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FDA grants orphan drug status to rofecoxib for hemophilic arthropathy
The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).
HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.
The attempt at a reintroduction of rofecoxib specifically for the treatment of HA is being developed by Tremeau Pharmaceuticals.
Patients with hemophilia look to avoid traditional NSAIDs, as those drugs risk gastrointestinal ulcers and impair platelet aggregation. The current standard of care for HA is opioid treatment.
Rofecoxib and other NSAIDs cause an increased risk of serious cardiovascular thrombotic events and gastrointestinal adverse events.
Orphan drug status is available to treatments for rare disorders and provides a 7-year marketing exclusivity period against competition, along with tax credits and a waiver of Prescription Drug User Fee Act filing fees.
The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).
HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.
The attempt at a reintroduction of rofecoxib specifically for the treatment of HA is being developed by Tremeau Pharmaceuticals.
Patients with hemophilia look to avoid traditional NSAIDs, as those drugs risk gastrointestinal ulcers and impair platelet aggregation. The current standard of care for HA is opioid treatment.
Rofecoxib and other NSAIDs cause an increased risk of serious cardiovascular thrombotic events and gastrointestinal adverse events.
Orphan drug status is available to treatments for rare disorders and provides a 7-year marketing exclusivity period against competition, along with tax credits and a waiver of Prescription Drug User Fee Act filing fees.
The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).
HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.
The attempt at a reintroduction of rofecoxib specifically for the treatment of HA is being developed by Tremeau Pharmaceuticals.
Patients with hemophilia look to avoid traditional NSAIDs, as those drugs risk gastrointestinal ulcers and impair platelet aggregation. The current standard of care for HA is opioid treatment.
Rofecoxib and other NSAIDs cause an increased risk of serious cardiovascular thrombotic events and gastrointestinal adverse events.
Orphan drug status is available to treatments for rare disorders and provides a 7-year marketing exclusivity period against competition, along with tax credits and a waiver of Prescription Drug User Fee Act filing fees.
Siponimod Improves MRI Outcomes in Patients With Secondary Progressive MS
PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues. 
The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.
The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.
The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.
The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.
At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm3 in the full analysis set and −634 mm3 in the per protocol analysis set. At month 24, the differences were −778 mm3 in the full analysis set and −830 mm3 in the per protocol analysis set.
At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.
Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.
This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.
PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.
The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.
The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.
The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.
The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.
At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm3 in the full analysis set and −634 mm3 in the per protocol analysis set. At month 24, the differences were −778 mm3 in the full analysis set and −830 mm3 in the per protocol analysis set.
At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.
Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.
This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.
PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.
The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.
The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.
The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.
The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.
At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm3 in the full analysis set and −634 mm3 in the per protocol analysis set. At month 24, the differences were −778 mm3 in the full analysis set and −830 mm3 in the per protocol analysis set.
At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.
Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.
This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.
REBOA improves survival for trauma patients
SCOTTSDALE, ARIZ. – In a small, single-center study of patients with subdiaphragmatic hemorrhage, resuscitative endovascular balloon occlusion of the aorta (REBOA) improved hemodynamic status and 30-day survival rates, compared with resuscitative thoracotomy (RT).
Although the technique was first developed during the Korean War, REBOA never really caught on, possibly because of limitations in endovascular technology. But recent advances in surgical technique have revitalized interest.
Despite the success of the study, some audience members expressed concerns about the skill set required. One questioner pointed out that emergency department physicians may be tempted to use the technique, even though they may not possess the requisite catheter and wire skills. That is a legitimate concern, according to senior author R. Stephen Smith, MD, FACS, professor of acute care surgery at the University of Florida, Gainesville. But this is already happening, he said. “They’ve already done it in the field in Britain, and most are placed by nonsurgeons in Japan. Frankly, we need to pay particular attention to the skills of those emergency medicine physicians, because the average emergency medicine physician at this point really doesn’t have the catheter or wire-based skills to do this safely,” Dr. Smith said at the annual meeting of the Western Surgical Association.
The researchers examined outcomes in patients who underwent REBOA versus RT over a 21-month (2015-2017) period at their institution. Before adopting REBOA, attending surgeons and senior surgical residents attended a 1.5-hour slide presentation combined with simulation training. No external course was required. Operating room personnel received a 30-minute slide presentation. The procedures were conducted in a dedicated trauma operating room equipped with imaging.
Sixteen patients underwent REBOA during the study period, with a mean injury severity score of 38.6. Preoperative hemoglobin levels ranged from 5 to 14.4 mg/dL, and the majority were acidotic because of trauma.
Fourteen of the 16 patients who underwent REBOA survived the operative procedure, and 6 survived to 30 days. By contrast, 8 patients were treated with RT, and none survived to 30 days. Ten of the 16 patients who underwent REBOA experienced an improvement in hemodynamic status, with systolic blood pressure improving to a mean of 131.83 mm Hg (±8.24) and improvement of heart rate to 87.5 (±5.47). One survivor developed a common femoral pseudoaneurysm.
Compared with nonsurvivors, REBOA patients who survived had a significant increase in Initial Glasgow Coma scores (15.0 vs. 6.18; P less than .05), and higher initial platelet counts (276.40 vs. 124.75; P = .01). Survivors also had higher initial postoperative systolic blood pressure (151.40 mm Hg vs. 112.33; P = .05), and a higher mean postoperative arterial blood pressure (109.00 mm Hg vs. 72.78; P = .01).
Overall, the findings were similar to those reported in previous multicenter trials.
The researchers pointed out that REBOA does not replace RT. The latter procedure is still appropriate for some moribund patients with super-diaphragmatic injury and in patients who require open cardiac massage.
The techniques are not mutually exclusive – two patients in the sample were treated with both techniques.
The researchers also mentioned some future possibilities for REBOA. Research in animals has demonstrated the promise of partial REBOA, in which an automated system can partially inflate the balloon and gradually deflate it as the patient’s vital signs improve. That can lighten the load for surgeons and anesthesiologists, according to Dr. Smith. “We look forward to developing that technology in the future,” he said.
The funding source was not disclosed. Dr. Smith is on the speakers bureau for Prytime Medical and is a consultant for Boehringer Laboratory LLC.
SCOTTSDALE, ARIZ. – In a small, single-center study of patients with subdiaphragmatic hemorrhage, resuscitative endovascular balloon occlusion of the aorta (REBOA) improved hemodynamic status and 30-day survival rates, compared with resuscitative thoracotomy (RT).
Although the technique was first developed during the Korean War, REBOA never really caught on, possibly because of limitations in endovascular technology. But recent advances in surgical technique have revitalized interest.
Despite the success of the study, some audience members expressed concerns about the skill set required. One questioner pointed out that emergency department physicians may be tempted to use the technique, even though they may not possess the requisite catheter and wire skills. That is a legitimate concern, according to senior author R. Stephen Smith, MD, FACS, professor of acute care surgery at the University of Florida, Gainesville. But this is already happening, he said. “They’ve already done it in the field in Britain, and most are placed by nonsurgeons in Japan. Frankly, we need to pay particular attention to the skills of those emergency medicine physicians, because the average emergency medicine physician at this point really doesn’t have the catheter or wire-based skills to do this safely,” Dr. Smith said at the annual meeting of the Western Surgical Association.
The researchers examined outcomes in patients who underwent REBOA versus RT over a 21-month (2015-2017) period at their institution. Before adopting REBOA, attending surgeons and senior surgical residents attended a 1.5-hour slide presentation combined with simulation training. No external course was required. Operating room personnel received a 30-minute slide presentation. The procedures were conducted in a dedicated trauma operating room equipped with imaging.
Sixteen patients underwent REBOA during the study period, with a mean injury severity score of 38.6. Preoperative hemoglobin levels ranged from 5 to 14.4 mg/dL, and the majority were acidotic because of trauma.
Fourteen of the 16 patients who underwent REBOA survived the operative procedure, and 6 survived to 30 days. By contrast, 8 patients were treated with RT, and none survived to 30 days. Ten of the 16 patients who underwent REBOA experienced an improvement in hemodynamic status, with systolic blood pressure improving to a mean of 131.83 mm Hg (±8.24) and improvement of heart rate to 87.5 (±5.47). One survivor developed a common femoral pseudoaneurysm.
Compared with nonsurvivors, REBOA patients who survived had a significant increase in Initial Glasgow Coma scores (15.0 vs. 6.18; P less than .05), and higher initial platelet counts (276.40 vs. 124.75; P = .01). Survivors also had higher initial postoperative systolic blood pressure (151.40 mm Hg vs. 112.33; P = .05), and a higher mean postoperative arterial blood pressure (109.00 mm Hg vs. 72.78; P = .01).
Overall, the findings were similar to those reported in previous multicenter trials.
The researchers pointed out that REBOA does not replace RT. The latter procedure is still appropriate for some moribund patients with super-diaphragmatic injury and in patients who require open cardiac massage.
The techniques are not mutually exclusive – two patients in the sample were treated with both techniques.
The researchers also mentioned some future possibilities for REBOA. Research in animals has demonstrated the promise of partial REBOA, in which an automated system can partially inflate the balloon and gradually deflate it as the patient’s vital signs improve. That can lighten the load for surgeons and anesthesiologists, according to Dr. Smith. “We look forward to developing that technology in the future,” he said.
The funding source was not disclosed. Dr. Smith is on the speakers bureau for Prytime Medical and is a consultant for Boehringer Laboratory LLC.
SCOTTSDALE, ARIZ. – In a small, single-center study of patients with subdiaphragmatic hemorrhage, resuscitative endovascular balloon occlusion of the aorta (REBOA) improved hemodynamic status and 30-day survival rates, compared with resuscitative thoracotomy (RT).
Although the technique was first developed during the Korean War, REBOA never really caught on, possibly because of limitations in endovascular technology. But recent advances in surgical technique have revitalized interest.
Despite the success of the study, some audience members expressed concerns about the skill set required. One questioner pointed out that emergency department physicians may be tempted to use the technique, even though they may not possess the requisite catheter and wire skills. That is a legitimate concern, according to senior author R. Stephen Smith, MD, FACS, professor of acute care surgery at the University of Florida, Gainesville. But this is already happening, he said. “They’ve already done it in the field in Britain, and most are placed by nonsurgeons in Japan. Frankly, we need to pay particular attention to the skills of those emergency medicine physicians, because the average emergency medicine physician at this point really doesn’t have the catheter or wire-based skills to do this safely,” Dr. Smith said at the annual meeting of the Western Surgical Association.
The researchers examined outcomes in patients who underwent REBOA versus RT over a 21-month (2015-2017) period at their institution. Before adopting REBOA, attending surgeons and senior surgical residents attended a 1.5-hour slide presentation combined with simulation training. No external course was required. Operating room personnel received a 30-minute slide presentation. The procedures were conducted in a dedicated trauma operating room equipped with imaging.
Sixteen patients underwent REBOA during the study period, with a mean injury severity score of 38.6. Preoperative hemoglobin levels ranged from 5 to 14.4 mg/dL, and the majority were acidotic because of trauma.
Fourteen of the 16 patients who underwent REBOA survived the operative procedure, and 6 survived to 30 days. By contrast, 8 patients were treated with RT, and none survived to 30 days. Ten of the 16 patients who underwent REBOA experienced an improvement in hemodynamic status, with systolic blood pressure improving to a mean of 131.83 mm Hg (±8.24) and improvement of heart rate to 87.5 (±5.47). One survivor developed a common femoral pseudoaneurysm.
Compared with nonsurvivors, REBOA patients who survived had a significant increase in Initial Glasgow Coma scores (15.0 vs. 6.18; P less than .05), and higher initial platelet counts (276.40 vs. 124.75; P = .01). Survivors also had higher initial postoperative systolic blood pressure (151.40 mm Hg vs. 112.33; P = .05), and a higher mean postoperative arterial blood pressure (109.00 mm Hg vs. 72.78; P = .01).
Overall, the findings were similar to those reported in previous multicenter trials.
The researchers pointed out that REBOA does not replace RT. The latter procedure is still appropriate for some moribund patients with super-diaphragmatic injury and in patients who require open cardiac massage.
The techniques are not mutually exclusive – two patients in the sample were treated with both techniques.
The researchers also mentioned some future possibilities for REBOA. Research in animals has demonstrated the promise of partial REBOA, in which an automated system can partially inflate the balloon and gradually deflate it as the patient’s vital signs improve. That can lighten the load for surgeons and anesthesiologists, according to Dr. Smith. “We look forward to developing that technology in the future,” he said.
The funding source was not disclosed. Dr. Smith is on the speakers bureau for Prytime Medical and is a consultant for Boehringer Laboratory LLC.
AT WSA 2017
Key clinical point: REBOA improved hematological outcomes and survival rates, compared with resuscitative thoracotomy.
Major finding: Six of 16 patients in the REBOA group survived to 30 days, compared with none of the 8 resuscitative thoracotomy patients.
Data source: Retrospective analysis of 24 patients at a single center.
Disclosures: The funding source was not disclosed. Dr. Smith is on the speakers bureau for Prytime Medical and is a consultant for Boehringer Laboratory LLC.
A compounded, nonbenzodiazepine option for treating acute anxiety
Treating short-term or situational anxiety or anxiety attacks with benzodiazepines carries the risk of withdrawal and dependence. Other options include various antidepressants and buspirone. Although such medications decrease overall anxiety and can prevent anxiety from building, they are not effective for breakthrough anxiety. Other mainstays are antihistamines, antipsychotics, or newer antiepileptics such as gabapentin and pregabalin, but none of these have strong clinical literature support regarding their effectiveness for treating anxiety disorders.
PanX compounded medications are dual drug combinations of a beta blocker plus an antiemetic antimuscarinic agent.1 They are designed and patented for as-needed treatment of anxiety disorders without using any controlled substances. Compounded medications are not FDA-approved, but are commercially available and subject to Section 503A of the Federal Food, Drug, and Cosmetics Act of 2013.2
In PanX medications, the beta blocker is intended to address the sympathetic cardiovascular symptoms of anxiety. Beta adrenergic receptor antagonists have been prescribed off-label for decades to treat social anxiety disorder, including performance anxiety. At least 7 beta blockers—atenolol, propranolol, pindolol, timolol, nadolol, betaxolol, and oxprenolol—have been reported to have anxiolytic effects, although these are limited to cardiovascular symptoms of anxiety.1
However, there is a need to augment the limited effects of the beta blocker with another agent, such as an antimuscarinic agent, which is intended for parasympathetic noncardiovascular and CNS symptoms of anxiety. Scopolamine is a preferred antimuscarinic because it has been known for over a century to exhibit anxiolytic effects.3 Scopolamine’s mechanism of action is antagonism of acetylcholine binding to the M1 and/or M2 muscarinic receptors.4
We present a case of a patient who needed a nonbenzodiazepine treatment for acute anxiety. She received a compounded PanX combination of the beta-1 selective beta blocker atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, as needed for acute anxiety.
Case report
Acute anxiety, benzodiazepine abuse
Ms. L, age 30, with a family history of depression and anxiety, has had anxiety, depression, and posttraumatic stress disorder since she was in her mid-20s. She is evaluated in a 30-day rehabilitation program for alprazolam abuse. She is detoxed from alprazolam and stabilized with lurasidone, 60 mg once in the morning, gabapentin, 1,200 mg 4 times a day, and quetiapine, 125 mg as needed for sleep.
Ms. L improves significantly and is transferred to an intensive outpatient program. While there, she experiences increased periods of anxiety related to ruminative thoughts about relationship, occupational, and living stressors. She requests a medication for breakthrough anxiety and recognizes that, because of her history, a benzodiazepine is not medically indicated.
Ms. L signs a consent to a physician-sponsored trial of a PanX medication consisting of orally disintegrating tablets of atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, (in a polyglycol troche base plus mannitol, silica gel, and Steviol glycosides), which is prepared by a compounding pharmacy. Over 6 days, she takes the PanX combination 3 times. Immediately before she takes the medication, her symptoms are intense anxiety, nervousness, and agitation; feelings of panic; increased heart rate and palpitations; and shortness of breath. Ms. L says these symptoms developed approximately 20 minutes before she took the PanX combination. Approximately 30 minutes after taking the medication, she describes having a complete resolution of these symptoms that lasted for 4 hours. She says the medication “calmed [her] down” and had a “Klonopin or benzo-like effect.” She notes that her heart rate slowed quickly, followed by her breathing, and that she also was “more focused.” No information regarding her heart rate or blood pressure when she experienced the symptoms or after treatment is available. She denies experiencing dry mouth, dizziness, fatigue, sleepiness, blurred vision, or confusion.
Targets for future research
This case provides some preliminary clinical evidence of a rapid anxiolytic effect from a novel medication—a beta blocker plus scopolamine combination—that was beneficial in a situation where it may be likely that a benzodiazepine would have been utilized. This is our first case report documenting a trial of any PanX combination (ie, a combination of any beta blocker with any antimuscarinic agent) regarding anxiolytic efficacy and timing, tolerability, and adverse effects. With recognition that this is a report of 1 patient who took the medication 3 times, there is much that is not known.
Additional clinical studies are needed to evaluate the efficacy, tolerability, and adverse effects associated with using a beta blocker/antiemetic antimuscarinic combination to treat acute anxiety. Medication interactions also need to be considered. Whether this combination medication would be best for treating breakthrough anxiety or other acute anxiety episodes, and/or used as a regularly dosed medication is unknown. With documented risks of long-term benzodiazepine use, other novel therapeutics, such as the atenolol/scopolamine combination, may be welcome in treating acute anxiety.
1. Dooley TP. Treating anxiety with either beta blockers or antiemetic antimuscarinic drugs: a review. Mental Health Fam Med. 2015;11(1):89-99.
2. U.S. Food and Drug Administration. Guidance, compliance and regulatory information: compounding. Section 503A of the Federal Food, Drug, and Cosmetic Act. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ucm376733.htm. Updated December 12, 2013. Accessed October 25, 2017.
3. Houde A. Scopolamine: a physiological and clinical study. The Am J Clin Med. 1906;13:365-367.
4. Witkin JM, Overshiner C, Li X, et al. M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther. 2014;351(2):448-456.
Treating short-term or situational anxiety or anxiety attacks with benzodiazepines carries the risk of withdrawal and dependence. Other options include various antidepressants and buspirone. Although such medications decrease overall anxiety and can prevent anxiety from building, they are not effective for breakthrough anxiety. Other mainstays are antihistamines, antipsychotics, or newer antiepileptics such as gabapentin and pregabalin, but none of these have strong clinical literature support regarding their effectiveness for treating anxiety disorders.
PanX compounded medications are dual drug combinations of a beta blocker plus an antiemetic antimuscarinic agent.1 They are designed and patented for as-needed treatment of anxiety disorders without using any controlled substances. Compounded medications are not FDA-approved, but are commercially available and subject to Section 503A of the Federal Food, Drug, and Cosmetics Act of 2013.2
In PanX medications, the beta blocker is intended to address the sympathetic cardiovascular symptoms of anxiety. Beta adrenergic receptor antagonists have been prescribed off-label for decades to treat social anxiety disorder, including performance anxiety. At least 7 beta blockers—atenolol, propranolol, pindolol, timolol, nadolol, betaxolol, and oxprenolol—have been reported to have anxiolytic effects, although these are limited to cardiovascular symptoms of anxiety.1
However, there is a need to augment the limited effects of the beta blocker with another agent, such as an antimuscarinic agent, which is intended for parasympathetic noncardiovascular and CNS symptoms of anxiety. Scopolamine is a preferred antimuscarinic because it has been known for over a century to exhibit anxiolytic effects.3 Scopolamine’s mechanism of action is antagonism of acetylcholine binding to the M1 and/or M2 muscarinic receptors.4
We present a case of a patient who needed a nonbenzodiazepine treatment for acute anxiety. She received a compounded PanX combination of the beta-1 selective beta blocker atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, as needed for acute anxiety.
Case report
Acute anxiety, benzodiazepine abuse
Ms. L, age 30, with a family history of depression and anxiety, has had anxiety, depression, and posttraumatic stress disorder since she was in her mid-20s. She is evaluated in a 30-day rehabilitation program for alprazolam abuse. She is detoxed from alprazolam and stabilized with lurasidone, 60 mg once in the morning, gabapentin, 1,200 mg 4 times a day, and quetiapine, 125 mg as needed for sleep.
Ms. L improves significantly and is transferred to an intensive outpatient program. While there, she experiences increased periods of anxiety related to ruminative thoughts about relationship, occupational, and living stressors. She requests a medication for breakthrough anxiety and recognizes that, because of her history, a benzodiazepine is not medically indicated.
Ms. L signs a consent to a physician-sponsored trial of a PanX medication consisting of orally disintegrating tablets of atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, (in a polyglycol troche base plus mannitol, silica gel, and Steviol glycosides), which is prepared by a compounding pharmacy. Over 6 days, she takes the PanX combination 3 times. Immediately before she takes the medication, her symptoms are intense anxiety, nervousness, and agitation; feelings of panic; increased heart rate and palpitations; and shortness of breath. Ms. L says these symptoms developed approximately 20 minutes before she took the PanX combination. Approximately 30 minutes after taking the medication, she describes having a complete resolution of these symptoms that lasted for 4 hours. She says the medication “calmed [her] down” and had a “Klonopin or benzo-like effect.” She notes that her heart rate slowed quickly, followed by her breathing, and that she also was “more focused.” No information regarding her heart rate or blood pressure when she experienced the symptoms or after treatment is available. She denies experiencing dry mouth, dizziness, fatigue, sleepiness, blurred vision, or confusion.
Targets for future research
This case provides some preliminary clinical evidence of a rapid anxiolytic effect from a novel medication—a beta blocker plus scopolamine combination—that was beneficial in a situation where it may be likely that a benzodiazepine would have been utilized. This is our first case report documenting a trial of any PanX combination (ie, a combination of any beta blocker with any antimuscarinic agent) regarding anxiolytic efficacy and timing, tolerability, and adverse effects. With recognition that this is a report of 1 patient who took the medication 3 times, there is much that is not known.
Additional clinical studies are needed to evaluate the efficacy, tolerability, and adverse effects associated with using a beta blocker/antiemetic antimuscarinic combination to treat acute anxiety. Medication interactions also need to be considered. Whether this combination medication would be best for treating breakthrough anxiety or other acute anxiety episodes, and/or used as a regularly dosed medication is unknown. With documented risks of long-term benzodiazepine use, other novel therapeutics, such as the atenolol/scopolamine combination, may be welcome in treating acute anxiety.
Treating short-term or situational anxiety or anxiety attacks with benzodiazepines carries the risk of withdrawal and dependence. Other options include various antidepressants and buspirone. Although such medications decrease overall anxiety and can prevent anxiety from building, they are not effective for breakthrough anxiety. Other mainstays are antihistamines, antipsychotics, or newer antiepileptics such as gabapentin and pregabalin, but none of these have strong clinical literature support regarding their effectiveness for treating anxiety disorders.
PanX compounded medications are dual drug combinations of a beta blocker plus an antiemetic antimuscarinic agent.1 They are designed and patented for as-needed treatment of anxiety disorders without using any controlled substances. Compounded medications are not FDA-approved, but are commercially available and subject to Section 503A of the Federal Food, Drug, and Cosmetics Act of 2013.2
In PanX medications, the beta blocker is intended to address the sympathetic cardiovascular symptoms of anxiety. Beta adrenergic receptor antagonists have been prescribed off-label for decades to treat social anxiety disorder, including performance anxiety. At least 7 beta blockers—atenolol, propranolol, pindolol, timolol, nadolol, betaxolol, and oxprenolol—have been reported to have anxiolytic effects, although these are limited to cardiovascular symptoms of anxiety.1
However, there is a need to augment the limited effects of the beta blocker with another agent, such as an antimuscarinic agent, which is intended for parasympathetic noncardiovascular and CNS symptoms of anxiety. Scopolamine is a preferred antimuscarinic because it has been known for over a century to exhibit anxiolytic effects.3 Scopolamine’s mechanism of action is antagonism of acetylcholine binding to the M1 and/or M2 muscarinic receptors.4
We present a case of a patient who needed a nonbenzodiazepine treatment for acute anxiety. She received a compounded PanX combination of the beta-1 selective beta blocker atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, as needed for acute anxiety.
Case report
Acute anxiety, benzodiazepine abuse
Ms. L, age 30, with a family history of depression and anxiety, has had anxiety, depression, and posttraumatic stress disorder since she was in her mid-20s. She is evaluated in a 30-day rehabilitation program for alprazolam abuse. She is detoxed from alprazolam and stabilized with lurasidone, 60 mg once in the morning, gabapentin, 1,200 mg 4 times a day, and quetiapine, 125 mg as needed for sleep.
Ms. L improves significantly and is transferred to an intensive outpatient program. While there, she experiences increased periods of anxiety related to ruminative thoughts about relationship, occupational, and living stressors. She requests a medication for breakthrough anxiety and recognizes that, because of her history, a benzodiazepine is not medically indicated.
Ms. L signs a consent to a physician-sponsored trial of a PanX medication consisting of orally disintegrating tablets of atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, (in a polyglycol troche base plus mannitol, silica gel, and Steviol glycosides), which is prepared by a compounding pharmacy. Over 6 days, she takes the PanX combination 3 times. Immediately before she takes the medication, her symptoms are intense anxiety, nervousness, and agitation; feelings of panic; increased heart rate and palpitations; and shortness of breath. Ms. L says these symptoms developed approximately 20 minutes before she took the PanX combination. Approximately 30 minutes after taking the medication, she describes having a complete resolution of these symptoms that lasted for 4 hours. She says the medication “calmed [her] down” and had a “Klonopin or benzo-like effect.” She notes that her heart rate slowed quickly, followed by her breathing, and that she also was “more focused.” No information regarding her heart rate or blood pressure when she experienced the symptoms or after treatment is available. She denies experiencing dry mouth, dizziness, fatigue, sleepiness, blurred vision, or confusion.
Targets for future research
This case provides some preliminary clinical evidence of a rapid anxiolytic effect from a novel medication—a beta blocker plus scopolamine combination—that was beneficial in a situation where it may be likely that a benzodiazepine would have been utilized. This is our first case report documenting a trial of any PanX combination (ie, a combination of any beta blocker with any antimuscarinic agent) regarding anxiolytic efficacy and timing, tolerability, and adverse effects. With recognition that this is a report of 1 patient who took the medication 3 times, there is much that is not known.
Additional clinical studies are needed to evaluate the efficacy, tolerability, and adverse effects associated with using a beta blocker/antiemetic antimuscarinic combination to treat acute anxiety. Medication interactions also need to be considered. Whether this combination medication would be best for treating breakthrough anxiety or other acute anxiety episodes, and/or used as a regularly dosed medication is unknown. With documented risks of long-term benzodiazepine use, other novel therapeutics, such as the atenolol/scopolamine combination, may be welcome in treating acute anxiety.
1. Dooley TP. Treating anxiety with either beta blockers or antiemetic antimuscarinic drugs: a review. Mental Health Fam Med. 2015;11(1):89-99.
2. U.S. Food and Drug Administration. Guidance, compliance and regulatory information: compounding. Section 503A of the Federal Food, Drug, and Cosmetic Act. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ucm376733.htm. Updated December 12, 2013. Accessed October 25, 2017.
3. Houde A. Scopolamine: a physiological and clinical study. The Am J Clin Med. 1906;13:365-367.
4. Witkin JM, Overshiner C, Li X, et al. M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther. 2014;351(2):448-456.
1. Dooley TP. Treating anxiety with either beta blockers or antiemetic antimuscarinic drugs: a review. Mental Health Fam Med. 2015;11(1):89-99.
2. U.S. Food and Drug Administration. Guidance, compliance and regulatory information: compounding. Section 503A of the Federal Food, Drug, and Cosmetic Act. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ucm376733.htm. Updated December 12, 2013. Accessed October 25, 2017.
3. Houde A. Scopolamine: a physiological and clinical study. The Am J Clin Med. 1906;13:365-367.
4. Witkin JM, Overshiner C, Li X, et al. M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther. 2014;351(2):448-456.
New and Noteworthy Information—December 2017
Brain Glucose Level Is Associated With Alzheimer’s Disease Severity
Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.
An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].
Is it Better to Be Asleep or Awake for DBS Implantation?
Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake.
Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.
Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?
People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm3 greater ventricular volume, 110 mm3 smaller hippocampal volume, 519 mm3 smaller occipital volume, and 532 mm3 smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.
Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].
Novel Wristbands Improve Seizure Detection
Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.
Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.
Focused Ultrasound Reduces Parkinson’s Disease Tremor
Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.
Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].
Biomarker of Multiple Sclerosis Identified
MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.
Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.
Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?
The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.
Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].
Dendritic Spine Plasticity May Protect Against Dementia
Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.
Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.
Opioid Versus Nonopioid Treatment for Acute Migraine
IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.
Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].
Frontotemporal Degeneration Entails High Economic Burden
The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.
Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].
FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy
The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.
—Kimberly Williams
Brain Glucose Level Is Associated With Alzheimer’s Disease Severity
Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.
An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].
Is it Better to Be Asleep or Awake for DBS Implantation?
Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake.
Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.
Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?
People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm3 greater ventricular volume, 110 mm3 smaller hippocampal volume, 519 mm3 smaller occipital volume, and 532 mm3 smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.
Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].
Novel Wristbands Improve Seizure Detection
Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.
Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.
Focused Ultrasound Reduces Parkinson’s Disease Tremor
Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.
Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].
Biomarker of Multiple Sclerosis Identified
MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.
Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.
Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?
The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.
Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].
Dendritic Spine Plasticity May Protect Against Dementia
Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.
Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.
Opioid Versus Nonopioid Treatment for Acute Migraine
IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.
Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].
Frontotemporal Degeneration Entails High Economic Burden
The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.
Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].
FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy
The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.
—Kimberly Williams
Brain Glucose Level Is Associated With Alzheimer’s Disease Severity
Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.
An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].
Is it Better to Be Asleep or Awake for DBS Implantation?
Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake.
Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.
Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?
People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm3 greater ventricular volume, 110 mm3 smaller hippocampal volume, 519 mm3 smaller occipital volume, and 532 mm3 smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.
Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].
Novel Wristbands Improve Seizure Detection
Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.
Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.
Focused Ultrasound Reduces Parkinson’s Disease Tremor
Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.
Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].
Biomarker of Multiple Sclerosis Identified
MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.
Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.
Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?
The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.
Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].
Dendritic Spine Plasticity May Protect Against Dementia
Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.
Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.
Opioid Versus Nonopioid Treatment for Acute Migraine
IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.
Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].
Frontotemporal Degeneration Entails High Economic Burden
The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.
Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].
FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy
The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.
—Kimberly Williams
Proposed SLE classification criteria prove highly sensitive, specific
SAN DIEGO – yielded a sensitivity of 98% and a specificity of 97%.
The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.
A synopsis of the first three phases from the ongoing effort was presented at the June 2017 EULAR meeting. It included results from a systematic review of the literature and a meta-regression analysis to determine whether antinuclear autoantibodies should be required in the classification of SLE. The analysis showed that an antinuclear antibody titer of greater than or equal to 1:80 by immunofluorescence on human epithelial type 2 cells had a sensitivity of 98.4% for correctly capturing SLE. This prompted the EULAR/ACR steering committee to propose this titer as an “entry criterion” for SLE classification.
At the ACR meeting, Dr. Johnson, a rheumatologist at the University of Toronto who also cochairs the ACR Classification and Response Criteria subcommittee, discussed the fourth phase of the collaboration, which involves fine-tuning and validating the proposed SLE classification criteria.
To date, 189 investigators and more than 3,500 patients have contributed to the effort. “In the most recent phase, 36 international lupus centers were approached to contribute 100 cases and 100 controls,” she explained. “We then had each case independently adjudicated by three lupus experts at three different lupus centers to make sure there was consensus on the diagnosis. Next, we randomly selected 500 cases and 500 controls, resulting in a derivation cohort of 1,000 subjects to test our draft criteria system.”
Dr. Johnson and her associates found that the proposed SLE criteria had a sensitivity of 98% and a specificity of 97%, which exceeds that of the old ACR criteria. “We have defined a system of criteria which produces a measure of the relative probability that a particular case with a combination of clinical symptoms or features has SLE,” she said.
Dr. Johnson emphasized that the proposed criteria are intended for the classification of SLE, not for diagnosing the condition. “The diagnosis of lupus still remains in the hands of the physician, who will take into account all of the symptoms, signs, and other investigations,” she said. “We have identified the highest yield of those, but there will be some people who do not fulfill classification criteria yet do have a diagnosis of SLE.”
The next few weeks is a period to solicit feedback from stakeholders, after which members of the EULAR/ACR steering committee will be weighing feedback on the proposed criteria. “After that, we will see if there are any final revisions that need to be made,” Dr. Johnson said. “If we’re happy with the product, then the final validation will occur. We still have more than 1,000 patients from the validation core that has been reserved for that final validation.”
Data from the final validation are expected to be presented at the June 2018 EULAR meeting and ultimately published in Arthritis and Rheumatism and the Annals of Rheumatic Diseases. “Before we can get there, though, it needs to be formally reviewed by the ACR and EULAR for their formal endorsement. We expect that will take another 6 months.” She reported having no disclosures.
SAN DIEGO – yielded a sensitivity of 98% and a specificity of 97%.
The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.
A synopsis of the first three phases from the ongoing effort was presented at the June 2017 EULAR meeting. It included results from a systematic review of the literature and a meta-regression analysis to determine whether antinuclear autoantibodies should be required in the classification of SLE. The analysis showed that an antinuclear antibody titer of greater than or equal to 1:80 by immunofluorescence on human epithelial type 2 cells had a sensitivity of 98.4% for correctly capturing SLE. This prompted the EULAR/ACR steering committee to propose this titer as an “entry criterion” for SLE classification.
At the ACR meeting, Dr. Johnson, a rheumatologist at the University of Toronto who also cochairs the ACR Classification and Response Criteria subcommittee, discussed the fourth phase of the collaboration, which involves fine-tuning and validating the proposed SLE classification criteria.
To date, 189 investigators and more than 3,500 patients have contributed to the effort. “In the most recent phase, 36 international lupus centers were approached to contribute 100 cases and 100 controls,” she explained. “We then had each case independently adjudicated by three lupus experts at three different lupus centers to make sure there was consensus on the diagnosis. Next, we randomly selected 500 cases and 500 controls, resulting in a derivation cohort of 1,000 subjects to test our draft criteria system.”
Dr. Johnson and her associates found that the proposed SLE criteria had a sensitivity of 98% and a specificity of 97%, which exceeds that of the old ACR criteria. “We have defined a system of criteria which produces a measure of the relative probability that a particular case with a combination of clinical symptoms or features has SLE,” she said.
Dr. Johnson emphasized that the proposed criteria are intended for the classification of SLE, not for diagnosing the condition. “The diagnosis of lupus still remains in the hands of the physician, who will take into account all of the symptoms, signs, and other investigations,” she said. “We have identified the highest yield of those, but there will be some people who do not fulfill classification criteria yet do have a diagnosis of SLE.”
The next few weeks is a period to solicit feedback from stakeholders, after which members of the EULAR/ACR steering committee will be weighing feedback on the proposed criteria. “After that, we will see if there are any final revisions that need to be made,” Dr. Johnson said. “If we’re happy with the product, then the final validation will occur. We still have more than 1,000 patients from the validation core that has been reserved for that final validation.”
Data from the final validation are expected to be presented at the June 2018 EULAR meeting and ultimately published in Arthritis and Rheumatism and the Annals of Rheumatic Diseases. “Before we can get there, though, it needs to be formally reviewed by the ACR and EULAR for their formal endorsement. We expect that will take another 6 months.” She reported having no disclosures.
SAN DIEGO – yielded a sensitivity of 98% and a specificity of 97%.
The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.
A synopsis of the first three phases from the ongoing effort was presented at the June 2017 EULAR meeting. It included results from a systematic review of the literature and a meta-regression analysis to determine whether antinuclear autoantibodies should be required in the classification of SLE. The analysis showed that an antinuclear antibody titer of greater than or equal to 1:80 by immunofluorescence on human epithelial type 2 cells had a sensitivity of 98.4% for correctly capturing SLE. This prompted the EULAR/ACR steering committee to propose this titer as an “entry criterion” for SLE classification.
At the ACR meeting, Dr. Johnson, a rheumatologist at the University of Toronto who also cochairs the ACR Classification and Response Criteria subcommittee, discussed the fourth phase of the collaboration, which involves fine-tuning and validating the proposed SLE classification criteria.
To date, 189 investigators and more than 3,500 patients have contributed to the effort. “In the most recent phase, 36 international lupus centers were approached to contribute 100 cases and 100 controls,” she explained. “We then had each case independently adjudicated by three lupus experts at three different lupus centers to make sure there was consensus on the diagnosis. Next, we randomly selected 500 cases and 500 controls, resulting in a derivation cohort of 1,000 subjects to test our draft criteria system.”
Dr. Johnson and her associates found that the proposed SLE criteria had a sensitivity of 98% and a specificity of 97%, which exceeds that of the old ACR criteria. “We have defined a system of criteria which produces a measure of the relative probability that a particular case with a combination of clinical symptoms or features has SLE,” she said.
Dr. Johnson emphasized that the proposed criteria are intended for the classification of SLE, not for diagnosing the condition. “The diagnosis of lupus still remains in the hands of the physician, who will take into account all of the symptoms, signs, and other investigations,” she said. “We have identified the highest yield of those, but there will be some people who do not fulfill classification criteria yet do have a diagnosis of SLE.”
The next few weeks is a period to solicit feedback from stakeholders, after which members of the EULAR/ACR steering committee will be weighing feedback on the proposed criteria. “After that, we will see if there are any final revisions that need to be made,” Dr. Johnson said. “If we’re happy with the product, then the final validation will occur. We still have more than 1,000 patients from the validation core that has been reserved for that final validation.”
Data from the final validation are expected to be presented at the June 2018 EULAR meeting and ultimately published in Arthritis and Rheumatism and the Annals of Rheumatic Diseases. “Before we can get there, though, it needs to be formally reviewed by the ACR and EULAR for their formal endorsement. We expect that will take another 6 months.” She reported having no disclosures.
AT ACR 2017
Hispanics trail blacks, whites in bariatric surgery rates
SAN DIEGO – A study of procedures at academic centers provides evidence that obese Hispanics in the United States undergo bariatric surgery at a much lower rate than whites and blacks. It also reveals marked regional variations in overall weight-loss surgery.
“Our findings do suggest that severely obese Hispanics are utilizing bariatric surgery much lower than other ethnic groups,” said study coauthor Ninh T. Nguyen, MD, FACS, chair of the department of surgery at the University of California Irvine Medical Center, in an interview. “Our research does not specifically address the reasons for this gap in the delivery of care. Further research will need to be done to understand the reasons and the ways to close this gap.”
According to Dr. Nguyen, the researchers undertook the study to better understand how bariatric surgery is delivered across ethnicities and geographic regions in the United States.
The researchers analyzed statistics from the Vizient health care performance database for the years 2013-2015. They focused on patients at about 120 academic centers who underwent 73,119 laparoscopic sleeve gastrectomy, laparoscopic Roux-en-Y gastric bypass, and laparoscopic adjustable gastric banding procedures. The patients were stratified by race and region.
Researchers found that bariatric procedures were performed at a much higher rate in the Northeast academic centers (2.21 per 1,000 obese persons), compared with the Midwest (0.73), South (0.50), and West (0.33).
In regard to race, the rates for blacks and whites were fairly similar in the Northwest (2.02 and 2.35 bariatric procedures per 1,000 obese persons, respectively), the South (0.59 and 0.63, respectively) and the West (0.45 and 0.43, respectively). There was a wider gap in the Midwest, with whites at 0.69 and blacks at 1.07.
Across the country, however, obese Hispanics were less likely than persons of the other two races to undergo weight-loss surgery. The gap was fairly small in the Northeast, where 1.74 per 1,000 obese Hispanics underwent weight-loss surgery, compared with rates of 2.02 and 2.35 among whites and blacks, respectively. But the disparity was much larger in the other parts of the country, with rates at 0.14 in the West, 0.11 in the South and 0.33 in the Midwest, compared with rates from 0.43 to 1.07 among blacks and whites.
The reasons for the surgery gap are unknown. Dr. Nguyen pointed to several possible explanations: “lack of education of obesity as a disease by the primary care providers and the need for referral to a bariatric surgeon for patients with body mass index greater than 40 kg/m2 or 35 kg/m2 with obesity-related comorbidities; poor understanding of the benefits of bariatric surgery and its low risk; lack of understanding of the urgency for treatment by the patient and provider; and hurdles in obtaining coverage for the operation by insurers.”
John Magaña Morton, MD, FACS, chief of bariatric and minimally invasive surgery at Stanford (Calif.) University School of Medicine and past president of the American Society for Metabolic and Bariatric Surgery, doesn’t think discrimination is causing the disparity.
“It’s probably a reflection of insurance status – Hispanics tend to be less insured than Caucasian or African American patients – as well as preference for patients to go to nonacademic centers,” he said.
Indeed, a Kaiser Family Foundation analysis found that 21% of the 52 million Hispanics younger than 65 years in the United States were uninsured in 2015, compared with 9% of whites and 13% of blacks. Only Native Americans/Alaska Natives had an uninsured rate as high as Hispanics.
“In terms of need [for weight-loss features], it’s certainly there for Hispanics,” said Dr. Morton. “[Hispanic patients] have high rates of obesity and diabetes, both of which are helped by bariatric surgery.”
He said about 40% of patients in his Palo Alto, Calif., practice are Hispanic, reflecting the high number in the local population.
It helps that Dr. Morton and several of his partners speak Spanish. “If you have a welcoming environment,” he said, “that can make a difference.”
The study authors and Dr. Morton report no relevant disclosures. No specific study funding is reported.
SAN DIEGO – A study of procedures at academic centers provides evidence that obese Hispanics in the United States undergo bariatric surgery at a much lower rate than whites and blacks. It also reveals marked regional variations in overall weight-loss surgery.
“Our findings do suggest that severely obese Hispanics are utilizing bariatric surgery much lower than other ethnic groups,” said study coauthor Ninh T. Nguyen, MD, FACS, chair of the department of surgery at the University of California Irvine Medical Center, in an interview. “Our research does not specifically address the reasons for this gap in the delivery of care. Further research will need to be done to understand the reasons and the ways to close this gap.”
According to Dr. Nguyen, the researchers undertook the study to better understand how bariatric surgery is delivered across ethnicities and geographic regions in the United States.
The researchers analyzed statistics from the Vizient health care performance database for the years 2013-2015. They focused on patients at about 120 academic centers who underwent 73,119 laparoscopic sleeve gastrectomy, laparoscopic Roux-en-Y gastric bypass, and laparoscopic adjustable gastric banding procedures. The patients were stratified by race and region.
Researchers found that bariatric procedures were performed at a much higher rate in the Northeast academic centers (2.21 per 1,000 obese persons), compared with the Midwest (0.73), South (0.50), and West (0.33).
In regard to race, the rates for blacks and whites were fairly similar in the Northwest (2.02 and 2.35 bariatric procedures per 1,000 obese persons, respectively), the South (0.59 and 0.63, respectively) and the West (0.45 and 0.43, respectively). There was a wider gap in the Midwest, with whites at 0.69 and blacks at 1.07.
Across the country, however, obese Hispanics were less likely than persons of the other two races to undergo weight-loss surgery. The gap was fairly small in the Northeast, where 1.74 per 1,000 obese Hispanics underwent weight-loss surgery, compared with rates of 2.02 and 2.35 among whites and blacks, respectively. But the disparity was much larger in the other parts of the country, with rates at 0.14 in the West, 0.11 in the South and 0.33 in the Midwest, compared with rates from 0.43 to 1.07 among blacks and whites.
The reasons for the surgery gap are unknown. Dr. Nguyen pointed to several possible explanations: “lack of education of obesity as a disease by the primary care providers and the need for referral to a bariatric surgeon for patients with body mass index greater than 40 kg/m2 or 35 kg/m2 with obesity-related comorbidities; poor understanding of the benefits of bariatric surgery and its low risk; lack of understanding of the urgency for treatment by the patient and provider; and hurdles in obtaining coverage for the operation by insurers.”
John Magaña Morton, MD, FACS, chief of bariatric and minimally invasive surgery at Stanford (Calif.) University School of Medicine and past president of the American Society for Metabolic and Bariatric Surgery, doesn’t think discrimination is causing the disparity.
“It’s probably a reflection of insurance status – Hispanics tend to be less insured than Caucasian or African American patients – as well as preference for patients to go to nonacademic centers,” he said.
Indeed, a Kaiser Family Foundation analysis found that 21% of the 52 million Hispanics younger than 65 years in the United States were uninsured in 2015, compared with 9% of whites and 13% of blacks. Only Native Americans/Alaska Natives had an uninsured rate as high as Hispanics.
“In terms of need [for weight-loss features], it’s certainly there for Hispanics,” said Dr. Morton. “[Hispanic patients] have high rates of obesity and diabetes, both of which are helped by bariatric surgery.”
He said about 40% of patients in his Palo Alto, Calif., practice are Hispanic, reflecting the high number in the local population.
It helps that Dr. Morton and several of his partners speak Spanish. “If you have a welcoming environment,” he said, “that can make a difference.”
The study authors and Dr. Morton report no relevant disclosures. No specific study funding is reported.
SAN DIEGO – A study of procedures at academic centers provides evidence that obese Hispanics in the United States undergo bariatric surgery at a much lower rate than whites and blacks. It also reveals marked regional variations in overall weight-loss surgery.
“Our findings do suggest that severely obese Hispanics are utilizing bariatric surgery much lower than other ethnic groups,” said study coauthor Ninh T. Nguyen, MD, FACS, chair of the department of surgery at the University of California Irvine Medical Center, in an interview. “Our research does not specifically address the reasons for this gap in the delivery of care. Further research will need to be done to understand the reasons and the ways to close this gap.”
According to Dr. Nguyen, the researchers undertook the study to better understand how bariatric surgery is delivered across ethnicities and geographic regions in the United States.
The researchers analyzed statistics from the Vizient health care performance database for the years 2013-2015. They focused on patients at about 120 academic centers who underwent 73,119 laparoscopic sleeve gastrectomy, laparoscopic Roux-en-Y gastric bypass, and laparoscopic adjustable gastric banding procedures. The patients were stratified by race and region.
Researchers found that bariatric procedures were performed at a much higher rate in the Northeast academic centers (2.21 per 1,000 obese persons), compared with the Midwest (0.73), South (0.50), and West (0.33).
In regard to race, the rates for blacks and whites were fairly similar in the Northwest (2.02 and 2.35 bariatric procedures per 1,000 obese persons, respectively), the South (0.59 and 0.63, respectively) and the West (0.45 and 0.43, respectively). There was a wider gap in the Midwest, with whites at 0.69 and blacks at 1.07.
Across the country, however, obese Hispanics were less likely than persons of the other two races to undergo weight-loss surgery. The gap was fairly small in the Northeast, where 1.74 per 1,000 obese Hispanics underwent weight-loss surgery, compared with rates of 2.02 and 2.35 among whites and blacks, respectively. But the disparity was much larger in the other parts of the country, with rates at 0.14 in the West, 0.11 in the South and 0.33 in the Midwest, compared with rates from 0.43 to 1.07 among blacks and whites.
The reasons for the surgery gap are unknown. Dr. Nguyen pointed to several possible explanations: “lack of education of obesity as a disease by the primary care providers and the need for referral to a bariatric surgeon for patients with body mass index greater than 40 kg/m2 or 35 kg/m2 with obesity-related comorbidities; poor understanding of the benefits of bariatric surgery and its low risk; lack of understanding of the urgency for treatment by the patient and provider; and hurdles in obtaining coverage for the operation by insurers.”
John Magaña Morton, MD, FACS, chief of bariatric and minimally invasive surgery at Stanford (Calif.) University School of Medicine and past president of the American Society for Metabolic and Bariatric Surgery, doesn’t think discrimination is causing the disparity.
“It’s probably a reflection of insurance status – Hispanics tend to be less insured than Caucasian or African American patients – as well as preference for patients to go to nonacademic centers,” he said.
Indeed, a Kaiser Family Foundation analysis found that 21% of the 52 million Hispanics younger than 65 years in the United States were uninsured in 2015, compared with 9% of whites and 13% of blacks. Only Native Americans/Alaska Natives had an uninsured rate as high as Hispanics.
“In terms of need [for weight-loss features], it’s certainly there for Hispanics,” said Dr. Morton. “[Hispanic patients] have high rates of obesity and diabetes, both of which are helped by bariatric surgery.”
He said about 40% of patients in his Palo Alto, Calif., practice are Hispanic, reflecting the high number in the local population.
It helps that Dr. Morton and several of his partners speak Spanish. “If you have a welcoming environment,” he said, “that can make a difference.”
The study authors and Dr. Morton report no relevant disclosures. No specific study funding is reported.
AT THE ACS CLINICAL CONGRESS
Key clinical point: At academic centers, obese Hispanics undergo bariatric surgery at a much lower rate than blacks and whites. U.S. regions outside the Northeast have lower rates of weight-loss procedures overall.
Major finding: Outside the Northeast, the bariatric surgery rate per 1,000 obese people is much lower for Hispanics (range, 0.11-0.33) than for blacks and whites (range, 0.43-1.07).
Data source: Analysis of 73,119 bariatric procedures from 2013-2015 at about 120 academic centers.
Disclosures: The study authors report no relevant disclosures. No specific study funding is reported.
Physician wellness needs attention at personal, institutional, and cultural levels
Do you know we have record rates of physician burnout, dissatisfaction, and suicide? Ongoing shortages in primary care, without improvement in sight? Physicians exiting medicine earlier than in the past?
What about burnout? Do you know it affects patients as well as their doctors? Affects physicians’ families and friends? Increases mistakes and malpractice risk? Affects patient adherence and outcomes? Is costly to the entire system?
How do we start to fix this? : personal wellness, organizational wellness, and wellness within the culture of medicine.
The high level of physician burnout indicates that addressing wellness at the personal level is not enough. It speaks to a systemic rather than individual etiology. Organizations have begun to recognize it is in their best interest to keep their physicians happy. Losing even one physician to burnout is expensive. In addition, burned out physicians are liabilities. Mistakes increase. Productivity decreases. Patient satisfaction decreases. Ripple effects touch other members of the team, which leads to further burnout. If for no other reason, physician wellness at the organizational level matters because it affects the bottom line.
Wellness within the culture of medicine is the third level of our framework. Western medicine has its own set of customs, traditions, and values that are learned early in the course of medical training. The value of sound scientific methods, the importance placed on logic and reason, and the significance of professional integrity are examples. Hard work, sacrifice, and commitment also are included. Unhealthy values include harsh judgment, shame, a sense of superiority, and perfection.
When examining physician wellness at the cultural level, we also must address discrimination within medicine. Overt racism, misogyny, ageism, and discrimination based upon sexual orientation are everyday occurrences and affect everyone within the culture of medicine. It’s difficult to experience wellness at the same time as discrimination.
At every level, physician wellness depends upon continuous, usually low-tech activities and habits based upon individual and shared values. Identifying and shaping these shared values is not going to happen on its own. We all have an obligation to speak and act up. We need improved physician health. Our families, our communities, patients, and even the institution of medicine deserves better.
Dr. Stepien practices pediatrics in Juneau, Alaska. She is on the Pediatric News editorial advisory board. Email her at [email protected]
Do you know we have record rates of physician burnout, dissatisfaction, and suicide? Ongoing shortages in primary care, without improvement in sight? Physicians exiting medicine earlier than in the past?
What about burnout? Do you know it affects patients as well as their doctors? Affects physicians’ families and friends? Increases mistakes and malpractice risk? Affects patient adherence and outcomes? Is costly to the entire system?
How do we start to fix this? : personal wellness, organizational wellness, and wellness within the culture of medicine.
The high level of physician burnout indicates that addressing wellness at the personal level is not enough. It speaks to a systemic rather than individual etiology. Organizations have begun to recognize it is in their best interest to keep their physicians happy. Losing even one physician to burnout is expensive. In addition, burned out physicians are liabilities. Mistakes increase. Productivity decreases. Patient satisfaction decreases. Ripple effects touch other members of the team, which leads to further burnout. If for no other reason, physician wellness at the organizational level matters because it affects the bottom line.
Wellness within the culture of medicine is the third level of our framework. Western medicine has its own set of customs, traditions, and values that are learned early in the course of medical training. The value of sound scientific methods, the importance placed on logic and reason, and the significance of professional integrity are examples. Hard work, sacrifice, and commitment also are included. Unhealthy values include harsh judgment, shame, a sense of superiority, and perfection.
When examining physician wellness at the cultural level, we also must address discrimination within medicine. Overt racism, misogyny, ageism, and discrimination based upon sexual orientation are everyday occurrences and affect everyone within the culture of medicine. It’s difficult to experience wellness at the same time as discrimination.
At every level, physician wellness depends upon continuous, usually low-tech activities and habits based upon individual and shared values. Identifying and shaping these shared values is not going to happen on its own. We all have an obligation to speak and act up. We need improved physician health. Our families, our communities, patients, and even the institution of medicine deserves better.
Dr. Stepien practices pediatrics in Juneau, Alaska. She is on the Pediatric News editorial advisory board. Email her at [email protected]
Do you know we have record rates of physician burnout, dissatisfaction, and suicide? Ongoing shortages in primary care, without improvement in sight? Physicians exiting medicine earlier than in the past?
What about burnout? Do you know it affects patients as well as their doctors? Affects physicians’ families and friends? Increases mistakes and malpractice risk? Affects patient adherence and outcomes? Is costly to the entire system?
How do we start to fix this? : personal wellness, organizational wellness, and wellness within the culture of medicine.
The high level of physician burnout indicates that addressing wellness at the personal level is not enough. It speaks to a systemic rather than individual etiology. Organizations have begun to recognize it is in their best interest to keep their physicians happy. Losing even one physician to burnout is expensive. In addition, burned out physicians are liabilities. Mistakes increase. Productivity decreases. Patient satisfaction decreases. Ripple effects touch other members of the team, which leads to further burnout. If for no other reason, physician wellness at the organizational level matters because it affects the bottom line.
Wellness within the culture of medicine is the third level of our framework. Western medicine has its own set of customs, traditions, and values that are learned early in the course of medical training. The value of sound scientific methods, the importance placed on logic and reason, and the significance of professional integrity are examples. Hard work, sacrifice, and commitment also are included. Unhealthy values include harsh judgment, shame, a sense of superiority, and perfection.
When examining physician wellness at the cultural level, we also must address discrimination within medicine. Overt racism, misogyny, ageism, and discrimination based upon sexual orientation are everyday occurrences and affect everyone within the culture of medicine. It’s difficult to experience wellness at the same time as discrimination.
At every level, physician wellness depends upon continuous, usually low-tech activities and habits based upon individual and shared values. Identifying and shaping these shared values is not going to happen on its own. We all have an obligation to speak and act up. We need improved physician health. Our families, our communities, patients, and even the institution of medicine deserves better.
Dr. Stepien practices pediatrics in Juneau, Alaska. She is on the Pediatric News editorial advisory board. Email her at [email protected]
CAR T-cells gain ground against hematologic cancers
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
FROM ASH 2017
Late-breaking abstracts highlight treatment advances in CLL, myeloma, and more
.
In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.
In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.
The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.
In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.
In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.
“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.
Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.
In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.
Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”
Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.
With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.
The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.
This year’s late-breaking abstracts at ASH are:
LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.
LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.
LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.
LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).
LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.
LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study
.
In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.
In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.
The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.
In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.
In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.
“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.
Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.
In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.
Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”
Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.
With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.
The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.
This year’s late-breaking abstracts at ASH are:
LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.
LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.
LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.
LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).
LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.
LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study
.
In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.
In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.
The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.
In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.
In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.
“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.
Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.
In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.
Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”
Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.
With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.
The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.
This year’s late-breaking abstracts at ASH are:
LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.
LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.
LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.
LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).
LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.
LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study
FROM ASH 2017