infection after transplantation are particularly susceptible because transplant recipients have a higher NHL risk if they are seronegative for EBV before transplantation.”
Among those at risk, Dr. Yanik and fellow investigators found transplant patients younger than 5 years were the most susceptible to NHL, making up 19.79% of those diagnosed with DLBCL.
The proportion of NHL in solid organ transplant recipients within the entire pediatric NHL population has risen over time, from 1.66% of the NHL population during 1990-1994 to 3.73% during 2010-2012.
“This trend is driven by the rising prevalence of transplant recipients in the general population and not by increases in NHL risk among transplant recipients,” noted Dr. Yanik and her coauthors. “The proportion of NHL diagnoses attributable to transplant recipients has grown over time, and it is likely that this population will be an important source of pediatric NHL cases in the future.”
This study was partially funded by the National Cancer Institute. One coauthor reported being an employee at GRAIL Inc. No other relevant financial disclosures were reported.
ezimmerman@fronlinemedcom.com
On Twitter @eaztweets
FROM CANCER
Key clinical point: Solid organ transplant recipients contribute a disproportionate fraction of pediatric NHL cases, especially DLBCL cases.
Major finding: Incidence of NHL among the pediatric transplant population was 257 times higher at 306 cases per 100,000 person-years (95% CI, 271-344), compared to 1.19 cases per 100,000 person-years (95% CI, 1.12-1.27) in the general pediatric population.
Data source: Retrospective cohort study of children and adolescents in the U.S. transplant registry and 16 cancer registries from around the country between 1990 and 2012.
Disclosures: This study was partially funded by the National Cancer Institute. One coauthor reported being an employee at GRAIL Inc. No other relevant financial disclosures were reported.
POLL: Draft classification criteria for SLE stir controversy
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