User login
FDA approves betrixaban for VTE prophylaxis
Betrixaban, a factor Xa inhibitor, has been approved for the prophylaxis of venous thromboembolism (VTE) in at-risk adult patients hospitalized with an acute illness, according to an announcement from the Food and Drug Administration.
Approval was based on results from a randomized, double-blind clinical trial in which over 7,000 hospitalized patients at risk for VTE received either extended-duration betrixaban (35-42 days) or short duration enoxaparin (6-14 days), a low molecular weight heparin administered subcutaneously. The rate of deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was 4.4% among patients receiving betrixaban and 6% among patients receiving enoxaparin (relative risk, 0.75; 95% confidence interval: 0.61, 0.91).
The recommended dosage for betrixaban is 80 mg per day for 35-42 days at the same time every day with food, after a dose of 160 mg on the first day of treatment.
Betrixaban will be marketed as Bevyxxa by Portola.
Find the full FDA announcement and prescribing information on the FDA website.
Betrixaban, a factor Xa inhibitor, has been approved for the prophylaxis of venous thromboembolism (VTE) in at-risk adult patients hospitalized with an acute illness, according to an announcement from the Food and Drug Administration.
Approval was based on results from a randomized, double-blind clinical trial in which over 7,000 hospitalized patients at risk for VTE received either extended-duration betrixaban (35-42 days) or short duration enoxaparin (6-14 days), a low molecular weight heparin administered subcutaneously. The rate of deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was 4.4% among patients receiving betrixaban and 6% among patients receiving enoxaparin (relative risk, 0.75; 95% confidence interval: 0.61, 0.91).
The recommended dosage for betrixaban is 80 mg per day for 35-42 days at the same time every day with food, after a dose of 160 mg on the first day of treatment.
Betrixaban will be marketed as Bevyxxa by Portola.
Find the full FDA announcement and prescribing information on the FDA website.
Betrixaban, a factor Xa inhibitor, has been approved for the prophylaxis of venous thromboembolism (VTE) in at-risk adult patients hospitalized with an acute illness, according to an announcement from the Food and Drug Administration.
Approval was based on results from a randomized, double-blind clinical trial in which over 7,000 hospitalized patients at risk for VTE received either extended-duration betrixaban (35-42 days) or short duration enoxaparin (6-14 days), a low molecular weight heparin administered subcutaneously. The rate of deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was 4.4% among patients receiving betrixaban and 6% among patients receiving enoxaparin (relative risk, 0.75; 95% confidence interval: 0.61, 0.91).
The recommended dosage for betrixaban is 80 mg per day for 35-42 days at the same time every day with food, after a dose of 160 mg on the first day of treatment.
Betrixaban will be marketed as Bevyxxa by Portola.
Find the full FDA announcement and prescribing information on the FDA website.
High TAVR rates linked to fewer readmissions
WASHINGTON – Hospitals with a higher volume of transcatheter aortic valve replacements (TAVRs) have significantly lower 30-day readmission rates, according to an observational study.
In a study of 129 hospitals, those that performed more than 100 TAVR procedures had a 24% and 25% lower readmission rate compared with hospitals that performed 50 to100 TAVRs (P less than .001) and hospitals that performed fewer that 50 TAVRs (P = .007) respectively (JAMA Cardiol. 2017 May 11. doi: 10.1001/jamacardio.2017.1630).
This finding could have serious financial and medical implications for hospitals that are deciding whether or not to focus on this minimally invasive procedure, according to Sahil Khera, MD, MPH, chief resident and cardiology fellow at New York Medical College, Valhalla, and his colleagues.
“Lower readmission rates at high-volume hospitals substantially reduce health care expenditure,” said Dr. Khera and colleagues. “As new TAVR programs open across the country, these data will guide policymakers to identify targets for optimizing and standardizing TAVR outcomes across hospitals.”
To study the correlation between TAVR procedures and readmission rates, the investigators gathered records on hospitals that performed at least five TAVRs in 2014, which were then categorized into high-, medium-, or low-volume categories, and cross-referenced with the 2014 Nationwide Readmissions Database.
Of the 16,252 TAVR procedures conducted in 2014, 663 (4%), 3,067 (19%), and 12,522 (77%) were performed at low-, medium-, and high-volume hospitals, respectively, according to the investigators.
Patients undergoing these procedures were on average 81 years of age, with an average of four Elixhauser comorbidities, most commonly dyslipidemia (64%), hypertension (80%), heart failure (75%), and known coronary artery disease (69%), with a majority having undergone an endovascular procedure (83%).
However, the researchers found the population of TAVR patients of high volume hospitals were slightly younger, had fewer women, were more likely to be in a higher income household, and were less likely to undergo a transapical procedure than in low volume hospitals, which Dr. Khera and fellow researchers believe may have some impact on their findings.
“Low-volume hospitals were more likely to operate on patients with a higher number of comorbidities compared with high-volume hospitals and were more likely to use the TA approach,” according to investigators, “Transapical TAVR is associated with poorer short- and intermediate-term mortality, increased use of skilled nursing care facilities, longer hospital stays, and readmissions when compared with transfemoral TAVR.”
Overall, there were 2,667 readmissions reported, among which high volume hospitals reported a 30-day readmission rate of 15.6%, while low- and medium-volume hospitals reported similarly higher rates of 19.5% and 19%.
When looking into the causes for these readmissions, the investigators found that 1,619 (61%) were due to noncardiac causes, which appeared in all three hospitals, despite a larger proportion present in low-volume hospitals as opposed to medium and high-volume hospitals (65.6% vs. 60.1% and 60.6%, respectively).
“Infection, respiratory, endocrine/metabolic, renal, and trauma problems were more common in low-volume hospitals,” according to the researchers. “Whereas gastrointestinal and TIA/stroke issues were more common in medium and high volume hospitals.”
While price and length of stay did not differ among the volume categories, the investigators estimate the lower rate of readmissions saved high-volume hospitals approximately $6.5 million.
They found that while the difference of readmissions between hospital classifications narrowed when controlling for experience, the margin was still significant. They admitted, however, that the possibility of greater access to more technologically advanced TAVR in high-volume hospitals may affect the findings.
This study was limited by administrative nature of the database used, which does not make available information such as valve type, patient risk scores, or medications.
One investigator has received personal fees from Edwards Lifesciences and Medtronic; another has received grants and personal fees from various pharmaceutical companies, educational institutions, and publications; and a third has consulted for Medtronic.
[email protected]
On Twitter @eaztweets
Considering the idea of using readmissions in comparison to rate of TAVR procedures is interesting, the number of confounds are too great to give any kind of accurate representation of medical practice. While the authors of this study do address its limitations, including a learning curve as it relates to the risk of inpatient mortality, the number of adjustments that must be made to account for the additional confounding factors are simply too insurmountable to give an accurate estimate of statistical and clinical importance.
For example, researchers found TAVR readmissions were associated with certain baseline comorbidities, access sites, and complications. However, association does not mean causation and so the categorization of cardiac-related vs. noncardiac-related readmissions must be approached with some caution.
If one were to try to use readmission rates after TAVR to argue for reimbursement of the procedure, one would need to determine a well established, validated reimbursement rate for TAVR readmissions, which has not been done.
Also, the advancing nature of this procedure, combined with a constant focus from hospitals to reduce readmission rates means any baseline for readmissions used would most likely be out of date.
It would be unlikely for investigators to factor in the cause of reduced readmission rates, which could be a factor of increased technology, more experienced physicians, lower-risk patients, or any combination thereof.
Holding TAVR sites accountable for quality of care is of course important, but using readmission rates to determine something like funding is not appropriate when the measurement being used is so complex.
Perhaps a better approach would be to widen access for low volume hospitals to resources that would improve the TAVR processes and encourage using financial incentives.
Evaluations by physical therapists or a similar procedure should be put into place before discharge to assess a patient’s risk of readmission.
Overall, this is a multifaceted issue that would be better helped by promoting TAVR best practices and encouraging hospitals to compare themselves against each other to reduce unnecessary readmissions.
John D. Carroll, MD, is professor of medicine and director of the Cardiac and Vascular Center at the University of Colorado, Denver. He made his remarks in an editorial in JAMA Cardiology ( doi: 10.1001/jamacardio.2017.1650 ).
Considering the idea of using readmissions in comparison to rate of TAVR procedures is interesting, the number of confounds are too great to give any kind of accurate representation of medical practice. While the authors of this study do address its limitations, including a learning curve as it relates to the risk of inpatient mortality, the number of adjustments that must be made to account for the additional confounding factors are simply too insurmountable to give an accurate estimate of statistical and clinical importance.
For example, researchers found TAVR readmissions were associated with certain baseline comorbidities, access sites, and complications. However, association does not mean causation and so the categorization of cardiac-related vs. noncardiac-related readmissions must be approached with some caution.
If one were to try to use readmission rates after TAVR to argue for reimbursement of the procedure, one would need to determine a well established, validated reimbursement rate for TAVR readmissions, which has not been done.
Also, the advancing nature of this procedure, combined with a constant focus from hospitals to reduce readmission rates means any baseline for readmissions used would most likely be out of date.
It would be unlikely for investigators to factor in the cause of reduced readmission rates, which could be a factor of increased technology, more experienced physicians, lower-risk patients, or any combination thereof.
Holding TAVR sites accountable for quality of care is of course important, but using readmission rates to determine something like funding is not appropriate when the measurement being used is so complex.
Perhaps a better approach would be to widen access for low volume hospitals to resources that would improve the TAVR processes and encourage using financial incentives.
Evaluations by physical therapists or a similar procedure should be put into place before discharge to assess a patient’s risk of readmission.
Overall, this is a multifaceted issue that would be better helped by promoting TAVR best practices and encouraging hospitals to compare themselves against each other to reduce unnecessary readmissions.
John D. Carroll, MD, is professor of medicine and director of the Cardiac and Vascular Center at the University of Colorado, Denver. He made his remarks in an editorial in JAMA Cardiology ( doi: 10.1001/jamacardio.2017.1650 ).
Considering the idea of using readmissions in comparison to rate of TAVR procedures is interesting, the number of confounds are too great to give any kind of accurate representation of medical practice. While the authors of this study do address its limitations, including a learning curve as it relates to the risk of inpatient mortality, the number of adjustments that must be made to account for the additional confounding factors are simply too insurmountable to give an accurate estimate of statistical and clinical importance.
For example, researchers found TAVR readmissions were associated with certain baseline comorbidities, access sites, and complications. However, association does not mean causation and so the categorization of cardiac-related vs. noncardiac-related readmissions must be approached with some caution.
If one were to try to use readmission rates after TAVR to argue for reimbursement of the procedure, one would need to determine a well established, validated reimbursement rate for TAVR readmissions, which has not been done.
Also, the advancing nature of this procedure, combined with a constant focus from hospitals to reduce readmission rates means any baseline for readmissions used would most likely be out of date.
It would be unlikely for investigators to factor in the cause of reduced readmission rates, which could be a factor of increased technology, more experienced physicians, lower-risk patients, or any combination thereof.
Holding TAVR sites accountable for quality of care is of course important, but using readmission rates to determine something like funding is not appropriate when the measurement being used is so complex.
Perhaps a better approach would be to widen access for low volume hospitals to resources that would improve the TAVR processes and encourage using financial incentives.
Evaluations by physical therapists or a similar procedure should be put into place before discharge to assess a patient’s risk of readmission.
Overall, this is a multifaceted issue that would be better helped by promoting TAVR best practices and encouraging hospitals to compare themselves against each other to reduce unnecessary readmissions.
John D. Carroll, MD, is professor of medicine and director of the Cardiac and Vascular Center at the University of Colorado, Denver. He made his remarks in an editorial in JAMA Cardiology ( doi: 10.1001/jamacardio.2017.1650 ).
WASHINGTON – Hospitals with a higher volume of transcatheter aortic valve replacements (TAVRs) have significantly lower 30-day readmission rates, according to an observational study.
In a study of 129 hospitals, those that performed more than 100 TAVR procedures had a 24% and 25% lower readmission rate compared with hospitals that performed 50 to100 TAVRs (P less than .001) and hospitals that performed fewer that 50 TAVRs (P = .007) respectively (JAMA Cardiol. 2017 May 11. doi: 10.1001/jamacardio.2017.1630).
This finding could have serious financial and medical implications for hospitals that are deciding whether or not to focus on this minimally invasive procedure, according to Sahil Khera, MD, MPH, chief resident and cardiology fellow at New York Medical College, Valhalla, and his colleagues.
“Lower readmission rates at high-volume hospitals substantially reduce health care expenditure,” said Dr. Khera and colleagues. “As new TAVR programs open across the country, these data will guide policymakers to identify targets for optimizing and standardizing TAVR outcomes across hospitals.”
To study the correlation between TAVR procedures and readmission rates, the investigators gathered records on hospitals that performed at least five TAVRs in 2014, which were then categorized into high-, medium-, or low-volume categories, and cross-referenced with the 2014 Nationwide Readmissions Database.
Of the 16,252 TAVR procedures conducted in 2014, 663 (4%), 3,067 (19%), and 12,522 (77%) were performed at low-, medium-, and high-volume hospitals, respectively, according to the investigators.
Patients undergoing these procedures were on average 81 years of age, with an average of four Elixhauser comorbidities, most commonly dyslipidemia (64%), hypertension (80%), heart failure (75%), and known coronary artery disease (69%), with a majority having undergone an endovascular procedure (83%).
However, the researchers found the population of TAVR patients of high volume hospitals were slightly younger, had fewer women, were more likely to be in a higher income household, and were less likely to undergo a transapical procedure than in low volume hospitals, which Dr. Khera and fellow researchers believe may have some impact on their findings.
“Low-volume hospitals were more likely to operate on patients with a higher number of comorbidities compared with high-volume hospitals and were more likely to use the TA approach,” according to investigators, “Transapical TAVR is associated with poorer short- and intermediate-term mortality, increased use of skilled nursing care facilities, longer hospital stays, and readmissions when compared with transfemoral TAVR.”
Overall, there were 2,667 readmissions reported, among which high volume hospitals reported a 30-day readmission rate of 15.6%, while low- and medium-volume hospitals reported similarly higher rates of 19.5% and 19%.
When looking into the causes for these readmissions, the investigators found that 1,619 (61%) were due to noncardiac causes, which appeared in all three hospitals, despite a larger proportion present in low-volume hospitals as opposed to medium and high-volume hospitals (65.6% vs. 60.1% and 60.6%, respectively).
“Infection, respiratory, endocrine/metabolic, renal, and trauma problems were more common in low-volume hospitals,” according to the researchers. “Whereas gastrointestinal and TIA/stroke issues were more common in medium and high volume hospitals.”
While price and length of stay did not differ among the volume categories, the investigators estimate the lower rate of readmissions saved high-volume hospitals approximately $6.5 million.
They found that while the difference of readmissions between hospital classifications narrowed when controlling for experience, the margin was still significant. They admitted, however, that the possibility of greater access to more technologically advanced TAVR in high-volume hospitals may affect the findings.
This study was limited by administrative nature of the database used, which does not make available information such as valve type, patient risk scores, or medications.
One investigator has received personal fees from Edwards Lifesciences and Medtronic; another has received grants and personal fees from various pharmaceutical companies, educational institutions, and publications; and a third has consulted for Medtronic.
[email protected]
On Twitter @eaztweets
WASHINGTON – Hospitals with a higher volume of transcatheter aortic valve replacements (TAVRs) have significantly lower 30-day readmission rates, according to an observational study.
In a study of 129 hospitals, those that performed more than 100 TAVR procedures had a 24% and 25% lower readmission rate compared with hospitals that performed 50 to100 TAVRs (P less than .001) and hospitals that performed fewer that 50 TAVRs (P = .007) respectively (JAMA Cardiol. 2017 May 11. doi: 10.1001/jamacardio.2017.1630).
This finding could have serious financial and medical implications for hospitals that are deciding whether or not to focus on this minimally invasive procedure, according to Sahil Khera, MD, MPH, chief resident and cardiology fellow at New York Medical College, Valhalla, and his colleagues.
“Lower readmission rates at high-volume hospitals substantially reduce health care expenditure,” said Dr. Khera and colleagues. “As new TAVR programs open across the country, these data will guide policymakers to identify targets for optimizing and standardizing TAVR outcomes across hospitals.”
To study the correlation between TAVR procedures and readmission rates, the investigators gathered records on hospitals that performed at least five TAVRs in 2014, which were then categorized into high-, medium-, or low-volume categories, and cross-referenced with the 2014 Nationwide Readmissions Database.
Of the 16,252 TAVR procedures conducted in 2014, 663 (4%), 3,067 (19%), and 12,522 (77%) were performed at low-, medium-, and high-volume hospitals, respectively, according to the investigators.
Patients undergoing these procedures were on average 81 years of age, with an average of four Elixhauser comorbidities, most commonly dyslipidemia (64%), hypertension (80%), heart failure (75%), and known coronary artery disease (69%), with a majority having undergone an endovascular procedure (83%).
However, the researchers found the population of TAVR patients of high volume hospitals were slightly younger, had fewer women, were more likely to be in a higher income household, and were less likely to undergo a transapical procedure than in low volume hospitals, which Dr. Khera and fellow researchers believe may have some impact on their findings.
“Low-volume hospitals were more likely to operate on patients with a higher number of comorbidities compared with high-volume hospitals and were more likely to use the TA approach,” according to investigators, “Transapical TAVR is associated with poorer short- and intermediate-term mortality, increased use of skilled nursing care facilities, longer hospital stays, and readmissions when compared with transfemoral TAVR.”
Overall, there were 2,667 readmissions reported, among which high volume hospitals reported a 30-day readmission rate of 15.6%, while low- and medium-volume hospitals reported similarly higher rates of 19.5% and 19%.
When looking into the causes for these readmissions, the investigators found that 1,619 (61%) were due to noncardiac causes, which appeared in all three hospitals, despite a larger proportion present in low-volume hospitals as opposed to medium and high-volume hospitals (65.6% vs. 60.1% and 60.6%, respectively).
“Infection, respiratory, endocrine/metabolic, renal, and trauma problems were more common in low-volume hospitals,” according to the researchers. “Whereas gastrointestinal and TIA/stroke issues were more common in medium and high volume hospitals.”
While price and length of stay did not differ among the volume categories, the investigators estimate the lower rate of readmissions saved high-volume hospitals approximately $6.5 million.
They found that while the difference of readmissions between hospital classifications narrowed when controlling for experience, the margin was still significant. They admitted, however, that the possibility of greater access to more technologically advanced TAVR in high-volume hospitals may affect the findings.
This study was limited by administrative nature of the database used, which does not make available information such as valve type, patient risk scores, or medications.
One investigator has received personal fees from Edwards Lifesciences and Medtronic; another has received grants and personal fees from various pharmaceutical companies, educational institutions, and publications; and a third has consulted for Medtronic.
[email protected]
On Twitter @eaztweets
FROM JAMA CARDIOLOGY
Key clinical point:
Major finding: Hospitals that performed more than 100 TAVR procedures reported significantly lower 30-day readmission rates, compared with those that performed 50-100 procedures and hospitals that performed less than 50.
Data source: Observational study of 129 hospitals that performed at least five TAVRs in 2015, and documents gathered from the 2014 Nationwide Readmissions Database.
Disclosures: One investigator has received personal fees from Edwards Lifesciences and Medtronic; another has received grants and personal fees from various pharmaceutical companies, educational institutions, and publications; and a third has consulted for Medtronic.
Optimizing therapy in relapsed CLL: ibrutinib and beyond
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
AT ASCO 2017
Key clinical point:
Major finding: Long-term progression-free survival was better with ibrutinib than with ofatumumab (hazard ratio, 0.133). The overall response rate with the triplet of ibrutinib, ublituximab, and umbralisib was 100%. Fully 89% of patients achieved no evidence of disease in marrow when anti-CD19 CAR-T cells were added to ibrutinib.
Data source: An update of a phase III randomized trial among 391 patients with previously treated CLL or SLL (RESONATE). A phase 1/1b trial including 19 patients with mainly relapsed or refractory CLL or SLL. A pilot trial among 10 patients with previously treated, mainly higher-risk, CLL or SLL.
Disclosures: Dr. Byrd disclosed that he receives research funding from Genentech, Acerta, and Pharmacyclics. The RESONATE trial was funded by Pharmacyclics. Dr. Nastoupil disclosed that she receives honoraria from Abbvie, Celgene, Genentech/Roche, Gilead Sciences, Pharmacyclics, and TG Therapeutics; receives research funding from Abbvie, Celgene, Janssen Biotech, and TG Therapeutics; and receives travel, accommodations, and/or expenses from Janssen Biotech. The trial was funded by TG Therapeutics. Dr. Gill disclosed that he receives honoraria from Alexion Pharmaceuticals, receives research funding from Novartis (institutional), and has patents for CAR-T cells for acute myeloid leukemia. The trial was funded by Novartis.
The latest news on pediatric migraine
Migraine is the most common disabling neurologic disease, with an estimated 1 billion sufferers worldwide.1 In children aged 5-15 years, migraine prevalence is 10%, and these children miss more school than their peers.2,3 Research specific to the child and adolescent migraine population is imperative, as the findings in adult studies do not always correlate or translate to pediatrics. The American Headache Society (AHS) held its 59th annual scientific meeting in Boston in June 2017, a meeting designed to showcase the latest advances in the field of headache medicine. Several interesting pediatric headache studies were presented.
Pediatric patient, parent goals and preferences for preventive treatment
There is a general consensus among headache specialists that migraine preventive treatment should be instituted when a migraineur has at least four headache days per month. Clinically, and in most research trials, migraine preventive treatment is considered effective when a 50% reduction in headache days or the headache frequency is reduced to no more than four headache days per month.
Perhaps not surprisingly, patients and families expect treatment to result in very few headaches with minimal side effects. It is helpful to understand patient and family treatment goals as clinicians so we can to better provide realistic expectations of care, improve treatment adherence, and reduce patient/parent frustration.
Premonitory symptoms
Migraine is disabling not simply because of the headache but because of the range of symptoms that occur around the headache. Migraine may involve four phases: premonitory, aura, headache, and postdrome. The premonitory phase involves symptoms that may occur hours to days prior to the headache. Functional imaging studies reveal hypothalamic activation during this phase.4 In a large retrospective study, premonitory symptoms occurred in approximately three-quarters of pediatric and adult migraineurs.5 In a prior pediatric chart review, the most common premonitory symptoms in order of decreasing frequency were fatigue, mood change, neck stiffness, and yawning.6
Understanding and identifying premonitory signs is important for better understanding the pathophysiology of migraine and to help our patients recognize when a migraine may be coming.
Mapping pain in pediatric migraine
Diagnosis of migraine is based on the International Classification of Headache Disorders 3rd edition beta (ICHD-3b). For adults with migraine, part of the diagnostic criteria requires at least two of a number of features: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or avoidance of routine physical activity. The comments section of the ICHD-3b mentions that, in children under 18 years, the pain may be bilateral.
This study sought to characterize the location and quality of headache pain in the pediatric and young adult population. Sixty migraineurs were enrolled and divided into three age groups: children (7-11 years), adolescents (12-18), and young adults (19-26). The patients were guided to use a diagram to draw pain location and quality. The pain was bilateral for the majority of patients in all age groups. Of the young adult group, 85% had bilateral headache. This is of interest, as adults with migraine are conventionally thought to have unilateral headache. The main descriptors among all three groups were throbbing, pounding, and pressing. In children, tightening was more common than throbbing.
When diagnosing migraine, it is helpful to take these differences into consideration. Overall, this study provides a better understanding of the quality and location of migraine in the pediatric and young adult population.
Efficacy of zolmitriptan nasal spray in adolescents
Zolmitriptan nasal spray (NS) was approved by the Food and Drug Administration in 2015 for acute migraine treatment in adolescents ages 12-17 years. This was the first triptan NS approved for use in pediatric migraine. The NS route benefits migraineurs who need a rapidly absorbed triptan or those who do not tolerate oral triptans because of significant nausea or emesis with their migraine. The efficacy of zolmitriptan NS in adolescents was established in a multicenter, double-blind, randomized placebo controlled study with 798 participants.7 The primary endpoint of pain freedom at 2 hours after treatment for the 5-mg dose was superior to placebo, 30% vs. 17%, respectively (P less than .001; odds ratio, 2.18; 95% confidence interval, 1.40, 3.39). Patients with migraine going from moderate or severe to mild or no headache at 2 hours post treatment were 51% vs. 39%, respectively (P = .010).
The follow-up study presented at AHS was a subgroup analysis of the above data in younger (12-14 years) and older (15-17 years) adolescents. The primary efficacy endpoint of being pain free at 2 hours post treatment was similarly better for zolmitriptan 5 mg, compared with placebo, in both the younger and older adolescent migraineurs.
This study reinforces that zolmitriptan 5-mg NS is an effective abortive migraine treatment in adolescents and is generally well tolerated.
New migraine treatments
Although not pediatric studies, several presentations addressed exciting new preventive treatments that target one of the main neuropeptides implicated in migraine pathophysiology, calcitonin gene related peptide. Four drug companies have completed phase II and phase III adult trials in which they have developed humanized monoclonal antibodies that bind to CGRP or its receptor. These medications have shown great promise and appear to be very well tolerated. These are the first medications developed specifically for migraine prevention, as opposed to current medications which we borrow from other fields of medicine. It is anticipated they will be available for use in adult migraineurs later this year.
Dr. Qubty is a pediatric headache specialist and an assistant professor of neurology at the University of California, San Francisco, and he is a member of the American Headache Society. He said he had no relevant financial disclosures.
*Correction, 8/10/2017: An earlier version of this article misstated the percentage of pediatric migraine patients who had premonitory signs, and how common premonitory signs were among episodic migraineurs with and without aura.
References
1. Lancet. 2016 Oct 8;388(10053):1545-1602.
2. Dev Med Child Neurol. 2010 Dec;52(12):1088-97.
3. Neurology. 2012 Oct 30;79(18):1881-8.
4. Brain. 2014 Jan;137(Pt 1):232-41.
5. Cephalalgia 2016;36:951-959.
6. J Headache Pain. 2016 Dec;17(1):94.
7. Headache. 2016 Jul;56(7):1107-19.
Migraine is the most common disabling neurologic disease, with an estimated 1 billion sufferers worldwide.1 In children aged 5-15 years, migraine prevalence is 10%, and these children miss more school than their peers.2,3 Research specific to the child and adolescent migraine population is imperative, as the findings in adult studies do not always correlate or translate to pediatrics. The American Headache Society (AHS) held its 59th annual scientific meeting in Boston in June 2017, a meeting designed to showcase the latest advances in the field of headache medicine. Several interesting pediatric headache studies were presented.
Pediatric patient, parent goals and preferences for preventive treatment
There is a general consensus among headache specialists that migraine preventive treatment should be instituted when a migraineur has at least four headache days per month. Clinically, and in most research trials, migraine preventive treatment is considered effective when a 50% reduction in headache days or the headache frequency is reduced to no more than four headache days per month.
Perhaps not surprisingly, patients and families expect treatment to result in very few headaches with minimal side effects. It is helpful to understand patient and family treatment goals as clinicians so we can to better provide realistic expectations of care, improve treatment adherence, and reduce patient/parent frustration.
Premonitory symptoms
Migraine is disabling not simply because of the headache but because of the range of symptoms that occur around the headache. Migraine may involve four phases: premonitory, aura, headache, and postdrome. The premonitory phase involves symptoms that may occur hours to days prior to the headache. Functional imaging studies reveal hypothalamic activation during this phase.4 In a large retrospective study, premonitory symptoms occurred in approximately three-quarters of pediatric and adult migraineurs.5 In a prior pediatric chart review, the most common premonitory symptoms in order of decreasing frequency were fatigue, mood change, neck stiffness, and yawning.6
Understanding and identifying premonitory signs is important for better understanding the pathophysiology of migraine and to help our patients recognize when a migraine may be coming.
Mapping pain in pediatric migraine
Diagnosis of migraine is based on the International Classification of Headache Disorders 3rd edition beta (ICHD-3b). For adults with migraine, part of the diagnostic criteria requires at least two of a number of features: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or avoidance of routine physical activity. The comments section of the ICHD-3b mentions that, in children under 18 years, the pain may be bilateral.
This study sought to characterize the location and quality of headache pain in the pediatric and young adult population. Sixty migraineurs were enrolled and divided into three age groups: children (7-11 years), adolescents (12-18), and young adults (19-26). The patients were guided to use a diagram to draw pain location and quality. The pain was bilateral for the majority of patients in all age groups. Of the young adult group, 85% had bilateral headache. This is of interest, as adults with migraine are conventionally thought to have unilateral headache. The main descriptors among all three groups were throbbing, pounding, and pressing. In children, tightening was more common than throbbing.
When diagnosing migraine, it is helpful to take these differences into consideration. Overall, this study provides a better understanding of the quality and location of migraine in the pediatric and young adult population.
Efficacy of zolmitriptan nasal spray in adolescents
Zolmitriptan nasal spray (NS) was approved by the Food and Drug Administration in 2015 for acute migraine treatment in adolescents ages 12-17 years. This was the first triptan NS approved for use in pediatric migraine. The NS route benefits migraineurs who need a rapidly absorbed triptan or those who do not tolerate oral triptans because of significant nausea or emesis with their migraine. The efficacy of zolmitriptan NS in adolescents was established in a multicenter, double-blind, randomized placebo controlled study with 798 participants.7 The primary endpoint of pain freedom at 2 hours after treatment for the 5-mg dose was superior to placebo, 30% vs. 17%, respectively (P less than .001; odds ratio, 2.18; 95% confidence interval, 1.40, 3.39). Patients with migraine going from moderate or severe to mild or no headache at 2 hours post treatment were 51% vs. 39%, respectively (P = .010).
The follow-up study presented at AHS was a subgroup analysis of the above data in younger (12-14 years) and older (15-17 years) adolescents. The primary efficacy endpoint of being pain free at 2 hours post treatment was similarly better for zolmitriptan 5 mg, compared with placebo, in both the younger and older adolescent migraineurs.
This study reinforces that zolmitriptan 5-mg NS is an effective abortive migraine treatment in adolescents and is generally well tolerated.
New migraine treatments
Although not pediatric studies, several presentations addressed exciting new preventive treatments that target one of the main neuropeptides implicated in migraine pathophysiology, calcitonin gene related peptide. Four drug companies have completed phase II and phase III adult trials in which they have developed humanized monoclonal antibodies that bind to CGRP or its receptor. These medications have shown great promise and appear to be very well tolerated. These are the first medications developed specifically for migraine prevention, as opposed to current medications which we borrow from other fields of medicine. It is anticipated they will be available for use in adult migraineurs later this year.
Dr. Qubty is a pediatric headache specialist and an assistant professor of neurology at the University of California, San Francisco, and he is a member of the American Headache Society. He said he had no relevant financial disclosures.
*Correction, 8/10/2017: An earlier version of this article misstated the percentage of pediatric migraine patients who had premonitory signs, and how common premonitory signs were among episodic migraineurs with and without aura.
References
1. Lancet. 2016 Oct 8;388(10053):1545-1602.
2. Dev Med Child Neurol. 2010 Dec;52(12):1088-97.
3. Neurology. 2012 Oct 30;79(18):1881-8.
4. Brain. 2014 Jan;137(Pt 1):232-41.
5. Cephalalgia 2016;36:951-959.
6. J Headache Pain. 2016 Dec;17(1):94.
7. Headache. 2016 Jul;56(7):1107-19.
Migraine is the most common disabling neurologic disease, with an estimated 1 billion sufferers worldwide.1 In children aged 5-15 years, migraine prevalence is 10%, and these children miss more school than their peers.2,3 Research specific to the child and adolescent migraine population is imperative, as the findings in adult studies do not always correlate or translate to pediatrics. The American Headache Society (AHS) held its 59th annual scientific meeting in Boston in June 2017, a meeting designed to showcase the latest advances in the field of headache medicine. Several interesting pediatric headache studies were presented.
Pediatric patient, parent goals and preferences for preventive treatment
There is a general consensus among headache specialists that migraine preventive treatment should be instituted when a migraineur has at least four headache days per month. Clinically, and in most research trials, migraine preventive treatment is considered effective when a 50% reduction in headache days or the headache frequency is reduced to no more than four headache days per month.
Perhaps not surprisingly, patients and families expect treatment to result in very few headaches with minimal side effects. It is helpful to understand patient and family treatment goals as clinicians so we can to better provide realistic expectations of care, improve treatment adherence, and reduce patient/parent frustration.
Premonitory symptoms
Migraine is disabling not simply because of the headache but because of the range of symptoms that occur around the headache. Migraine may involve four phases: premonitory, aura, headache, and postdrome. The premonitory phase involves symptoms that may occur hours to days prior to the headache. Functional imaging studies reveal hypothalamic activation during this phase.4 In a large retrospective study, premonitory symptoms occurred in approximately three-quarters of pediatric and adult migraineurs.5 In a prior pediatric chart review, the most common premonitory symptoms in order of decreasing frequency were fatigue, mood change, neck stiffness, and yawning.6
Understanding and identifying premonitory signs is important for better understanding the pathophysiology of migraine and to help our patients recognize when a migraine may be coming.
Mapping pain in pediatric migraine
Diagnosis of migraine is based on the International Classification of Headache Disorders 3rd edition beta (ICHD-3b). For adults with migraine, part of the diagnostic criteria requires at least two of a number of features: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or avoidance of routine physical activity. The comments section of the ICHD-3b mentions that, in children under 18 years, the pain may be bilateral.
This study sought to characterize the location and quality of headache pain in the pediatric and young adult population. Sixty migraineurs were enrolled and divided into three age groups: children (7-11 years), adolescents (12-18), and young adults (19-26). The patients were guided to use a diagram to draw pain location and quality. The pain was bilateral for the majority of patients in all age groups. Of the young adult group, 85% had bilateral headache. This is of interest, as adults with migraine are conventionally thought to have unilateral headache. The main descriptors among all three groups were throbbing, pounding, and pressing. In children, tightening was more common than throbbing.
When diagnosing migraine, it is helpful to take these differences into consideration. Overall, this study provides a better understanding of the quality and location of migraine in the pediatric and young adult population.
Efficacy of zolmitriptan nasal spray in adolescents
Zolmitriptan nasal spray (NS) was approved by the Food and Drug Administration in 2015 for acute migraine treatment in adolescents ages 12-17 years. This was the first triptan NS approved for use in pediatric migraine. The NS route benefits migraineurs who need a rapidly absorbed triptan or those who do not tolerate oral triptans because of significant nausea or emesis with their migraine. The efficacy of zolmitriptan NS in adolescents was established in a multicenter, double-blind, randomized placebo controlled study with 798 participants.7 The primary endpoint of pain freedom at 2 hours after treatment for the 5-mg dose was superior to placebo, 30% vs. 17%, respectively (P less than .001; odds ratio, 2.18; 95% confidence interval, 1.40, 3.39). Patients with migraine going from moderate or severe to mild or no headache at 2 hours post treatment were 51% vs. 39%, respectively (P = .010).
The follow-up study presented at AHS was a subgroup analysis of the above data in younger (12-14 years) and older (15-17 years) adolescents. The primary efficacy endpoint of being pain free at 2 hours post treatment was similarly better for zolmitriptan 5 mg, compared with placebo, in both the younger and older adolescent migraineurs.
This study reinforces that zolmitriptan 5-mg NS is an effective abortive migraine treatment in adolescents and is generally well tolerated.
New migraine treatments
Although not pediatric studies, several presentations addressed exciting new preventive treatments that target one of the main neuropeptides implicated in migraine pathophysiology, calcitonin gene related peptide. Four drug companies have completed phase II and phase III adult trials in which they have developed humanized monoclonal antibodies that bind to CGRP or its receptor. These medications have shown great promise and appear to be very well tolerated. These are the first medications developed specifically for migraine prevention, as opposed to current medications which we borrow from other fields of medicine. It is anticipated they will be available for use in adult migraineurs later this year.
Dr. Qubty is a pediatric headache specialist and an assistant professor of neurology at the University of California, San Francisco, and he is a member of the American Headache Society. He said he had no relevant financial disclosures.
*Correction, 8/10/2017: An earlier version of this article misstated the percentage of pediatric migraine patients who had premonitory signs, and how common premonitory signs were among episodic migraineurs with and without aura.
References
1. Lancet. 2016 Oct 8;388(10053):1545-1602.
2. Dev Med Child Neurol. 2010 Dec;52(12):1088-97.
3. Neurology. 2012 Oct 30;79(18):1881-8.
4. Brain. 2014 Jan;137(Pt 1):232-41.
5. Cephalalgia 2016;36:951-959.
6. J Headache Pain. 2016 Dec;17(1):94.
7. Headache. 2016 Jul;56(7):1107-19.
Twofer drug blocks SYK/JAK pathways in advanced NHL
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
AT EHA 2017
Key clinical point: Cerdulatinib, an inhibitor of the SYK and JAK pathways, has shown efficacy against relapsed/refractory non-Hodgkin lymphomas.
Major finding: The overall response rate was 50%, including one complete response in a patient with peripheral T-cell lymphoma.
Data source: An open label, phase II study in 47 patients with non-Hodgkin lymphoma or peripheral T-cell lymphoma.
Disclosures: The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant roles for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
Follow five tips to mitigate opioid prescribing risks
CHICAGO – As the epidemic of opioid addiction and overdose deaths continues to surge, state and federal authorities are keeping a close eye on physicians who prescribe controlled substances.
Experts offer the following guidance on how well-meaning doctors can avoid coming under scrutiny for prescribing opioids and successfully manage investigations and audits.
1. Know who’s on the radar: The Drug Enforcement Agency (DEA) compiles a “black list” yearly of physicians and health care providers they plan to target for audits, said Natalia Mazina, a San Francisco–based attorney who specializes in health and pharmacy law. For 2017, the list includes physicians who have prior noncompliance records, providers who specialize in pain management, and those who dispense or administer large quantities of controlled substances.
In addition, family physicians, psychiatrists, and other specialists who come under investigation by a state medical board because of suspected inappropriate prescribing or reporting violations may also come under the purview of federal authorities, Ms. Mazina said.
“If they come on the medical board radar, they may come on the [DEA’s] radar as well,” she said during the interview. “They just have to watch how many prescriptions they write for controlled substances and make sure they are legitimate prescriptions.”
2. Maintain proper records: Poor record keeping is a top reason that the DEA investigates health care providers for potential prescribing violations, said Dennis A. Wichern, a DEA agent with the Chicago Field Division. Federal law requires that registered practitioners who store or dispense controlled substances keep records of controlled substances coming in and out of the practice. That includes physicians who hand out samples of controlled substances to patients and also pertains to samples provided to doctors by pharmaceutical companies.
Records should include whether the inventory was taken at the beginning or close of business, names of controlled substances, each finished form of the substances, the number of dosage units of each finished form in the commercial container, the number of commercial containers of each finished form, and disposition of the controlled substances.
Law requires that physicians take a new inventory of all controlled substances on hand every 2 years. Doctors are not required to keep records of controlled substances that are merely prescribed, unless such substances are prescribed in the course of maintenance or detoxification treatment.
Ms. Mazina notes that there are many software platforms that can assist practices with proper inventory and record keeping for opioids and other drugs.
3. Check the state database: Before prescribing opioids, check your state’s prescription drug monitoring program (PDMP) database, advises Ms. Mazina. At least 37 states have operational PDMPs that receive and distribute controlled substance prescription information to authorized users. About 11 states have enacted legislation to establish a PDMP, but some databases are not fully operational.
A state’s PDMP can reveal whether patients may be obtaining multiple controlled substance prescriptions from different doctors or doctor-shopping, Ms. Mazina said. Such due diligence helps inform treatment decisions and can assist a doctor’s case if a medical board or DEA investigation later arises.
“Even if your state law does not require you to check a patient’s history prior to prescribing, you have to check it to protect yourself,” she said. “If you want to avoid controlled substances problems, PDMP is the way to go.”
4. Establish an audit response plan: Have an audit response plan ready to roll should an inquiry arise, experts advise. The policies ensure that only approved information is released to authorities, and that all staff members are on the same page about how to react to audits, Ms. Mazina said.
Plans should clearly state what information can be collected and what data should be kept confidential. Financial information, for example, should be off limits, she said. Government agents are entitled to inventory, dispensary data, and records of receipts.
“Agents very often do the mirror image of the database, and they get too much information,” she said. “You don’t want to [allow] that.”
Train staff members how to respond to government authorities seeking audit information, and explain they have the right to refuse being interviewed, Ms. Mazina said.
“Train your employees on what’s going to happen if the DEA comes in,” she said. “If I don’t have clear policies and procedures, and I’m not trained, I might disclose everything and blame someone. That puts everyone in a [bad] position, because [authorities] will record everything and use it against [the practice].”
5. Confer with the experts: It doesn’t hurt to consult with other medical professionals, such as emergency physicians or pain management specialists, for practical advice on inventory policies or software suggestions. But when it comes to staying updated on new drug laws and regulations, confer with a health law attorney or compliance officer, Ms. Mazina said. The DEA website also includes useful information about recent laws and rules pertaining to prescription drugs, as does the Centers for Disease Control and Prevention website.
If an investigation or audit emerges, work with an attorney as early as possible. Often, practices wait until too late after an investigation begins to contact legal counsel, Ms. Mazina noted. The earlier an attorney gets involved, the sooner that person can build a strong case for the practice and work toward the best resolution.
“Very often, the physician thinks they are right, and there’s nothing for them to fear,” she said. “There is something for you to fear. There’s a lot at stake.”
[email protected]
On Twitter @legal_med
CHICAGO – As the epidemic of opioid addiction and overdose deaths continues to surge, state and federal authorities are keeping a close eye on physicians who prescribe controlled substances.
Experts offer the following guidance on how well-meaning doctors can avoid coming under scrutiny for prescribing opioids and successfully manage investigations and audits.
1. Know who’s on the radar: The Drug Enforcement Agency (DEA) compiles a “black list” yearly of physicians and health care providers they plan to target for audits, said Natalia Mazina, a San Francisco–based attorney who specializes in health and pharmacy law. For 2017, the list includes physicians who have prior noncompliance records, providers who specialize in pain management, and those who dispense or administer large quantities of controlled substances.
In addition, family physicians, psychiatrists, and other specialists who come under investigation by a state medical board because of suspected inappropriate prescribing or reporting violations may also come under the purview of federal authorities, Ms. Mazina said.
“If they come on the medical board radar, they may come on the [DEA’s] radar as well,” she said during the interview. “They just have to watch how many prescriptions they write for controlled substances and make sure they are legitimate prescriptions.”
2. Maintain proper records: Poor record keeping is a top reason that the DEA investigates health care providers for potential prescribing violations, said Dennis A. Wichern, a DEA agent with the Chicago Field Division. Federal law requires that registered practitioners who store or dispense controlled substances keep records of controlled substances coming in and out of the practice. That includes physicians who hand out samples of controlled substances to patients and also pertains to samples provided to doctors by pharmaceutical companies.
Records should include whether the inventory was taken at the beginning or close of business, names of controlled substances, each finished form of the substances, the number of dosage units of each finished form in the commercial container, the number of commercial containers of each finished form, and disposition of the controlled substances.
Law requires that physicians take a new inventory of all controlled substances on hand every 2 years. Doctors are not required to keep records of controlled substances that are merely prescribed, unless such substances are prescribed in the course of maintenance or detoxification treatment.
Ms. Mazina notes that there are many software platforms that can assist practices with proper inventory and record keeping for opioids and other drugs.
3. Check the state database: Before prescribing opioids, check your state’s prescription drug monitoring program (PDMP) database, advises Ms. Mazina. At least 37 states have operational PDMPs that receive and distribute controlled substance prescription information to authorized users. About 11 states have enacted legislation to establish a PDMP, but some databases are not fully operational.
A state’s PDMP can reveal whether patients may be obtaining multiple controlled substance prescriptions from different doctors or doctor-shopping, Ms. Mazina said. Such due diligence helps inform treatment decisions and can assist a doctor’s case if a medical board or DEA investigation later arises.
“Even if your state law does not require you to check a patient’s history prior to prescribing, you have to check it to protect yourself,” she said. “If you want to avoid controlled substances problems, PDMP is the way to go.”
4. Establish an audit response plan: Have an audit response plan ready to roll should an inquiry arise, experts advise. The policies ensure that only approved information is released to authorities, and that all staff members are on the same page about how to react to audits, Ms. Mazina said.
Plans should clearly state what information can be collected and what data should be kept confidential. Financial information, for example, should be off limits, she said. Government agents are entitled to inventory, dispensary data, and records of receipts.
“Agents very often do the mirror image of the database, and they get too much information,” she said. “You don’t want to [allow] that.”
Train staff members how to respond to government authorities seeking audit information, and explain they have the right to refuse being interviewed, Ms. Mazina said.
“Train your employees on what’s going to happen if the DEA comes in,” she said. “If I don’t have clear policies and procedures, and I’m not trained, I might disclose everything and blame someone. That puts everyone in a [bad] position, because [authorities] will record everything and use it against [the practice].”
5. Confer with the experts: It doesn’t hurt to consult with other medical professionals, such as emergency physicians or pain management specialists, for practical advice on inventory policies or software suggestions. But when it comes to staying updated on new drug laws and regulations, confer with a health law attorney or compliance officer, Ms. Mazina said. The DEA website also includes useful information about recent laws and rules pertaining to prescription drugs, as does the Centers for Disease Control and Prevention website.
If an investigation or audit emerges, work with an attorney as early as possible. Often, practices wait until too late after an investigation begins to contact legal counsel, Ms. Mazina noted. The earlier an attorney gets involved, the sooner that person can build a strong case for the practice and work toward the best resolution.
“Very often, the physician thinks they are right, and there’s nothing for them to fear,” she said. “There is something for you to fear. There’s a lot at stake.”
[email protected]
On Twitter @legal_med
CHICAGO – As the epidemic of opioid addiction and overdose deaths continues to surge, state and federal authorities are keeping a close eye on physicians who prescribe controlled substances.
Experts offer the following guidance on how well-meaning doctors can avoid coming under scrutiny for prescribing opioids and successfully manage investigations and audits.
1. Know who’s on the radar: The Drug Enforcement Agency (DEA) compiles a “black list” yearly of physicians and health care providers they plan to target for audits, said Natalia Mazina, a San Francisco–based attorney who specializes in health and pharmacy law. For 2017, the list includes physicians who have prior noncompliance records, providers who specialize in pain management, and those who dispense or administer large quantities of controlled substances.
In addition, family physicians, psychiatrists, and other specialists who come under investigation by a state medical board because of suspected inappropriate prescribing or reporting violations may also come under the purview of federal authorities, Ms. Mazina said.
“If they come on the medical board radar, they may come on the [DEA’s] radar as well,” she said during the interview. “They just have to watch how many prescriptions they write for controlled substances and make sure they are legitimate prescriptions.”
2. Maintain proper records: Poor record keeping is a top reason that the DEA investigates health care providers for potential prescribing violations, said Dennis A. Wichern, a DEA agent with the Chicago Field Division. Federal law requires that registered practitioners who store or dispense controlled substances keep records of controlled substances coming in and out of the practice. That includes physicians who hand out samples of controlled substances to patients and also pertains to samples provided to doctors by pharmaceutical companies.
Records should include whether the inventory was taken at the beginning or close of business, names of controlled substances, each finished form of the substances, the number of dosage units of each finished form in the commercial container, the number of commercial containers of each finished form, and disposition of the controlled substances.
Law requires that physicians take a new inventory of all controlled substances on hand every 2 years. Doctors are not required to keep records of controlled substances that are merely prescribed, unless such substances are prescribed in the course of maintenance or detoxification treatment.
Ms. Mazina notes that there are many software platforms that can assist practices with proper inventory and record keeping for opioids and other drugs.
3. Check the state database: Before prescribing opioids, check your state’s prescription drug monitoring program (PDMP) database, advises Ms. Mazina. At least 37 states have operational PDMPs that receive and distribute controlled substance prescription information to authorized users. About 11 states have enacted legislation to establish a PDMP, but some databases are not fully operational.
A state’s PDMP can reveal whether patients may be obtaining multiple controlled substance prescriptions from different doctors or doctor-shopping, Ms. Mazina said. Such due diligence helps inform treatment decisions and can assist a doctor’s case if a medical board or DEA investigation later arises.
“Even if your state law does not require you to check a patient’s history prior to prescribing, you have to check it to protect yourself,” she said. “If you want to avoid controlled substances problems, PDMP is the way to go.”
4. Establish an audit response plan: Have an audit response plan ready to roll should an inquiry arise, experts advise. The policies ensure that only approved information is released to authorities, and that all staff members are on the same page about how to react to audits, Ms. Mazina said.
Plans should clearly state what information can be collected and what data should be kept confidential. Financial information, for example, should be off limits, she said. Government agents are entitled to inventory, dispensary data, and records of receipts.
“Agents very often do the mirror image of the database, and they get too much information,” she said. “You don’t want to [allow] that.”
Train staff members how to respond to government authorities seeking audit information, and explain they have the right to refuse being interviewed, Ms. Mazina said.
“Train your employees on what’s going to happen if the DEA comes in,” she said. “If I don’t have clear policies and procedures, and I’m not trained, I might disclose everything and blame someone. That puts everyone in a [bad] position, because [authorities] will record everything and use it against [the practice].”
5. Confer with the experts: It doesn’t hurt to consult with other medical professionals, such as emergency physicians or pain management specialists, for practical advice on inventory policies or software suggestions. But when it comes to staying updated on new drug laws and regulations, confer with a health law attorney or compliance officer, Ms. Mazina said. The DEA website also includes useful information about recent laws and rules pertaining to prescription drugs, as does the Centers for Disease Control and Prevention website.
If an investigation or audit emerges, work with an attorney as early as possible. Often, practices wait until too late after an investigation begins to contact legal counsel, Ms. Mazina noted. The earlier an attorney gets involved, the sooner that person can build a strong case for the practice and work toward the best resolution.
“Very often, the physician thinks they are right, and there’s nothing for them to fear,” she said. “There is something for you to fear. There’s a lot at stake.”
[email protected]
On Twitter @legal_med
AT THE PHYSICIANS LEGAL ISSUES CONFERENCE
Keep a symptom diary!
A friend sent me an article from the New Yorker called “The Algorithm Will See You Now,” in which Siddhartha Mukherjee, MD, author of the magisterial “The Emperor of All Maladies,” ponders the effect artificial intelligence may have on medicine. One possible outcome may be that computers replace radiologists and dermatologists. (They already beat top humans at Jeopardy, chess, and Go, so why not lick Homo sapiens at pattern recognition?)
No worries for me. When Watson takes over, I will be off somewhere playing shuffleboard.
“It’s a particularly bad case. But, the question is why it appeared now, and why it’s getting worse.” She asked the patient about new hair products or family stress. The man said he’d just lost his job.
“Keep a diary,” she advised. “We can determine if there’s a link.”
Thus was my pedagogic legacy shattered in an instant. I’ve spent decades advising students not to tell patients they have a bad case of anything and never to ask them to keep diaries. Then, a foremost medical writer in a leading cultural journal endorses the reverse of both lessons. What was I thinking all these years?
I counseled students not to call any case “bad” because I saw how patients took it personally if I told them that. No matter how mild their diagnosis – rosacea and seborrhea, maladies less emperors than footmen– patients who heard theirs called “bad” looked sad, even insulted. Sad and insulted patients may give up and don’t follow treatment advice. (With such a bad case, why bother?) I didn’t urge patients to think that way. I just couldn’t ignore that they did. By contrast, assuring people that their case “wasn’t bad at all!” made them light up like Halloween pumpkins.
As for diaries, I’ve filed a few that patients handed me over the years. I showed these detailed chronicles to students to illustrate the lengths to which people will go to explain the unexplainable, like the ups and downs of idiopathic urticaria, eczema, and so forth:
- Thursday, August 6th, had sushi at a restaurant with friends.
- Sunday, September 3rd, watched science-fiction movie, unable to sleep that night.
- Monday, October 2nd, discarded fourth new detergent.
And so on.
In the meantime, several times each working day patients would troop in with randomly reoccurring conditions, atopic dermatitis above all, prompting dialogues like these:
“This is crazy! I never had anything like this before!”
“Well, actually, Ms. Jones, I treated you for the same thing in 2006.”
*********************
“This is bizarre! I never had this, and no one in my family ever did either.”
“I see. Well, here’s a prescription.”
“Come to think of it, my Mom had sensitive skin, and I get these dry patches on my arms and legs every winter.”
********************
“I’ve changed my soap three times and thrown out my makeup four times, and the rash keeps coming back. What should I do?”
“Stop throwing out your soap and makeup?”
And so on and on.
Sometimes, of course, semi-plausible causes seem to surface, such as stress. The question is, How useful is it to point this out? Consider the New Yorker case. Once the doctor “determined there is a link,” how might the conversation go?
“We have found the trigger, Mr. Smith. It’s stress.”
“Great! What should I do?”
“Don’t get laid off.”
No doctor (I hope) would ever say that, but patients present reports like the following all the time:
“As a kid, I was allergic to milk, but I’m not anymore.” (No, he wasn’t – he had infantile eczema that got blamed on milk.)
“Penicillin gave me hives.” (But, the hives lasted 6 weeks after the penicillin was stopped, which showed that the hives were idiopathic.)
“I’m very sensitive. I can’t use any moisturizer, any makeup, or all pills.” (People generate long litanies of sensitivities, piling one spurious correlation on another.)
Who benefits from “determining the link” when there isn’t any? Not the patients I’ve been seeing for forty years. Your patients? Maybe detergent manufacturers?
As to my errant pedagogy, with any luck, my students don’t remember a word I told them, a safe assumption for any teacher.
Either that or they don’t read the New Yorker.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].
A friend sent me an article from the New Yorker called “The Algorithm Will See You Now,” in which Siddhartha Mukherjee, MD, author of the magisterial “The Emperor of All Maladies,” ponders the effect artificial intelligence may have on medicine. One possible outcome may be that computers replace radiologists and dermatologists. (They already beat top humans at Jeopardy, chess, and Go, so why not lick Homo sapiens at pattern recognition?)
No worries for me. When Watson takes over, I will be off somewhere playing shuffleboard.
“It’s a particularly bad case. But, the question is why it appeared now, and why it’s getting worse.” She asked the patient about new hair products or family stress. The man said he’d just lost his job.
“Keep a diary,” she advised. “We can determine if there’s a link.”
Thus was my pedagogic legacy shattered in an instant. I’ve spent decades advising students not to tell patients they have a bad case of anything and never to ask them to keep diaries. Then, a foremost medical writer in a leading cultural journal endorses the reverse of both lessons. What was I thinking all these years?
I counseled students not to call any case “bad” because I saw how patients took it personally if I told them that. No matter how mild their diagnosis – rosacea and seborrhea, maladies less emperors than footmen– patients who heard theirs called “bad” looked sad, even insulted. Sad and insulted patients may give up and don’t follow treatment advice. (With such a bad case, why bother?) I didn’t urge patients to think that way. I just couldn’t ignore that they did. By contrast, assuring people that their case “wasn’t bad at all!” made them light up like Halloween pumpkins.
As for diaries, I’ve filed a few that patients handed me over the years. I showed these detailed chronicles to students to illustrate the lengths to which people will go to explain the unexplainable, like the ups and downs of idiopathic urticaria, eczema, and so forth:
- Thursday, August 6th, had sushi at a restaurant with friends.
- Sunday, September 3rd, watched science-fiction movie, unable to sleep that night.
- Monday, October 2nd, discarded fourth new detergent.
And so on.
In the meantime, several times each working day patients would troop in with randomly reoccurring conditions, atopic dermatitis above all, prompting dialogues like these:
“This is crazy! I never had anything like this before!”
“Well, actually, Ms. Jones, I treated you for the same thing in 2006.”
*********************
“This is bizarre! I never had this, and no one in my family ever did either.”
“I see. Well, here’s a prescription.”
“Come to think of it, my Mom had sensitive skin, and I get these dry patches on my arms and legs every winter.”
********************
“I’ve changed my soap three times and thrown out my makeup four times, and the rash keeps coming back. What should I do?”
“Stop throwing out your soap and makeup?”
And so on and on.
Sometimes, of course, semi-plausible causes seem to surface, such as stress. The question is, How useful is it to point this out? Consider the New Yorker case. Once the doctor “determined there is a link,” how might the conversation go?
“We have found the trigger, Mr. Smith. It’s stress.”
“Great! What should I do?”
“Don’t get laid off.”
No doctor (I hope) would ever say that, but patients present reports like the following all the time:
“As a kid, I was allergic to milk, but I’m not anymore.” (No, he wasn’t – he had infantile eczema that got blamed on milk.)
“Penicillin gave me hives.” (But, the hives lasted 6 weeks after the penicillin was stopped, which showed that the hives were idiopathic.)
“I’m very sensitive. I can’t use any moisturizer, any makeup, or all pills.” (People generate long litanies of sensitivities, piling one spurious correlation on another.)
Who benefits from “determining the link” when there isn’t any? Not the patients I’ve been seeing for forty years. Your patients? Maybe detergent manufacturers?
As to my errant pedagogy, with any luck, my students don’t remember a word I told them, a safe assumption for any teacher.
Either that or they don’t read the New Yorker.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].
A friend sent me an article from the New Yorker called “The Algorithm Will See You Now,” in which Siddhartha Mukherjee, MD, author of the magisterial “The Emperor of All Maladies,” ponders the effect artificial intelligence may have on medicine. One possible outcome may be that computers replace radiologists and dermatologists. (They already beat top humans at Jeopardy, chess, and Go, so why not lick Homo sapiens at pattern recognition?)
No worries for me. When Watson takes over, I will be off somewhere playing shuffleboard.
“It’s a particularly bad case. But, the question is why it appeared now, and why it’s getting worse.” She asked the patient about new hair products or family stress. The man said he’d just lost his job.
“Keep a diary,” she advised. “We can determine if there’s a link.”
Thus was my pedagogic legacy shattered in an instant. I’ve spent decades advising students not to tell patients they have a bad case of anything and never to ask them to keep diaries. Then, a foremost medical writer in a leading cultural journal endorses the reverse of both lessons. What was I thinking all these years?
I counseled students not to call any case “bad” because I saw how patients took it personally if I told them that. No matter how mild their diagnosis – rosacea and seborrhea, maladies less emperors than footmen– patients who heard theirs called “bad” looked sad, even insulted. Sad and insulted patients may give up and don’t follow treatment advice. (With such a bad case, why bother?) I didn’t urge patients to think that way. I just couldn’t ignore that they did. By contrast, assuring people that their case “wasn’t bad at all!” made them light up like Halloween pumpkins.
As for diaries, I’ve filed a few that patients handed me over the years. I showed these detailed chronicles to students to illustrate the lengths to which people will go to explain the unexplainable, like the ups and downs of idiopathic urticaria, eczema, and so forth:
- Thursday, August 6th, had sushi at a restaurant with friends.
- Sunday, September 3rd, watched science-fiction movie, unable to sleep that night.
- Monday, October 2nd, discarded fourth new detergent.
And so on.
In the meantime, several times each working day patients would troop in with randomly reoccurring conditions, atopic dermatitis above all, prompting dialogues like these:
“This is crazy! I never had anything like this before!”
“Well, actually, Ms. Jones, I treated you for the same thing in 2006.”
*********************
“This is bizarre! I never had this, and no one in my family ever did either.”
“I see. Well, here’s a prescription.”
“Come to think of it, my Mom had sensitive skin, and I get these dry patches on my arms and legs every winter.”
********************
“I’ve changed my soap three times and thrown out my makeup four times, and the rash keeps coming back. What should I do?”
“Stop throwing out your soap and makeup?”
And so on and on.
Sometimes, of course, semi-plausible causes seem to surface, such as stress. The question is, How useful is it to point this out? Consider the New Yorker case. Once the doctor “determined there is a link,” how might the conversation go?
“We have found the trigger, Mr. Smith. It’s stress.”
“Great! What should I do?”
“Don’t get laid off.”
No doctor (I hope) would ever say that, but patients present reports like the following all the time:
“As a kid, I was allergic to milk, but I’m not anymore.” (No, he wasn’t – he had infantile eczema that got blamed on milk.)
“Penicillin gave me hives.” (But, the hives lasted 6 weeks after the penicillin was stopped, which showed that the hives were idiopathic.)
“I’m very sensitive. I can’t use any moisturizer, any makeup, or all pills.” (People generate long litanies of sensitivities, piling one spurious correlation on another.)
Who benefits from “determining the link” when there isn’t any? Not the patients I’ve been seeing for forty years. Your patients? Maybe detergent manufacturers?
As to my errant pedagogy, with any luck, my students don’t remember a word I told them, a safe assumption for any teacher.
Either that or they don’t read the New Yorker.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].
Inhaled Levodopa Treats Off Periods in Phase III Trial
VANCOUVER—Inhaled levodopa significantly improves motor function during off periods in patients with Parkinson’s disease, according to phase III trial results presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders.
Levodopa inhalation powder, CVT-301, is being developed by Acorda Therapeutics in Ardsley, New York, for intermittent treatment of off periods. The treatment improved motor scores in a phase II study.
Peter A. LeWitt, MD, Professor of Neurology at Henry Ford Hospital and Wayne State University School of Medicine in Detroit, and colleagues conducted the phase III SPAN-PD study, a 12-week, double-blind, multinational trial, to assess the treatment’s efficacy and safety. The investigators randomized 339 patients 1:1:1 to inhaled placebo, CVT-301 (84 mg), or CVT-301 (60 mg) for use up to five times daily as needed. 
Patients had idiopathic Parkinson’s disease and two or more hours per day of off time, excluding morning off time. Patients were receiving a stable dopa decarboxylase inhibitor and levodopa regimen, and they did not have chronic respiratory disease within the previous five years. Patients’ mean age was 63.3, and 73.5% were male.
The primary end point was change in Unified Parkinson’s Disease Rating Scale (UPDRS) Part III motor score from predose to 30 minutes post dose with CVT-301 (84 mg) or placebo at week 12, when subjects were evaluated during an off period.
At 30 minutes, improvement in motor scores was significantly greater among patients who received CVT-301 (84 mg), compared with patients who received placebo (9.83 vs 5.91).
A greater proportion of patients who received CVT-301 were in an on state (ie, treatment benefited mobility, slowness, and stiffness) at 60 minutes, compared with patients who received placebo (57.7% of patients who received CVT-301 [84 mg], 55.6% of patients who received CVT-301 [60 mg], and 36.1% of patients who received placebo).
Motor improvement occurred as soon as 10 minutes after the 84-mg dose. Furthermore, a greater percentage of patients reported improvement in Patient Global Impression of Change with CVT-301 than with placebo.
Inhaled levodopa was generally well tolerated, and the adverse events and safety profile were consistent with those in a phase IIb study.
Cough was the most common adverse event with CVT-301 versus placebo (15% vs 1.8%). Other adverse events in the 84-mg group included upper respiratory tract infection (6.1%), nausea (5.3%), and sputum discoloration (5.3%).
—Jake Remaly
VANCOUVER—Inhaled levodopa significantly improves motor function during off periods in patients with Parkinson’s disease, according to phase III trial results presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders.
Levodopa inhalation powder, CVT-301, is being developed by Acorda Therapeutics in Ardsley, New York, for intermittent treatment of off periods. The treatment improved motor scores in a phase II study.
Peter A. LeWitt, MD, Professor of Neurology at Henry Ford Hospital and Wayne State University School of Medicine in Detroit, and colleagues conducted the phase III SPAN-PD study, a 12-week, double-blind, multinational trial, to assess the treatment’s efficacy and safety. The investigators randomized 339 patients 1:1:1 to inhaled placebo, CVT-301 (84 mg), or CVT-301 (60 mg) for use up to five times daily as needed.
Patients had idiopathic Parkinson’s disease and two or more hours per day of off time, excluding morning off time. Patients were receiving a stable dopa decarboxylase inhibitor and levodopa regimen, and they did not have chronic respiratory disease within the previous five years. Patients’ mean age was 63.3, and 73.5% were male.
The primary end point was change in Unified Parkinson’s Disease Rating Scale (UPDRS) Part III motor score from predose to 30 minutes post dose with CVT-301 (84 mg) or placebo at week 12, when subjects were evaluated during an off period.
At 30 minutes, improvement in motor scores was significantly greater among patients who received CVT-301 (84 mg), compared with patients who received placebo (9.83 vs 5.91).
A greater proportion of patients who received CVT-301 were in an on state (ie, treatment benefited mobility, slowness, and stiffness) at 60 minutes, compared with patients who received placebo (57.7% of patients who received CVT-301 [84 mg], 55.6% of patients who received CVT-301 [60 mg], and 36.1% of patients who received placebo).
Motor improvement occurred as soon as 10 minutes after the 84-mg dose. Furthermore, a greater percentage of patients reported improvement in Patient Global Impression of Change with CVT-301 than with placebo.
Inhaled levodopa was generally well tolerated, and the adverse events and safety profile were consistent with those in a phase IIb study.
Cough was the most common adverse event with CVT-301 versus placebo (15% vs 1.8%). Other adverse events in the 84-mg group included upper respiratory tract infection (6.1%), nausea (5.3%), and sputum discoloration (5.3%).
—Jake Remaly
VANCOUVER—Inhaled levodopa significantly improves motor function during off periods in patients with Parkinson’s disease, according to phase III trial results presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders.
Levodopa inhalation powder, CVT-301, is being developed by Acorda Therapeutics in Ardsley, New York, for intermittent treatment of off periods. The treatment improved motor scores in a phase II study.
Peter A. LeWitt, MD, Professor of Neurology at Henry Ford Hospital and Wayne State University School of Medicine in Detroit, and colleagues conducted the phase III SPAN-PD study, a 12-week, double-blind, multinational trial, to assess the treatment’s efficacy and safety. The investigators randomized 339 patients 1:1:1 to inhaled placebo, CVT-301 (84 mg), or CVT-301 (60 mg) for use up to five times daily as needed.
Patients had idiopathic Parkinson’s disease and two or more hours per day of off time, excluding morning off time. Patients were receiving a stable dopa decarboxylase inhibitor and levodopa regimen, and they did not have chronic respiratory disease within the previous five years. Patients’ mean age was 63.3, and 73.5% were male.
The primary end point was change in Unified Parkinson’s Disease Rating Scale (UPDRS) Part III motor score from predose to 30 minutes post dose with CVT-301 (84 mg) or placebo at week 12, when subjects were evaluated during an off period.
At 30 minutes, improvement in motor scores was significantly greater among patients who received CVT-301 (84 mg), compared with patients who received placebo (9.83 vs 5.91).
A greater proportion of patients who received CVT-301 were in an on state (ie, treatment benefited mobility, slowness, and stiffness) at 60 minutes, compared with patients who received placebo (57.7% of patients who received CVT-301 [84 mg], 55.6% of patients who received CVT-301 [60 mg], and 36.1% of patients who received placebo).
Motor improvement occurred as soon as 10 minutes after the 84-mg dose. Furthermore, a greater percentage of patients reported improvement in Patient Global Impression of Change with CVT-301 than with placebo.
Inhaled levodopa was generally well tolerated, and the adverse events and safety profile were consistent with those in a phase IIb study.
Cough was the most common adverse event with CVT-301 versus placebo (15% vs 1.8%). Other adverse events in the 84-mg group included upper respiratory tract infection (6.1%), nausea (5.3%), and sputum discoloration (5.3%).
—Jake Remaly
FDA approves dabrafenib and trametinib for BRAF V600E+ metastatic NSCLC
The FDA also approved a diagnostic, the Oncomine Dx Target Test, a next-generation sequencing test to detect gene mutations or alterations, including BRAF, from a single tissue specimen, the FDA reported in a statement.
The approvals are based on overall response rate (ORR) for the combination in a phase II, nonrandomized, noncomparative, open-label trial of patients with locally confirmed BRAF V600E mutation-positive metastatic NSCLC. The ORR for the combination treatment was 61% (95% confidence interval, 44%-77%) among 36 patients who had received no prior systemic therapy for metastatic NSCLC, and 63% (95% CI, 49%-76%) among 57 patients who had received at least one platinum-based chemotherapy regimen with demonstrated disease progression before enrollment. Those 93 patients were all treated with the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily).
The ORR was 27% (95% CI, 18%-38%) among a third cohort of 78 patients with previously treated BRAF V600E mutation-positive NSCLC who received single-agent dabrafenib.
The most common adverse reactions were similar to those reported in prior approvals for patients with melanoma, including pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. The most common grade 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea. The most common grade 3-4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18% and 19% of patients, respectively, the FDA said.
Novartis is marketing Dabrafenib as Tafinlar and trametinib as Mekinist.
The recommended doses are dabrafenib 150 mg orally twice daily, approximately 12 hours apart, with trametinib 2 mg orally once daily, following confirmation of BRAF V600E mutation in a tumor specimen by an FDA-approved test.
The FDA also approved a diagnostic, the Oncomine Dx Target Test, a next-generation sequencing test to detect gene mutations or alterations, including BRAF, from a single tissue specimen, the FDA reported in a statement.
The approvals are based on overall response rate (ORR) for the combination in a phase II, nonrandomized, noncomparative, open-label trial of patients with locally confirmed BRAF V600E mutation-positive metastatic NSCLC. The ORR for the combination treatment was 61% (95% confidence interval, 44%-77%) among 36 patients who had received no prior systemic therapy for metastatic NSCLC, and 63% (95% CI, 49%-76%) among 57 patients who had received at least one platinum-based chemotherapy regimen with demonstrated disease progression before enrollment. Those 93 patients were all treated with the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily).
The ORR was 27% (95% CI, 18%-38%) among a third cohort of 78 patients with previously treated BRAF V600E mutation-positive NSCLC who received single-agent dabrafenib.
The most common adverse reactions were similar to those reported in prior approvals for patients with melanoma, including pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. The most common grade 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea. The most common grade 3-4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18% and 19% of patients, respectively, the FDA said.
Novartis is marketing Dabrafenib as Tafinlar and trametinib as Mekinist.
The recommended doses are dabrafenib 150 mg orally twice daily, approximately 12 hours apart, with trametinib 2 mg orally once daily, following confirmation of BRAF V600E mutation in a tumor specimen by an FDA-approved test.
The FDA also approved a diagnostic, the Oncomine Dx Target Test, a next-generation sequencing test to detect gene mutations or alterations, including BRAF, from a single tissue specimen, the FDA reported in a statement.
The approvals are based on overall response rate (ORR) for the combination in a phase II, nonrandomized, noncomparative, open-label trial of patients with locally confirmed BRAF V600E mutation-positive metastatic NSCLC. The ORR for the combination treatment was 61% (95% confidence interval, 44%-77%) among 36 patients who had received no prior systemic therapy for metastatic NSCLC, and 63% (95% CI, 49%-76%) among 57 patients who had received at least one platinum-based chemotherapy regimen with demonstrated disease progression before enrollment. Those 93 patients were all treated with the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily).
The ORR was 27% (95% CI, 18%-38%) among a third cohort of 78 patients with previously treated BRAF V600E mutation-positive NSCLC who received single-agent dabrafenib.
The most common adverse reactions were similar to those reported in prior approvals for patients with melanoma, including pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. The most common grade 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea. The most common grade 3-4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18% and 19% of patients, respectively, the FDA said.
Novartis is marketing Dabrafenib as Tafinlar and trametinib as Mekinist.
The recommended doses are dabrafenib 150 mg orally twice daily, approximately 12 hours apart, with trametinib 2 mg orally once daily, following confirmation of BRAF V600E mutation in a tumor specimen by an FDA-approved test.
Neurologists Review the Data on Treatments for Spinocerebellar Ataxias
MIAMI—Advances in genetic testing have enabled precise identification of many spinocerebellar ataxias, but no pharmacologic therapy for the disorders has been approved, according to an overview presented at the First Pan American Parkinson’s Disease and Movement Disorders Congress. Nevertheless, the literature does indicate that various therapies have beneficial effects, said Theresa Zesiewicz, MD, Director of the University of South Florida Ataxia Research Center in Tampa.
She and her colleagues examined the evidence from the past 40 years of research on ataxia. The recommendations that they developed about treatment options currently are in press.
The Evidence for Pharmaceutical Treatment
“One of the most robust treatments for spinocerebellar ataxias … is going to be 4-aminopyridine for episodic ataxia type II,” said Dr. Zesiewicz. The drug is approved as a treatment for multiple sclerosis, and researchers have examined it in a double-blind, placebo-controlled trial of patients with episodic ataxia type II. After three months of treatment, the median number of monthly attacks was about 1.5 in participants who received 15 mg/day of 4-aminopyridine, compared with 6.5 for controls. The drug is fairly well tolerated and also can be used to treat downbeat nystagmus. 
Two recent studies have investigated the effects of riluzole, a treatment for amyotrophic lateral sclerosis, in patients with various ataxias. Ristori et al examined 40 patients with ataxia of mixed etiology (eg, fragile X-associated tremor/ataxia syndrome, Friedreich’s ataxia, spinocerebellar ataxia, and multiple system atrophy). Patients received 100 mg/day of riluzole or placebo for eight weeks. After four weeks of treatment, about 47% of the riluzole group had a five-point improvement on the International Cooperative Ataxia Rating Scale (ICARS), compared with 5% in the placebo group. After eight weeks, 68% of the riluzole group had this outcome, compared with 5% of the placebo group.
In a 12-month study, Romano et al randomized 60 patients with spinocerebellar ataxia or Friedreich’s ataxia to 50 mg of riluzole b.i.d. or placebo. At 12 months, the proportion of patients with a decrease in Scale for the Assessment and Rating of Ataxia (SARA) score was 50% in the riluzole group, compared with 11% in the placebo group. The mean change in SARA score was greater in the riluzole group (2.6), compared with controls (1.39). The clinical relevance of the improvements in these two studies, however, is uncertain, said Dr. Zesiewicz.
An ongoing phase III study is examining a prodrug of riluzole in 120 patients with spinocerebellar ataxia. Various doses are being examined, and the treatment period will be eight weeks.
In a 1983 study, 250 patients with spinocerebellar ataxia were randomized to thyrotropin-releasing hormone or placebo. Outcomes were reported using a visual analog scale. Participants receiving thyrotropin-releasing hormone had improvement in dysarthria, stance, and gait, but the clinical significance is questionable, said Dr. Zesiewicz.
She and her colleagues compared varenicline, a drug approved for smoking cessation, with placebo in patients with spinocerebellar ataxia type III. After a four-week titration period, patients received treatment for four weeks. The investigators observed significant improvements in gait, stance, and rapid alternating movements among patients receiving varenicline. After data correction, the improvement in rapid alternating movements remained significant. Varenicline has been associated with suicide risk, but Dr. Zesiewicz and colleagues noted a trend toward improvement in Beck Depression Scale among treated participants. Approximately 40% of patients receiving varenicline dropped out of the study, however, because of tremulousness, weakness, and unpleasant dreams.
Examining Nonpharmacologic Options
In addition to pharmacotherapy, some nonpharmacologic treatments may improve function in spinocerebellar ataxia. In one double-blind trial, researchers randomized participants with various ataxias to a single session of transcranial magnetic stimulation (TMS) or sham stimulation. TMS was associated with improvement in SARA score and cerebellar motor function at 21 days. “Harvard just finished a TMS study, and we are waiting for results from that,” said Dr. Zesiewicz.
“Physical therapy is vital for patients with spinocerebellar ataxia,” she continued. One study indicated that intensive exercises such as core strength training, stepping, and dynamic balance yielded significant increases in the Berg Balance Scale. In another randomized controlled trial, four weeks of physical and occupational therapy were associated with a three-point decrease in SARA score. In addition, patients with spinocerebellar ataxia had a two-point decrease in ICARS score after undergoing four weeks of intensive cycling.
A Search for Future Therapies
Investigations of new potential treatments for spinocerebellar ataxia are ongoing. Researchers published the results of a phase II study of IV trehalose in January. Participants’ SARA score remained stable after six months of treatment.
Mesenchymal stem cells may one day provide benefits for patients. After one month of treatment with mesenchymal stromal cells, study participants with spinocerebellar ataxia had improved walking, standing, slow movement, and fine movements. Patients returned to their pretreatment condition after a few months, however.
In addition, screens of small molecules may reveal possible new therapies. One such screen identified aripiprazole as a candidate, and the drug increased longevity in a Drosophila model of Machado-Joseph disease.
“We are looking for great things. We are looking for a cure. But we will use what we have now,” Dr. Zesiewicz concluded.
—Erik Greb
Suggested Reading
Lei LF, Yang GP, Wang JL, et al. Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord. 2016;26:55-61.
Ristori G, Romano S, Visconti A, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010;74(10):839-845.
Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14(10):985-891.
Strupp M, Kalla R, Claassen J, et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology. 2011;77(3):269-275.
Zesiewicz TA, Greenstein PE, Sullivan KL, et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology. 2012;78(8):545-550.
MIAMI—Advances in genetic testing have enabled precise identification of many spinocerebellar ataxias, but no pharmacologic therapy for the disorders has been approved, according to an overview presented at the First Pan American Parkinson’s Disease and Movement Disorders Congress. Nevertheless, the literature does indicate that various therapies have beneficial effects, said Theresa Zesiewicz, MD, Director of the University of South Florida Ataxia Research Center in Tampa.
She and her colleagues examined the evidence from the past 40 years of research on ataxia. The recommendations that they developed about treatment options currently are in press.
The Evidence for Pharmaceutical Treatment
“One of the most robust treatments for spinocerebellar ataxias … is going to be 4-aminopyridine for episodic ataxia type II,” said Dr. Zesiewicz. The drug is approved as a treatment for multiple sclerosis, and researchers have examined it in a double-blind, placebo-controlled trial of patients with episodic ataxia type II. After three months of treatment, the median number of monthly attacks was about 1.5 in participants who received 15 mg/day of 4-aminopyridine, compared with 6.5 for controls. The drug is fairly well tolerated and also can be used to treat downbeat nystagmus.
Two recent studies have investigated the effects of riluzole, a treatment for amyotrophic lateral sclerosis, in patients with various ataxias. Ristori et al examined 40 patients with ataxia of mixed etiology (eg, fragile X-associated tremor/ataxia syndrome, Friedreich’s ataxia, spinocerebellar ataxia, and multiple system atrophy). Patients received 100 mg/day of riluzole or placebo for eight weeks. After four weeks of treatment, about 47% of the riluzole group had a five-point improvement on the International Cooperative Ataxia Rating Scale (ICARS), compared with 5% in the placebo group. After eight weeks, 68% of the riluzole group had this outcome, compared with 5% of the placebo group.
In a 12-month study, Romano et al randomized 60 patients with spinocerebellar ataxia or Friedreich’s ataxia to 50 mg of riluzole b.i.d. or placebo. At 12 months, the proportion of patients with a decrease in Scale for the Assessment and Rating of Ataxia (SARA) score was 50% in the riluzole group, compared with 11% in the placebo group. The mean change in SARA score was greater in the riluzole group (2.6), compared with controls (1.39). The clinical relevance of the improvements in these two studies, however, is uncertain, said Dr. Zesiewicz.
An ongoing phase III study is examining a prodrug of riluzole in 120 patients with spinocerebellar ataxia. Various doses are being examined, and the treatment period will be eight weeks.
In a 1983 study, 250 patients with spinocerebellar ataxia were randomized to thyrotropin-releasing hormone or placebo. Outcomes were reported using a visual analog scale. Participants receiving thyrotropin-releasing hormone had improvement in dysarthria, stance, and gait, but the clinical significance is questionable, said Dr. Zesiewicz.
She and her colleagues compared varenicline, a drug approved for smoking cessation, with placebo in patients with spinocerebellar ataxia type III. After a four-week titration period, patients received treatment for four weeks. The investigators observed significant improvements in gait, stance, and rapid alternating movements among patients receiving varenicline. After data correction, the improvement in rapid alternating movements remained significant. Varenicline has been associated with suicide risk, but Dr. Zesiewicz and colleagues noted a trend toward improvement in Beck Depression Scale among treated participants. Approximately 40% of patients receiving varenicline dropped out of the study, however, because of tremulousness, weakness, and unpleasant dreams.
Examining Nonpharmacologic Options
In addition to pharmacotherapy, some nonpharmacologic treatments may improve function in spinocerebellar ataxia. In one double-blind trial, researchers randomized participants with various ataxias to a single session of transcranial magnetic stimulation (TMS) or sham stimulation. TMS was associated with improvement in SARA score and cerebellar motor function at 21 days. “Harvard just finished a TMS study, and we are waiting for results from that,” said Dr. Zesiewicz.
“Physical therapy is vital for patients with spinocerebellar ataxia,” she continued. One study indicated that intensive exercises such as core strength training, stepping, and dynamic balance yielded significant increases in the Berg Balance Scale. In another randomized controlled trial, four weeks of physical and occupational therapy were associated with a three-point decrease in SARA score. In addition, patients with spinocerebellar ataxia had a two-point decrease in ICARS score after undergoing four weeks of intensive cycling.
A Search for Future Therapies
Investigations of new potential treatments for spinocerebellar ataxia are ongoing. Researchers published the results of a phase II study of IV trehalose in January. Participants’ SARA score remained stable after six months of treatment.
Mesenchymal stem cells may one day provide benefits for patients. After one month of treatment with mesenchymal stromal cells, study participants with spinocerebellar ataxia had improved walking, standing, slow movement, and fine movements. Patients returned to their pretreatment condition after a few months, however.
In addition, screens of small molecules may reveal possible new therapies. One such screen identified aripiprazole as a candidate, and the drug increased longevity in a Drosophila model of Machado-Joseph disease.
“We are looking for great things. We are looking for a cure. But we will use what we have now,” Dr. Zesiewicz concluded.
—Erik Greb
Suggested Reading
Lei LF, Yang GP, Wang JL, et al. Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord. 2016;26:55-61.
Ristori G, Romano S, Visconti A, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010;74(10):839-845.
Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14(10):985-891.
Strupp M, Kalla R, Claassen J, et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology. 2011;77(3):269-275.
Zesiewicz TA, Greenstein PE, Sullivan KL, et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology. 2012;78(8):545-550.
MIAMI—Advances in genetic testing have enabled precise identification of many spinocerebellar ataxias, but no pharmacologic therapy for the disorders has been approved, according to an overview presented at the First Pan American Parkinson’s Disease and Movement Disorders Congress. Nevertheless, the literature does indicate that various therapies have beneficial effects, said Theresa Zesiewicz, MD, Director of the University of South Florida Ataxia Research Center in Tampa.
She and her colleagues examined the evidence from the past 40 years of research on ataxia. The recommendations that they developed about treatment options currently are in press.
The Evidence for Pharmaceutical Treatment
“One of the most robust treatments for spinocerebellar ataxias … is going to be 4-aminopyridine for episodic ataxia type II,” said Dr. Zesiewicz. The drug is approved as a treatment for multiple sclerosis, and researchers have examined it in a double-blind, placebo-controlled trial of patients with episodic ataxia type II. After three months of treatment, the median number of monthly attacks was about 1.5 in participants who received 15 mg/day of 4-aminopyridine, compared with 6.5 for controls. The drug is fairly well tolerated and also can be used to treat downbeat nystagmus.
Two recent studies have investigated the effects of riluzole, a treatment for amyotrophic lateral sclerosis, in patients with various ataxias. Ristori et al examined 40 patients with ataxia of mixed etiology (eg, fragile X-associated tremor/ataxia syndrome, Friedreich’s ataxia, spinocerebellar ataxia, and multiple system atrophy). Patients received 100 mg/day of riluzole or placebo for eight weeks. After four weeks of treatment, about 47% of the riluzole group had a five-point improvement on the International Cooperative Ataxia Rating Scale (ICARS), compared with 5% in the placebo group. After eight weeks, 68% of the riluzole group had this outcome, compared with 5% of the placebo group.
In a 12-month study, Romano et al randomized 60 patients with spinocerebellar ataxia or Friedreich’s ataxia to 50 mg of riluzole b.i.d. or placebo. At 12 months, the proportion of patients with a decrease in Scale for the Assessment and Rating of Ataxia (SARA) score was 50% in the riluzole group, compared with 11% in the placebo group. The mean change in SARA score was greater in the riluzole group (2.6), compared with controls (1.39). The clinical relevance of the improvements in these two studies, however, is uncertain, said Dr. Zesiewicz.
An ongoing phase III study is examining a prodrug of riluzole in 120 patients with spinocerebellar ataxia. Various doses are being examined, and the treatment period will be eight weeks.
In a 1983 study, 250 patients with spinocerebellar ataxia were randomized to thyrotropin-releasing hormone or placebo. Outcomes were reported using a visual analog scale. Participants receiving thyrotropin-releasing hormone had improvement in dysarthria, stance, and gait, but the clinical significance is questionable, said Dr. Zesiewicz.
She and her colleagues compared varenicline, a drug approved for smoking cessation, with placebo in patients with spinocerebellar ataxia type III. After a four-week titration period, patients received treatment for four weeks. The investigators observed significant improvements in gait, stance, and rapid alternating movements among patients receiving varenicline. After data correction, the improvement in rapid alternating movements remained significant. Varenicline has been associated with suicide risk, but Dr. Zesiewicz and colleagues noted a trend toward improvement in Beck Depression Scale among treated participants. Approximately 40% of patients receiving varenicline dropped out of the study, however, because of tremulousness, weakness, and unpleasant dreams.
Examining Nonpharmacologic Options
In addition to pharmacotherapy, some nonpharmacologic treatments may improve function in spinocerebellar ataxia. In one double-blind trial, researchers randomized participants with various ataxias to a single session of transcranial magnetic stimulation (TMS) or sham stimulation. TMS was associated with improvement in SARA score and cerebellar motor function at 21 days. “Harvard just finished a TMS study, and we are waiting for results from that,” said Dr. Zesiewicz.
“Physical therapy is vital for patients with spinocerebellar ataxia,” she continued. One study indicated that intensive exercises such as core strength training, stepping, and dynamic balance yielded significant increases in the Berg Balance Scale. In another randomized controlled trial, four weeks of physical and occupational therapy were associated with a three-point decrease in SARA score. In addition, patients with spinocerebellar ataxia had a two-point decrease in ICARS score after undergoing four weeks of intensive cycling.
A Search for Future Therapies
Investigations of new potential treatments for spinocerebellar ataxia are ongoing. Researchers published the results of a phase II study of IV trehalose in January. Participants’ SARA score remained stable after six months of treatment.
Mesenchymal stem cells may one day provide benefits for patients. After one month of treatment with mesenchymal stromal cells, study participants with spinocerebellar ataxia had improved walking, standing, slow movement, and fine movements. Patients returned to their pretreatment condition after a few months, however.
In addition, screens of small molecules may reveal possible new therapies. One such screen identified aripiprazole as a candidate, and the drug increased longevity in a Drosophila model of Machado-Joseph disease.
“We are looking for great things. We are looking for a cure. But we will use what we have now,” Dr. Zesiewicz concluded.
—Erik Greb
Suggested Reading
Lei LF, Yang GP, Wang JL, et al. Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord. 2016;26:55-61.
Ristori G, Romano S, Visconti A, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010;74(10):839-845.
Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14(10):985-891.
Strupp M, Kalla R, Claassen J, et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology. 2011;77(3):269-275.
Zesiewicz TA, Greenstein PE, Sullivan KL, et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology. 2012;78(8):545-550.