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CAR T may have curative potential in Hodgkin lymphoma
NEW YORK – Although the data set is small and not yet mature, chimeric antigen receptor (CAR) T-cell therapy appears to be a promising approach for Hodgkin lymphoma, according to Philippe Armand, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center and the Massachusetts General Hospital Cancer Center in Boston.
While based on a handful of patients, the data do suggest this approach may play a role by targeting CD30 or Epstein Barr virus (EBV), Dr. Armand said at the NCCN Annual Congress: Hematologic Malignancies.
“Most importantly perhaps, like its experience outside of Hodgkin lymphoma, it may really have curative potential, based on the long [complete response] rates that have been already exhibited,” he said.
Much of the published clinical experience to date is with CD30-directed CAR Ts, Dr. Armand said, noting that in Hodgkin lymphoma, results so far show promise for this particular approach.
In a recent phase 1 dose escalation study, nine patients with relapsed/refractory Hodgkin lymphoma or anaplastic large-cell lymphoma (ALCL) received infusions of autologous T cells modified to express CD30-specific CAR T cells encoding the CD28 costimulatory domain, with no conditioning regimen.
Out of seven relapsed Hodgkin lymphoma patients, one had a complete response (CR) lasting beyond 2.5 years following a second infusion. Another patient had a CR persisting almost 2 years, and three patients had transient stable disease. One of the two ALCL patients had a CR lasting 9 months after a fourth infusion.
No toxicities attributable to the therapy were seen, according to the investigators.
The CD30 CAR T cells are being evaluated with a conditioning regimen in the phase 1 RELY-30 trial. Preliminary results presented at the 2018 European Society for Blood and Marrow Transplantation meeting in Lisbon showed better expansion of CAR T cells and responses in three out of five patients, including two CRs, according to Dr. Armand.
A CD30-directed CAR T-cell therapy with a 4-1BB costimulatory domain has also been tested in a small group of Hodgkin patients with a response rate of 35% – including some CRs – with an apparent lower response rate in patients with extranodal involvement. Dr. Armand noted that those findings need to be validated in additional studies.
Among non CD-30 targeted products, a CD19 CAR-T approach has been tried in Hodgkin lymphoma, though preliminary results suggest only transient activity, according to the presenter.
One interesting approach has been the targeting of EBV, he added. Recently reported results showed that two doses of T cells with specificity for EBV-derived tumor antigens induced clinical responses in patients with EBV-positive Hodgkin lymphoma.
The cells were engineered to express dominant-negative TGF-beta receptor type 2, according to the report. “We know that TGF-beta provides a strong immunosuppressant signal in the tumor microenvironment,” Dr. Armand said, noting that some of the responses in the seven evaluable patients lasted 4 years or more.
Dr. Armand reported financial disclosures related to Adaptive Biotechnologies/Sequenta, Affimed, Bristol-Myers Squibb, Merck, and Roche.
NEW YORK – Although the data set is small and not yet mature, chimeric antigen receptor (CAR) T-cell therapy appears to be a promising approach for Hodgkin lymphoma, according to Philippe Armand, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center and the Massachusetts General Hospital Cancer Center in Boston.
While based on a handful of patients, the data do suggest this approach may play a role by targeting CD30 or Epstein Barr virus (EBV), Dr. Armand said at the NCCN Annual Congress: Hematologic Malignancies.
“Most importantly perhaps, like its experience outside of Hodgkin lymphoma, it may really have curative potential, based on the long [complete response] rates that have been already exhibited,” he said.
Much of the published clinical experience to date is with CD30-directed CAR Ts, Dr. Armand said, noting that in Hodgkin lymphoma, results so far show promise for this particular approach.
In a recent phase 1 dose escalation study, nine patients with relapsed/refractory Hodgkin lymphoma or anaplastic large-cell lymphoma (ALCL) received infusions of autologous T cells modified to express CD30-specific CAR T cells encoding the CD28 costimulatory domain, with no conditioning regimen.
Out of seven relapsed Hodgkin lymphoma patients, one had a complete response (CR) lasting beyond 2.5 years following a second infusion. Another patient had a CR persisting almost 2 years, and three patients had transient stable disease. One of the two ALCL patients had a CR lasting 9 months after a fourth infusion.
No toxicities attributable to the therapy were seen, according to the investigators.
The CD30 CAR T cells are being evaluated with a conditioning regimen in the phase 1 RELY-30 trial. Preliminary results presented at the 2018 European Society for Blood and Marrow Transplantation meeting in Lisbon showed better expansion of CAR T cells and responses in three out of five patients, including two CRs, according to Dr. Armand.
A CD30-directed CAR T-cell therapy with a 4-1BB costimulatory domain has also been tested in a small group of Hodgkin patients with a response rate of 35% – including some CRs – with an apparent lower response rate in patients with extranodal involvement. Dr. Armand noted that those findings need to be validated in additional studies.
Among non CD-30 targeted products, a CD19 CAR-T approach has been tried in Hodgkin lymphoma, though preliminary results suggest only transient activity, according to the presenter.
One interesting approach has been the targeting of EBV, he added. Recently reported results showed that two doses of T cells with specificity for EBV-derived tumor antigens induced clinical responses in patients with EBV-positive Hodgkin lymphoma.
The cells were engineered to express dominant-negative TGF-beta receptor type 2, according to the report. “We know that TGF-beta provides a strong immunosuppressant signal in the tumor microenvironment,” Dr. Armand said, noting that some of the responses in the seven evaluable patients lasted 4 years or more.
Dr. Armand reported financial disclosures related to Adaptive Biotechnologies/Sequenta, Affimed, Bristol-Myers Squibb, Merck, and Roche.
NEW YORK – Although the data set is small and not yet mature, chimeric antigen receptor (CAR) T-cell therapy appears to be a promising approach for Hodgkin lymphoma, according to Philippe Armand, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center and the Massachusetts General Hospital Cancer Center in Boston.
While based on a handful of patients, the data do suggest this approach may play a role by targeting CD30 or Epstein Barr virus (EBV), Dr. Armand said at the NCCN Annual Congress: Hematologic Malignancies.
“Most importantly perhaps, like its experience outside of Hodgkin lymphoma, it may really have curative potential, based on the long [complete response] rates that have been already exhibited,” he said.
Much of the published clinical experience to date is with CD30-directed CAR Ts, Dr. Armand said, noting that in Hodgkin lymphoma, results so far show promise for this particular approach.
In a recent phase 1 dose escalation study, nine patients with relapsed/refractory Hodgkin lymphoma or anaplastic large-cell lymphoma (ALCL) received infusions of autologous T cells modified to express CD30-specific CAR T cells encoding the CD28 costimulatory domain, with no conditioning regimen.
Out of seven relapsed Hodgkin lymphoma patients, one had a complete response (CR) lasting beyond 2.5 years following a second infusion. Another patient had a CR persisting almost 2 years, and three patients had transient stable disease. One of the two ALCL patients had a CR lasting 9 months after a fourth infusion.
No toxicities attributable to the therapy were seen, according to the investigators.
The CD30 CAR T cells are being evaluated with a conditioning regimen in the phase 1 RELY-30 trial. Preliminary results presented at the 2018 European Society for Blood and Marrow Transplantation meeting in Lisbon showed better expansion of CAR T cells and responses in three out of five patients, including two CRs, according to Dr. Armand.
A CD30-directed CAR T-cell therapy with a 4-1BB costimulatory domain has also been tested in a small group of Hodgkin patients with a response rate of 35% – including some CRs – with an apparent lower response rate in patients with extranodal involvement. Dr. Armand noted that those findings need to be validated in additional studies.
Among non CD-30 targeted products, a CD19 CAR-T approach has been tried in Hodgkin lymphoma, though preliminary results suggest only transient activity, according to the presenter.
One interesting approach has been the targeting of EBV, he added. Recently reported results showed that two doses of T cells with specificity for EBV-derived tumor antigens induced clinical responses in patients with EBV-positive Hodgkin lymphoma.
The cells were engineered to express dominant-negative TGF-beta receptor type 2, according to the report. “We know that TGF-beta provides a strong immunosuppressant signal in the tumor microenvironment,” Dr. Armand said, noting that some of the responses in the seven evaluable patients lasted 4 years or more.
Dr. Armand reported financial disclosures related to Adaptive Biotechnologies/Sequenta, Affimed, Bristol-Myers Squibb, Merck, and Roche.
EXPERT ANALYSIS FROM NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
FAST-FFR: Noninvasive FFR nearly as good as wire
SAN DIEGO – A less-invasive way to measure fractional flow reserve using angiography had a sensitivity of 94% and specificity of 91%, compared with standard wire-based techniques, according to a report at the Transcatheter Cardiovascular Therapeutics annual meeting.
The method may provide an easier and potentially faster method for performing physiology-guided assessment of the overall coronary angiogram than with coronary pressure wire–based FFR, William Fearon, MD, said in presenting results of the FAST-FFR trial.
The added bonus of the FFRangio system, from the Israeli company CathWorks, is that it automatically produces a 3-D reconstruction of the entire coronary tree and can calculate FFR values for all occlusions. It requires high-quality angiograms, which are transferred to a proprietary counsel; the system estimates resistance and flow across stenoses using an algorithm. After a few cases, the process takes less than 5 minutes. CathWorks is working on Food and Drug Administration clearance, Dr. Fearon reported.
Several other companies are also developing noninvasive ways to measure FFR, the pressure gradient across lesions. It helps clinicians make the call on revascularization, since angiograms can be deceiving; occlusions that look bad might not really be causing a problem, and vice-versa.
FFR is recommended in assessment guidelines, but it’s not used much. The problem is that traditional measurement requires threading wires down coronary arteries; the technique is a bit risky and takes time and training. It also has to be repeated for each lesion.
The new system “has the potential to eventually replace wire-based FFR measurement and substantially increase physiologic coronary lesion assessment in the catheterization laboratory, thereby leading to improved patient outcomes,” said Dr. Fearon, professor of cardiology at Stanford (Calif.) University.
He said that he thought FFRangio could change practice, and several panelists agreed. “This is a real advance in the field. The use of FFR is not as great as it should be. I hope this will improve the ability of the assessor to identify ischemic lesions. I think that’s what’s going to happen. This is going to drive us forward,” said Mark Reisman, MD, head of cardiology and director of the Center for Emerging Cardiovascular Therapies at the University of Washington, Seattle.
The FAST-FFR (FFRangio Accuracy versus Standard FFR) study was conducted at 10 centers in the United States, Europe, and Israel; FFRangio was used to obtain FFRs in 319 vessels among 301 patients; the results were checked against FFR measured by wire. FFRangio operators were blinded to wire results.
The mean FFR was 0.81, and 43% of vessels had an FFR of 0.80 or less, signaling a possible abnormality. The diagnostic accuracy of FFRangio against wire measurement was 92%, and 87% when only gray-zone values between 0.75-0.85 were considered. Correlation with wire measurements was good (r = 0.80; P less than 0.001). Mismatches with the wire were more likely in the right coronary artery. The results were published online at the time of the presentation at TCT, sponsored by the Cardiovascular Research Foundation (Circulation. 2018 Sept 24. doi: 10.1161/circulationaha.118.037350).
“The main issue with this is that we need to do optimal angiographies. We should be doing them on a routine basis, but oftentimes, cardiologists want to be quick; they get lazy. But you do need to fill the entire vessel with contrast,” Dr. Fearon said.
“One of the nice things is you can rotate” the 3-D coronary artery tree reconstruction. “You can get a better idea of the relationship between the lesion and side branches, the length of the lesion, and a lot of additional information you don’t have on the angiogram [alone]. Then, you can pull back the cursor and measure FFR all along the vessel and different branches, all based on one angiography,” he said.
The majority of patients in the study were overweight or obese with complex coronary anatomy, as in daily practice. The investigation was limited to lesions amenable to wire measurement, so it didn’t include left main disease, low ejection fraction, and in-stent restenosis, although assessment may be possible.
Dr. Fearon didn’t know how much FFRangio will cost if it’s cleared or how CathWorks will be made available.
The work was funded by CathWorks. Dr. Fearon disclosed institutional research support from the company. One of the investigators was a cofounder of the company, with shares and intellectual property rights. The TCT meeting is sponsored by the Cardiovascular Research Foundation.
SAN DIEGO – A less-invasive way to measure fractional flow reserve using angiography had a sensitivity of 94% and specificity of 91%, compared with standard wire-based techniques, according to a report at the Transcatheter Cardiovascular Therapeutics annual meeting.
The method may provide an easier and potentially faster method for performing physiology-guided assessment of the overall coronary angiogram than with coronary pressure wire–based FFR, William Fearon, MD, said in presenting results of the FAST-FFR trial.
The added bonus of the FFRangio system, from the Israeli company CathWorks, is that it automatically produces a 3-D reconstruction of the entire coronary tree and can calculate FFR values for all occlusions. It requires high-quality angiograms, which are transferred to a proprietary counsel; the system estimates resistance and flow across stenoses using an algorithm. After a few cases, the process takes less than 5 minutes. CathWorks is working on Food and Drug Administration clearance, Dr. Fearon reported.
Several other companies are also developing noninvasive ways to measure FFR, the pressure gradient across lesions. It helps clinicians make the call on revascularization, since angiograms can be deceiving; occlusions that look bad might not really be causing a problem, and vice-versa.
FFR is recommended in assessment guidelines, but it’s not used much. The problem is that traditional measurement requires threading wires down coronary arteries; the technique is a bit risky and takes time and training. It also has to be repeated for each lesion.
The new system “has the potential to eventually replace wire-based FFR measurement and substantially increase physiologic coronary lesion assessment in the catheterization laboratory, thereby leading to improved patient outcomes,” said Dr. Fearon, professor of cardiology at Stanford (Calif.) University.
He said that he thought FFRangio could change practice, and several panelists agreed. “This is a real advance in the field. The use of FFR is not as great as it should be. I hope this will improve the ability of the assessor to identify ischemic lesions. I think that’s what’s going to happen. This is going to drive us forward,” said Mark Reisman, MD, head of cardiology and director of the Center for Emerging Cardiovascular Therapies at the University of Washington, Seattle.
The FAST-FFR (FFRangio Accuracy versus Standard FFR) study was conducted at 10 centers in the United States, Europe, and Israel; FFRangio was used to obtain FFRs in 319 vessels among 301 patients; the results were checked against FFR measured by wire. FFRangio operators were blinded to wire results.
The mean FFR was 0.81, and 43% of vessels had an FFR of 0.80 or less, signaling a possible abnormality. The diagnostic accuracy of FFRangio against wire measurement was 92%, and 87% when only gray-zone values between 0.75-0.85 were considered. Correlation with wire measurements was good (r = 0.80; P less than 0.001). Mismatches with the wire were more likely in the right coronary artery. The results were published online at the time of the presentation at TCT, sponsored by the Cardiovascular Research Foundation (Circulation. 2018 Sept 24. doi: 10.1161/circulationaha.118.037350).
“The main issue with this is that we need to do optimal angiographies. We should be doing them on a routine basis, but oftentimes, cardiologists want to be quick; they get lazy. But you do need to fill the entire vessel with contrast,” Dr. Fearon said.
“One of the nice things is you can rotate” the 3-D coronary artery tree reconstruction. “You can get a better idea of the relationship between the lesion and side branches, the length of the lesion, and a lot of additional information you don’t have on the angiogram [alone]. Then, you can pull back the cursor and measure FFR all along the vessel and different branches, all based on one angiography,” he said.
The majority of patients in the study were overweight or obese with complex coronary anatomy, as in daily practice. The investigation was limited to lesions amenable to wire measurement, so it didn’t include left main disease, low ejection fraction, and in-stent restenosis, although assessment may be possible.
Dr. Fearon didn’t know how much FFRangio will cost if it’s cleared or how CathWorks will be made available.
The work was funded by CathWorks. Dr. Fearon disclosed institutional research support from the company. One of the investigators was a cofounder of the company, with shares and intellectual property rights. The TCT meeting is sponsored by the Cardiovascular Research Foundation.
SAN DIEGO – A less-invasive way to measure fractional flow reserve using angiography had a sensitivity of 94% and specificity of 91%, compared with standard wire-based techniques, according to a report at the Transcatheter Cardiovascular Therapeutics annual meeting.
The method may provide an easier and potentially faster method for performing physiology-guided assessment of the overall coronary angiogram than with coronary pressure wire–based FFR, William Fearon, MD, said in presenting results of the FAST-FFR trial.
The added bonus of the FFRangio system, from the Israeli company CathWorks, is that it automatically produces a 3-D reconstruction of the entire coronary tree and can calculate FFR values for all occlusions. It requires high-quality angiograms, which are transferred to a proprietary counsel; the system estimates resistance and flow across stenoses using an algorithm. After a few cases, the process takes less than 5 minutes. CathWorks is working on Food and Drug Administration clearance, Dr. Fearon reported.
Several other companies are also developing noninvasive ways to measure FFR, the pressure gradient across lesions. It helps clinicians make the call on revascularization, since angiograms can be deceiving; occlusions that look bad might not really be causing a problem, and vice-versa.
FFR is recommended in assessment guidelines, but it’s not used much. The problem is that traditional measurement requires threading wires down coronary arteries; the technique is a bit risky and takes time and training. It also has to be repeated for each lesion.
The new system “has the potential to eventually replace wire-based FFR measurement and substantially increase physiologic coronary lesion assessment in the catheterization laboratory, thereby leading to improved patient outcomes,” said Dr. Fearon, professor of cardiology at Stanford (Calif.) University.
He said that he thought FFRangio could change practice, and several panelists agreed. “This is a real advance in the field. The use of FFR is not as great as it should be. I hope this will improve the ability of the assessor to identify ischemic lesions. I think that’s what’s going to happen. This is going to drive us forward,” said Mark Reisman, MD, head of cardiology and director of the Center for Emerging Cardiovascular Therapies at the University of Washington, Seattle.
The FAST-FFR (FFRangio Accuracy versus Standard FFR) study was conducted at 10 centers in the United States, Europe, and Israel; FFRangio was used to obtain FFRs in 319 vessels among 301 patients; the results were checked against FFR measured by wire. FFRangio operators were blinded to wire results.
The mean FFR was 0.81, and 43% of vessels had an FFR of 0.80 or less, signaling a possible abnormality. The diagnostic accuracy of FFRangio against wire measurement was 92%, and 87% when only gray-zone values between 0.75-0.85 were considered. Correlation with wire measurements was good (r = 0.80; P less than 0.001). Mismatches with the wire were more likely in the right coronary artery. The results were published online at the time of the presentation at TCT, sponsored by the Cardiovascular Research Foundation (Circulation. 2018 Sept 24. doi: 10.1161/circulationaha.118.037350).
“The main issue with this is that we need to do optimal angiographies. We should be doing them on a routine basis, but oftentimes, cardiologists want to be quick; they get lazy. But you do need to fill the entire vessel with contrast,” Dr. Fearon said.
“One of the nice things is you can rotate” the 3-D coronary artery tree reconstruction. “You can get a better idea of the relationship between the lesion and side branches, the length of the lesion, and a lot of additional information you don’t have on the angiogram [alone]. Then, you can pull back the cursor and measure FFR all along the vessel and different branches, all based on one angiography,” he said.
The majority of patients in the study were overweight or obese with complex coronary anatomy, as in daily practice. The investigation was limited to lesions amenable to wire measurement, so it didn’t include left main disease, low ejection fraction, and in-stent restenosis, although assessment may be possible.
Dr. Fearon didn’t know how much FFRangio will cost if it’s cleared or how CathWorks will be made available.
The work was funded by CathWorks. Dr. Fearon disclosed institutional research support from the company. One of the investigators was a cofounder of the company, with shares and intellectual property rights. The TCT meeting is sponsored by the Cardiovascular Research Foundation.
REPORTING FROM TCT 2018
Key clinical point:
Major finding: FFRangio, a less-invasive way to measure fractional flow reserve using angiograms, had a sensitivity of 94% and specificity of 91%, compared with standard, wire-based techniques.
Study details: The prospective, multicenter FAST-FFR compared FFRangio with pressure wire–derived fractional flow reserve in 301 subjects.
Disclosures: The work was funded by FFRangio maker, CathWorks. Dr. Fearon disclosed institutional research support from the company. One of the authors was a cofounder of the company, with shares and intellectual property rights.
All children deserve support for their gender identities
The Atlantic published the article “When Children Say They’re Trans” by Jesse Singal in its July/August edition not too long ago. In this article, the author wrote about the increasing availability of treatments for affirming one’s gender identity and the rising concerns about the risks surrounding those treatments.
A key issue in the article is the concept of desistance. Desistance is a phenomenon in which individuals no longer feel that their gender identities are incongruent with their physical appearance. Highly related to desistance is detransitioning, a phenomenon in which transgender individuals no longer take the steps (e.g., hormone therapy) to affirm their gender identity. Singal highlights the concern surrounding starting medical treatments to affirm an individual’s gender identity, considering that the changes are irreversible and that it is possible for children to change their minds. Implied in the article is a call for a cautious approach for treating children who identify as transgender because it will be difficult to predict what one’s final gender identity is; however, I believe that a better approach is to support the child in the journey in affirming the gender identity.
The evidence on the rate of desistance may not be accurate
One argument for the cautious approach is the often cited statistic that 80% of children with gender nonconforming behaviors do not identify as transgender when they are adults. This is derived from four published studies that track the gender identity of individuals with gender nonconforming behaviors in childhood.1-4 These estimates may not be accurate, mainly due to these studies’ methodological shortcomings. For example, those who were lost to follow-up were assumed to be cisgender as adults and no efforts were made to verify these individuals’ gender identity.2-4 I do not intend to thoroughly critique these studies in this column. This is best left to peer-reviewed commentaries (a good example is one written by Newhook et al. 2018).5 I worry, however, that some clinicians may dismiss a child’s gender identity based on these studies and recommend to the parents to delay supporting a transition until the child “knows for sure.” The problem with this approach is that it may worsen the health and well-being of transgender youth, as there is growing evidence that transgender children who are supported by their parents are less likely to have mental health problems.6,7
The reasons for desistance are far more complicated
The common narrative of desistance is that the individuals simply change their minds because they were “confused” during adolescence. However, the truth is more complicated. Children can identify their own gender as early as 2 years old;8 however, when a child’s gender identity matches the assigned sex at birth, this is often reinforced. In contrast, if a child’s gender identity does not match the assigned sex at birth, it often is challenged by peers and adults. This challenge by peers, their families, and medical providers may be one of the reasons why transitioning is so difficult for many transgender youth – and many do give up.3,9 In these cases, some people wait for years, if not decades, to come out again and start transitioning when they finally feel supported and safe – even in their 90s! Other transgender people realize that their gender identity is not on the binary (neither male nor female), so they no longer need cross-sex hormones or surgeries to affirm their gender identity. Finally, others are concerned about the side effects, such as infertility, and feel that the risks for those side effects are not worth it, so they find other, nonmedical or nonsurgical ways to affirm their gender identity or manage their gender dysphoria.
Positive outcomes are more common
Reports of youth detransitioning highlight many physicians’ fears of making a mistake; however, these reports obscure the more common – and positive – outcomes for transgender individuals who took steps to affirm their gender identity. The Report of the 2011 Transition Survey shows that 97% were satisfied with being on hormone therapy and 90% were satisfied with obtaining bottom surgery.10 Furthermore, there is growing evidence showing that such treatments are associated with better health.11 A study by de Vries et al. found that transgender youth who transitioned in adolescence had less depression and better adjustment as adults.12 Finally, there is a lack of evidence supporting the concept that someone whose gender identity is fluid over time is any less healthy than those whose gender identity is static over time. Rare outcomes should never be dismissed; however, providers should not use rare events as the primary driver for discouraging evidence-based treatment.
The key is support
I believe that every child’s gender identity should be supported and affirmed. Clinicians can provide this support and affirmation through the following actions:
- At the first visit, clinicians should ask what the child’s hopes and expectations are for pursuing gender-affirming medical treatments.
- Clinicians should allow the child the opportunity to describe and process their gender identity instead of assuming that they are on the binary.
- Clinicians must recognize the varied reasons for desistance – stigma, discrimination, shame, or need to fit within a gender binary – and find ways to address those factors.
- Clinicians should have a thorough discussion with patients and their families about the risks of not supporting the child’s gender identity versus the risk of medical or surgical treatments used to affirm one’s gender identity and process with the child and the family where the values and wishes are within the context of those risks.
- Most importantly, clinicians should emphasize support for whatever decisions the child makes to affirm their gender identity. Providing support is essential in promoting the health and well-being of any child.
Dr. Montano is assistant professor of pediatrics at the University of Pittsburgh and an adolescent medicine physician at Children’s Hospital of Pittsburgh of UPMC. Email him at [email protected].
References
1. Dev Psychol. 2008;44(1):34-45.
2. J Am Acad Child Adolesc Psychiatry. 2013 Jun;52(6):582-90.
3. Clin Child Psychol Psychiatry. 2011 Oct;16(4):499-516.
4. J Am Acad Child Adolesc Psychiatry. 2008 Dec;47(12):1413-23.
5. International Journal of Transgenderism. 2018;19(2):212-24.
6. Pediatrics. 2016 Mar;137(3):e20153223.
7. J Sex Marital Ther. 2010;36(1):6-23.
8. “Adolescence,” 11th ed. (New York: McGraw-Hill Education; 2016).
9. Graduate Journal of Social Science. 2010;7(2):26-43.
10. “Affirming Gender, Affirming Lives: A Report of the 2011 Transition Survey,” Gender Advocacy Training & Education, 2012.
11. Transgend Health. 2016 Jan;1(1):21-31.
12. Pediatrics. 2014 Oct;134(4):696-704.
The Atlantic published the article “When Children Say They’re Trans” by Jesse Singal in its July/August edition not too long ago. In this article, the author wrote about the increasing availability of treatments for affirming one’s gender identity and the rising concerns about the risks surrounding those treatments.
A key issue in the article is the concept of desistance. Desistance is a phenomenon in which individuals no longer feel that their gender identities are incongruent with their physical appearance. Highly related to desistance is detransitioning, a phenomenon in which transgender individuals no longer take the steps (e.g., hormone therapy) to affirm their gender identity. Singal highlights the concern surrounding starting medical treatments to affirm an individual’s gender identity, considering that the changes are irreversible and that it is possible for children to change their minds. Implied in the article is a call for a cautious approach for treating children who identify as transgender because it will be difficult to predict what one’s final gender identity is; however, I believe that a better approach is to support the child in the journey in affirming the gender identity.
The evidence on the rate of desistance may not be accurate
One argument for the cautious approach is the often cited statistic that 80% of children with gender nonconforming behaviors do not identify as transgender when they are adults. This is derived from four published studies that track the gender identity of individuals with gender nonconforming behaviors in childhood.1-4 These estimates may not be accurate, mainly due to these studies’ methodological shortcomings. For example, those who were lost to follow-up were assumed to be cisgender as adults and no efforts were made to verify these individuals’ gender identity.2-4 I do not intend to thoroughly critique these studies in this column. This is best left to peer-reviewed commentaries (a good example is one written by Newhook et al. 2018).5 I worry, however, that some clinicians may dismiss a child’s gender identity based on these studies and recommend to the parents to delay supporting a transition until the child “knows for sure.” The problem with this approach is that it may worsen the health and well-being of transgender youth, as there is growing evidence that transgender children who are supported by their parents are less likely to have mental health problems.6,7
The reasons for desistance are far more complicated
The common narrative of desistance is that the individuals simply change their minds because they were “confused” during adolescence. However, the truth is more complicated. Children can identify their own gender as early as 2 years old;8 however, when a child’s gender identity matches the assigned sex at birth, this is often reinforced. In contrast, if a child’s gender identity does not match the assigned sex at birth, it often is challenged by peers and adults. This challenge by peers, their families, and medical providers may be one of the reasons why transitioning is so difficult for many transgender youth – and many do give up.3,9 In these cases, some people wait for years, if not decades, to come out again and start transitioning when they finally feel supported and safe – even in their 90s! Other transgender people realize that their gender identity is not on the binary (neither male nor female), so they no longer need cross-sex hormones or surgeries to affirm their gender identity. Finally, others are concerned about the side effects, such as infertility, and feel that the risks for those side effects are not worth it, so they find other, nonmedical or nonsurgical ways to affirm their gender identity or manage their gender dysphoria.
Positive outcomes are more common
Reports of youth detransitioning highlight many physicians’ fears of making a mistake; however, these reports obscure the more common – and positive – outcomes for transgender individuals who took steps to affirm their gender identity. The Report of the 2011 Transition Survey shows that 97% were satisfied with being on hormone therapy and 90% were satisfied with obtaining bottom surgery.10 Furthermore, there is growing evidence showing that such treatments are associated with better health.11 A study by de Vries et al. found that transgender youth who transitioned in adolescence had less depression and better adjustment as adults.12 Finally, there is a lack of evidence supporting the concept that someone whose gender identity is fluid over time is any less healthy than those whose gender identity is static over time. Rare outcomes should never be dismissed; however, providers should not use rare events as the primary driver for discouraging evidence-based treatment.
The key is support
I believe that every child’s gender identity should be supported and affirmed. Clinicians can provide this support and affirmation through the following actions:
- At the first visit, clinicians should ask what the child’s hopes and expectations are for pursuing gender-affirming medical treatments.
- Clinicians should allow the child the opportunity to describe and process their gender identity instead of assuming that they are on the binary.
- Clinicians must recognize the varied reasons for desistance – stigma, discrimination, shame, or need to fit within a gender binary – and find ways to address those factors.
- Clinicians should have a thorough discussion with patients and their families about the risks of not supporting the child’s gender identity versus the risk of medical or surgical treatments used to affirm one’s gender identity and process with the child and the family where the values and wishes are within the context of those risks.
- Most importantly, clinicians should emphasize support for whatever decisions the child makes to affirm their gender identity. Providing support is essential in promoting the health and well-being of any child.
Dr. Montano is assistant professor of pediatrics at the University of Pittsburgh and an adolescent medicine physician at Children’s Hospital of Pittsburgh of UPMC. Email him at [email protected].
References
1. Dev Psychol. 2008;44(1):34-45.
2. J Am Acad Child Adolesc Psychiatry. 2013 Jun;52(6):582-90.
3. Clin Child Psychol Psychiatry. 2011 Oct;16(4):499-516.
4. J Am Acad Child Adolesc Psychiatry. 2008 Dec;47(12):1413-23.
5. International Journal of Transgenderism. 2018;19(2):212-24.
6. Pediatrics. 2016 Mar;137(3):e20153223.
7. J Sex Marital Ther. 2010;36(1):6-23.
8. “Adolescence,” 11th ed. (New York: McGraw-Hill Education; 2016).
9. Graduate Journal of Social Science. 2010;7(2):26-43.
10. “Affirming Gender, Affirming Lives: A Report of the 2011 Transition Survey,” Gender Advocacy Training & Education, 2012.
11. Transgend Health. 2016 Jan;1(1):21-31.
12. Pediatrics. 2014 Oct;134(4):696-704.
The Atlantic published the article “When Children Say They’re Trans” by Jesse Singal in its July/August edition not too long ago. In this article, the author wrote about the increasing availability of treatments for affirming one’s gender identity and the rising concerns about the risks surrounding those treatments.
A key issue in the article is the concept of desistance. Desistance is a phenomenon in which individuals no longer feel that their gender identities are incongruent with their physical appearance. Highly related to desistance is detransitioning, a phenomenon in which transgender individuals no longer take the steps (e.g., hormone therapy) to affirm their gender identity. Singal highlights the concern surrounding starting medical treatments to affirm an individual’s gender identity, considering that the changes are irreversible and that it is possible for children to change their minds. Implied in the article is a call for a cautious approach for treating children who identify as transgender because it will be difficult to predict what one’s final gender identity is; however, I believe that a better approach is to support the child in the journey in affirming the gender identity.
The evidence on the rate of desistance may not be accurate
One argument for the cautious approach is the often cited statistic that 80% of children with gender nonconforming behaviors do not identify as transgender when they are adults. This is derived from four published studies that track the gender identity of individuals with gender nonconforming behaviors in childhood.1-4 These estimates may not be accurate, mainly due to these studies’ methodological shortcomings. For example, those who were lost to follow-up were assumed to be cisgender as adults and no efforts were made to verify these individuals’ gender identity.2-4 I do not intend to thoroughly critique these studies in this column. This is best left to peer-reviewed commentaries (a good example is one written by Newhook et al. 2018).5 I worry, however, that some clinicians may dismiss a child’s gender identity based on these studies and recommend to the parents to delay supporting a transition until the child “knows for sure.” The problem with this approach is that it may worsen the health and well-being of transgender youth, as there is growing evidence that transgender children who are supported by their parents are less likely to have mental health problems.6,7
The reasons for desistance are far more complicated
The common narrative of desistance is that the individuals simply change their minds because they were “confused” during adolescence. However, the truth is more complicated. Children can identify their own gender as early as 2 years old;8 however, when a child’s gender identity matches the assigned sex at birth, this is often reinforced. In contrast, if a child’s gender identity does not match the assigned sex at birth, it often is challenged by peers and adults. This challenge by peers, their families, and medical providers may be one of the reasons why transitioning is so difficult for many transgender youth – and many do give up.3,9 In these cases, some people wait for years, if not decades, to come out again and start transitioning when they finally feel supported and safe – even in their 90s! Other transgender people realize that their gender identity is not on the binary (neither male nor female), so they no longer need cross-sex hormones or surgeries to affirm their gender identity. Finally, others are concerned about the side effects, such as infertility, and feel that the risks for those side effects are not worth it, so they find other, nonmedical or nonsurgical ways to affirm their gender identity or manage their gender dysphoria.
Positive outcomes are more common
Reports of youth detransitioning highlight many physicians’ fears of making a mistake; however, these reports obscure the more common – and positive – outcomes for transgender individuals who took steps to affirm their gender identity. The Report of the 2011 Transition Survey shows that 97% were satisfied with being on hormone therapy and 90% were satisfied with obtaining bottom surgery.10 Furthermore, there is growing evidence showing that such treatments are associated with better health.11 A study by de Vries et al. found that transgender youth who transitioned in adolescence had less depression and better adjustment as adults.12 Finally, there is a lack of evidence supporting the concept that someone whose gender identity is fluid over time is any less healthy than those whose gender identity is static over time. Rare outcomes should never be dismissed; however, providers should not use rare events as the primary driver for discouraging evidence-based treatment.
The key is support
I believe that every child’s gender identity should be supported and affirmed. Clinicians can provide this support and affirmation through the following actions:
- At the first visit, clinicians should ask what the child’s hopes and expectations are for pursuing gender-affirming medical treatments.
- Clinicians should allow the child the opportunity to describe and process their gender identity instead of assuming that they are on the binary.
- Clinicians must recognize the varied reasons for desistance – stigma, discrimination, shame, or need to fit within a gender binary – and find ways to address those factors.
- Clinicians should have a thorough discussion with patients and their families about the risks of not supporting the child’s gender identity versus the risk of medical or surgical treatments used to affirm one’s gender identity and process with the child and the family where the values and wishes are within the context of those risks.
- Most importantly, clinicians should emphasize support for whatever decisions the child makes to affirm their gender identity. Providing support is essential in promoting the health and well-being of any child.
Dr. Montano is assistant professor of pediatrics at the University of Pittsburgh and an adolescent medicine physician at Children’s Hospital of Pittsburgh of UPMC. Email him at [email protected].
References
1. Dev Psychol. 2008;44(1):34-45.
2. J Am Acad Child Adolesc Psychiatry. 2013 Jun;52(6):582-90.
3. Clin Child Psychol Psychiatry. 2011 Oct;16(4):499-516.
4. J Am Acad Child Adolesc Psychiatry. 2008 Dec;47(12):1413-23.
5. International Journal of Transgenderism. 2018;19(2):212-24.
6. Pediatrics. 2016 Mar;137(3):e20153223.
7. J Sex Marital Ther. 2010;36(1):6-23.
8. “Adolescence,” 11th ed. (New York: McGraw-Hill Education; 2016).
9. Graduate Journal of Social Science. 2010;7(2):26-43.
10. “Affirming Gender, Affirming Lives: A Report of the 2011 Transition Survey,” Gender Advocacy Training & Education, 2012.
11. Transgend Health. 2016 Jan;1(1):21-31.
12. Pediatrics. 2014 Oct;134(4):696-704.
Outpatient lenalidomide/rituximab yields long-term MCL remission
After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.
After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.
The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.
“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.
In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m2 weekly for 4 weeks during cycle 1, then once every other cycle.
Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.
Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.
At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.
Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.
Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.
Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).
Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.
Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.
“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.
The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.
SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.
After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.
After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.
The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.
“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.
In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m2 weekly for 4 weeks during cycle 1, then once every other cycle.
Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.
Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.
At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.
Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.
Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.
Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).
Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.
Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.
“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.
The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.
SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.
After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.
After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.
The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.
“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.
In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m2 weekly for 4 weeks during cycle 1, then once every other cycle.
Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.
Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.
At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.
Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.
Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.
Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).
Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.
Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.
“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.
The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.
SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.
FROM BLOOD
Key clinical point:
Major finding: After 64-months of median follow-up, 21 of 33 patients with initial responses remained in remission.
Study details: Five-year follow-up of a phase 2 single arm trial of lenalidomide/rituximab induction and maintenance in 38 patients with mantle cell lymphoma.
Disclosures: The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.
Source: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.
FDA approves new drug for CLL/SLL and follicular lymphoma
The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.
who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.
Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.
Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.
The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.
The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).
Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.
The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.
The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.
Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.
Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.
Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.
The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.
who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.
Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.
Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.
The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.
The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).
Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.
The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.
The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.
Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.
Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.
Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.
The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.
who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.
Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.
Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.
The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.
The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).
Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.
The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.
The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.
Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.
Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.
Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.
IVUS guidance cuts target-vessel failure risk by 47%
SAN DIEGO – An all-comers trial conducted in China confirms that intravascular ultrasound (IVUS)–guided implantation of drug-eluting stents (DES) resulted in better clinical outcomes than did angiography-guided procedures, Jun-Jie Zhang, MD, said in reporting results of the ULTIMATE trial at the Transcatheter Cardiovascular Therapeutics annual meeting.
The ULTIMATE trial is the latest in a line of evidence showing the utility of IVUS guidance, though uptake of the procedure is not high in the United States or Europe. Its broader focus also rounds out the findings of earlier studies, which focused on patients with more complex lesions.
“How can people continue to ignore the importance of imaging-guided stent optimization? Even with second-generation DES, the results are consistent across the studies. This is just another piece of irrefutable evidence,” said discussant Gary Mintz, MD.
That sentiment was generally echoed by the rest of the panel. John McB Hodgson, MD, a professor of medicine at MetroHealth Medical Center in Cleveland, also pointed out the consistency of the body of evidence supporting the use of imaging. The study also represented a variety of cases, and the angiography arm of the study showed that the procedure was performed to a high standard. “It shows that even with a good angiographic approach, IVUS still wins. I’m amazed that there’s still some resistance to image guidance,” said Dr. Hodgson.
In ULTIMATE, 1,448 all-comer patients were randomized to either IVUS-guided or angiography-guided DES implantation. Patients with a life-expectancy shorter than 12 months, who were intolerant of dual-antiplatelet therapy, or who had severe calcification needing rotational atherectomy were excluded.
The procedural time was longer in the IVUS group, at 61 min, compared with 45 min in the angiography group, and the contrast volume was higher, at 178 mL and 162 mL, respectively (P less than .001 for both). At 30 days, the incidence of target vessel failure (TVF) was 0.8% in the IVUS group and 1.9% in the angiographic group, though this difference did not reach statistical significance (P = .08). The trend did reach significance at 1 year, with failure occurring in 2.9% of IVUS patients and 5.4% of angiography patients (P = .019). The hazard ratio for TVF in the IVUS group was 0.53 (95% confidence interval, 0.312-0.901), for a relative risk reduction of 47%, reported Dr. Zhang of Nanjing (China) Medical University.
Patients also underwent a postprocedure IVUS assessment to determine whether the stent was deployed optimally or suboptimally. The criteria for optimal deployment included minimal lumen area in the stented segment at least 5.0 mm2, or 90% of the minimal lumen area at distal reference segment meeting that criteria; a less than 50% plaque burden at the 5 mm of vessel proximal or distal to the stent edge; and no edge dissection involving media greater than 3 mm in length.
More than half (53%) of patients in the IVUS group had optimal placement, and 47% did not. Significantly fewer (1.6%) of patients with optimal IVUS experienced TVF at 12 months, compared with 4.4% of the suboptimal group (HR, 0.35; 95% CI, 0.135-0.898). The results were published online simultaneously with the presentation in the Journal of the American College of Cardiology.
“I’m particularly impressed by the analysis of the optimal versus nonoptimal group. If you don’t use IVUS correctly, you don’t get a benefit. The ones who did not get optimal stenting were very similar to the angiographic group,” said Dr. Mintz, chief medical officer at the Cardiovascular Research Foundation, which sponsored the meeting.
ULTIMATE was funded by the National Science Foundation of China and several other research organizations. Dr. Zhang had no relevant disclosures. Dr. Mintz has received research support and/or consulting fees from Abbott Vascular, Boston Scientific, Volcano, and Infraredx. Dr. Hodgson has received research support and consulted for Volcano.
SAN DIEGO – An all-comers trial conducted in China confirms that intravascular ultrasound (IVUS)–guided implantation of drug-eluting stents (DES) resulted in better clinical outcomes than did angiography-guided procedures, Jun-Jie Zhang, MD, said in reporting results of the ULTIMATE trial at the Transcatheter Cardiovascular Therapeutics annual meeting.
The ULTIMATE trial is the latest in a line of evidence showing the utility of IVUS guidance, though uptake of the procedure is not high in the United States or Europe. Its broader focus also rounds out the findings of earlier studies, which focused on patients with more complex lesions.
“How can people continue to ignore the importance of imaging-guided stent optimization? Even with second-generation DES, the results are consistent across the studies. This is just another piece of irrefutable evidence,” said discussant Gary Mintz, MD.
That sentiment was generally echoed by the rest of the panel. John McB Hodgson, MD, a professor of medicine at MetroHealth Medical Center in Cleveland, also pointed out the consistency of the body of evidence supporting the use of imaging. The study also represented a variety of cases, and the angiography arm of the study showed that the procedure was performed to a high standard. “It shows that even with a good angiographic approach, IVUS still wins. I’m amazed that there’s still some resistance to image guidance,” said Dr. Hodgson.
In ULTIMATE, 1,448 all-comer patients were randomized to either IVUS-guided or angiography-guided DES implantation. Patients with a life-expectancy shorter than 12 months, who were intolerant of dual-antiplatelet therapy, or who had severe calcification needing rotational atherectomy were excluded.
The procedural time was longer in the IVUS group, at 61 min, compared with 45 min in the angiography group, and the contrast volume was higher, at 178 mL and 162 mL, respectively (P less than .001 for both). At 30 days, the incidence of target vessel failure (TVF) was 0.8% in the IVUS group and 1.9% in the angiographic group, though this difference did not reach statistical significance (P = .08). The trend did reach significance at 1 year, with failure occurring in 2.9% of IVUS patients and 5.4% of angiography patients (P = .019). The hazard ratio for TVF in the IVUS group was 0.53 (95% confidence interval, 0.312-0.901), for a relative risk reduction of 47%, reported Dr. Zhang of Nanjing (China) Medical University.
Patients also underwent a postprocedure IVUS assessment to determine whether the stent was deployed optimally or suboptimally. The criteria for optimal deployment included minimal lumen area in the stented segment at least 5.0 mm2, or 90% of the minimal lumen area at distal reference segment meeting that criteria; a less than 50% plaque burden at the 5 mm of vessel proximal or distal to the stent edge; and no edge dissection involving media greater than 3 mm in length.
More than half (53%) of patients in the IVUS group had optimal placement, and 47% did not. Significantly fewer (1.6%) of patients with optimal IVUS experienced TVF at 12 months, compared with 4.4% of the suboptimal group (HR, 0.35; 95% CI, 0.135-0.898). The results were published online simultaneously with the presentation in the Journal of the American College of Cardiology.
“I’m particularly impressed by the analysis of the optimal versus nonoptimal group. If you don’t use IVUS correctly, you don’t get a benefit. The ones who did not get optimal stenting were very similar to the angiographic group,” said Dr. Mintz, chief medical officer at the Cardiovascular Research Foundation, which sponsored the meeting.
ULTIMATE was funded by the National Science Foundation of China and several other research organizations. Dr. Zhang had no relevant disclosures. Dr. Mintz has received research support and/or consulting fees from Abbott Vascular, Boston Scientific, Volcano, and Infraredx. Dr. Hodgson has received research support and consulted for Volcano.
SAN DIEGO – An all-comers trial conducted in China confirms that intravascular ultrasound (IVUS)–guided implantation of drug-eluting stents (DES) resulted in better clinical outcomes than did angiography-guided procedures, Jun-Jie Zhang, MD, said in reporting results of the ULTIMATE trial at the Transcatheter Cardiovascular Therapeutics annual meeting.
The ULTIMATE trial is the latest in a line of evidence showing the utility of IVUS guidance, though uptake of the procedure is not high in the United States or Europe. Its broader focus also rounds out the findings of earlier studies, which focused on patients with more complex lesions.
“How can people continue to ignore the importance of imaging-guided stent optimization? Even with second-generation DES, the results are consistent across the studies. This is just another piece of irrefutable evidence,” said discussant Gary Mintz, MD.
That sentiment was generally echoed by the rest of the panel. John McB Hodgson, MD, a professor of medicine at MetroHealth Medical Center in Cleveland, also pointed out the consistency of the body of evidence supporting the use of imaging. The study also represented a variety of cases, and the angiography arm of the study showed that the procedure was performed to a high standard. “It shows that even with a good angiographic approach, IVUS still wins. I’m amazed that there’s still some resistance to image guidance,” said Dr. Hodgson.
In ULTIMATE, 1,448 all-comer patients were randomized to either IVUS-guided or angiography-guided DES implantation. Patients with a life-expectancy shorter than 12 months, who were intolerant of dual-antiplatelet therapy, or who had severe calcification needing rotational atherectomy were excluded.
The procedural time was longer in the IVUS group, at 61 min, compared with 45 min in the angiography group, and the contrast volume was higher, at 178 mL and 162 mL, respectively (P less than .001 for both). At 30 days, the incidence of target vessel failure (TVF) was 0.8% in the IVUS group and 1.9% in the angiographic group, though this difference did not reach statistical significance (P = .08). The trend did reach significance at 1 year, with failure occurring in 2.9% of IVUS patients and 5.4% of angiography patients (P = .019). The hazard ratio for TVF in the IVUS group was 0.53 (95% confidence interval, 0.312-0.901), for a relative risk reduction of 47%, reported Dr. Zhang of Nanjing (China) Medical University.
Patients also underwent a postprocedure IVUS assessment to determine whether the stent was deployed optimally or suboptimally. The criteria for optimal deployment included minimal lumen area in the stented segment at least 5.0 mm2, or 90% of the minimal lumen area at distal reference segment meeting that criteria; a less than 50% plaque burden at the 5 mm of vessel proximal or distal to the stent edge; and no edge dissection involving media greater than 3 mm in length.
More than half (53%) of patients in the IVUS group had optimal placement, and 47% did not. Significantly fewer (1.6%) of patients with optimal IVUS experienced TVF at 12 months, compared with 4.4% of the suboptimal group (HR, 0.35; 95% CI, 0.135-0.898). The results were published online simultaneously with the presentation in the Journal of the American College of Cardiology.
“I’m particularly impressed by the analysis of the optimal versus nonoptimal group. If you don’t use IVUS correctly, you don’t get a benefit. The ones who did not get optimal stenting were very similar to the angiographic group,” said Dr. Mintz, chief medical officer at the Cardiovascular Research Foundation, which sponsored the meeting.
ULTIMATE was funded by the National Science Foundation of China and several other research organizations. Dr. Zhang had no relevant disclosures. Dr. Mintz has received research support and/or consulting fees from Abbott Vascular, Boston Scientific, Volcano, and Infraredx. Dr. Hodgson has received research support and consulted for Volcano.
REPORTING FROM TCT 2018
Key clinical point:
Major finding: IVUS guidance reduced target vessel failure by 47%.
Study details: ULTIMATE, a randomized, controlled trial of 1,448 patients.
Disclosures: ULTIMATE was funded by the National Science Foundation of China and several other research organizations. Dr. Zhang had no relevant disclosures. Dr. Mintz has received research support from Abbott Vascular and Boston Scientific. He has been a consultant for Boston Scientific, Volcano, and Infraredx. Dr. Hodgson has received research support and consulted for Volcano.
Rotablation aids in prepping highly calcified lesions: PREPARE-CALC
SAN DIEGO – When it comes to preparing highly calcified coronary lesions for drug-eluting stents, rotational atherectomy has an early procedural advantage over modified balloons that cut or score the lesion, but yields similar clinical outcomes over time, according to results of the randomized PREPARE-CALC trial.
“Because severe calcification is mostly excluded from randomized PCI [percutaneous coronary intervention] trials, there is poor evidence for best PCI practice,” commented presenter Gert Richardt, MD, PhD, chief of cardiology and angiology at the Heart Center Segeberger Kliniken, Bad Segeberg, Germany. “Most interventional cardiologists will agree it is essential to facilitate stent delivery and adequate stent expansion in severely calcified lesions.”
Compared with standard balloon preparation, rotational atherectomy (rotablation) achieves a higher stenting success rate and better acute luminal gain, but its stimulatory effect leads to neointima formation that translates to late lumen loss, he noted. New balloons and drug-eluting stents may alter that calculus, however.
The 200 patients in PREPARE-CALC were randomized evenly to undergo preparation of their severely calcified coronary lesions with rotational atherectomy or a modified cutting/scoring balloon, each followed by placement of drug-eluting stents.
Compared with modified balloons, rotational atherectomy yielded a higher rate of successful stent delivery and expansion, according to data reported at the Transcatheter Cardiovascular Therapeutics annual meeting and simultaneously published online (Circ Cardiovasc Interv. 2018;11:e007415). The two methods did not differ significantly with respect to the 9-month magnitude of restenosis or rate of target vessel failure, at 6% with rotational atherectomy and 8% with modified balloons.
Importantly, about one in six patients in the modified balloon group had to cross over to rotational atherectomy because the balloon could not pass or sufficiently dilate the lesion.
“In patients with severely calcified coronary lesions, elective rotablation is feasible in nearly all patients, and the acute success rate is superior to modified balloons. Both approaches, elective rotational atherectomy and balloon plus bailout rotational atherectomy, are equally safe and effective,” Dr. Richardt summarized at the meeting sponsored by the Cardiovascular Research Foundation. “Use of rotablation is no longer associated with excessive late lumen loss in the era of modern drug-eluting stents.”
An underused tool
“This is a little bit ‘back to the future’ for me,” commented press conference panelist Mark Reisman, MD, director of the Center for Emerging Cardiovascular Therapies and head of UW Cardiology, Seattle. The PREPARE-CALC results are not surprising, but low uptake of rotablation in Europe, at just 1%-2%, is surprising and unexplained.
Importantly, the trial allows a sound comparison of rotational atherectomy with the best available alternatives, he said. “This may significantly impact the behavior and maybe some of the reimbursement in Europe. ... I’m sure that drives a lot of the decisions: cost as well as technique.”
Many of the original rotational atherectomy studies used larger burrs and multiple burrs, whereas the trial investigators applied less aggressive, more refined parameters. It will be interesting to look at their technique as it may have contributed to the favorable findings, according to Dr. Reisman.
“Based on what we just heard, there are very complex lesions that were maybe not being approached historically, which now people will feel a lot more confident in approaching, looking at the durable outcome with the Rotablator [Boston Scientific],” he summarized.
“From the practice of a clinician, it’s very frustrating to hit a calcified lesion and attempt to work on it up front and find you can’t cross it,” commented press conference panelist Morton J. Kern, MD, professor of medicine at the school of medicine and chief of medicine, VA Long Beach Health Care System, University of California, Irvine Medical Center. The high rate of crossover to rotablation in PREPARE-CALC speaks to this problem. Having to resort to this tool after failure of other lesional interventions often translates to a rockier overall procedure and clinical course.
“Lesion preparation is underestimated. I know from my own experience that [in] those calcified long lesions where I didn’t use the Rotablator, I regretted it in a fair number of cases,” Dr. Kern said. “So my view is that we probably don’t use it enough. This trial suggests that you can get away [without it], but I think ultimately, we are going to need this tool, even though it’s not used in a huge number of patients.”
Trial details
Patients enrolled in PREPARE-CALC had severely calcified coronary lesions according to angiographic criteria. For lesion preparation, half underwent high-speed rotational atherectomy (Rotablator), and half underwent treatment with either a cutting balloon (Flextome, Boston Scientific) or a scoring balloon (AngioSculpt, AngioScore, or Scoreflex, OrbusNeich Medical). Thereafter, all received sirolimus-eluting stents (Orsiro, Biotronik).
Results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that, compared with the modified balloons, rotational atherectomy yielded a higher rate of strategy success, defined as successful stent delivery and expansion with less than 20% in-stent residual stenosis and TIMI 3 flow, without crossover to the other arm or stent failure. The rotational atherectomy patients had a success rate of 98%, compared with 81% for the balloon patients (P = .0001).
“This difference was mainly driven by a high rate of crossovers from balloon to rotablation,” Dr. Richardt, noted, with 16% of patients assigned to the former modality ultimately receiving the latter. “These crossovers were due to noncrossable or nondilated lesions.”
Analyses suggested three subgroups did not benefit from rotational atherectomy when it came to strategy success: women, patients in whom the left anterior descending artery was the target, and patients not having type C lesions.
Quantitative coronary analysis showed that the acute lumen gain, whether in-stent or in-segment, did not differ significantly between the two preparation methods. “This is different from what we know from historical studies where the Rotablator was always achieving more acute gain than standard balloons,” Dr. Richardt commented.
Rotational atherectomy and modified balloons were similar with respect to the magnitude of in-stent late lumen loss (0.22 vs. 0.16 mm, P = .021 for superiority; P = .01 for noninferiority) and the rate of target-vessel failure (6% vs. 8%) at 9 months. Those failure rates were lower than the 10% expected from previous trials, he pointed out. “This might increase over time, but it’s not so far away from what we see in contemporary drug-eluting stent trials.”
Fluoroscopy time was about 4 minutes longer with rotational atherectomy than with modified balloons. “You may say that’s a lot. I would say in these 75-year-old patients, it is acceptable,” Dr. Richardt commented. “But to be honest, we had some cases where we had to place a pacemaker, and this increases the duration of the fluoroscopy time.”
The PREPARE-CALC findings should improve the rate of rotational atherectomy use in Europe, he said. “If you believe my data, then the rate should go up to 10% or 12%.”
Dr. Richardt disclosed that he receives speaker’s honoraria from Boston Scientific and Biotronik. The trial was sponsored by the Herz-Kreislauf-Zentrum Segeberger Kliniken GmbH.
SAN DIEGO – When it comes to preparing highly calcified coronary lesions for drug-eluting stents, rotational atherectomy has an early procedural advantage over modified balloons that cut or score the lesion, but yields similar clinical outcomes over time, according to results of the randomized PREPARE-CALC trial.
“Because severe calcification is mostly excluded from randomized PCI [percutaneous coronary intervention] trials, there is poor evidence for best PCI practice,” commented presenter Gert Richardt, MD, PhD, chief of cardiology and angiology at the Heart Center Segeberger Kliniken, Bad Segeberg, Germany. “Most interventional cardiologists will agree it is essential to facilitate stent delivery and adequate stent expansion in severely calcified lesions.”
Compared with standard balloon preparation, rotational atherectomy (rotablation) achieves a higher stenting success rate and better acute luminal gain, but its stimulatory effect leads to neointima formation that translates to late lumen loss, he noted. New balloons and drug-eluting stents may alter that calculus, however.
The 200 patients in PREPARE-CALC were randomized evenly to undergo preparation of their severely calcified coronary lesions with rotational atherectomy or a modified cutting/scoring balloon, each followed by placement of drug-eluting stents.
Compared with modified balloons, rotational atherectomy yielded a higher rate of successful stent delivery and expansion, according to data reported at the Transcatheter Cardiovascular Therapeutics annual meeting and simultaneously published online (Circ Cardiovasc Interv. 2018;11:e007415). The two methods did not differ significantly with respect to the 9-month magnitude of restenosis or rate of target vessel failure, at 6% with rotational atherectomy and 8% with modified balloons.
Importantly, about one in six patients in the modified balloon group had to cross over to rotational atherectomy because the balloon could not pass or sufficiently dilate the lesion.
“In patients with severely calcified coronary lesions, elective rotablation is feasible in nearly all patients, and the acute success rate is superior to modified balloons. Both approaches, elective rotational atherectomy and balloon plus bailout rotational atherectomy, are equally safe and effective,” Dr. Richardt summarized at the meeting sponsored by the Cardiovascular Research Foundation. “Use of rotablation is no longer associated with excessive late lumen loss in the era of modern drug-eluting stents.”
An underused tool
“This is a little bit ‘back to the future’ for me,” commented press conference panelist Mark Reisman, MD, director of the Center for Emerging Cardiovascular Therapies and head of UW Cardiology, Seattle. The PREPARE-CALC results are not surprising, but low uptake of rotablation in Europe, at just 1%-2%, is surprising and unexplained.
Importantly, the trial allows a sound comparison of rotational atherectomy with the best available alternatives, he said. “This may significantly impact the behavior and maybe some of the reimbursement in Europe. ... I’m sure that drives a lot of the decisions: cost as well as technique.”
Many of the original rotational atherectomy studies used larger burrs and multiple burrs, whereas the trial investigators applied less aggressive, more refined parameters. It will be interesting to look at their technique as it may have contributed to the favorable findings, according to Dr. Reisman.
“Based on what we just heard, there are very complex lesions that were maybe not being approached historically, which now people will feel a lot more confident in approaching, looking at the durable outcome with the Rotablator [Boston Scientific],” he summarized.
“From the practice of a clinician, it’s very frustrating to hit a calcified lesion and attempt to work on it up front and find you can’t cross it,” commented press conference panelist Morton J. Kern, MD, professor of medicine at the school of medicine and chief of medicine, VA Long Beach Health Care System, University of California, Irvine Medical Center. The high rate of crossover to rotablation in PREPARE-CALC speaks to this problem. Having to resort to this tool after failure of other lesional interventions often translates to a rockier overall procedure and clinical course.
“Lesion preparation is underestimated. I know from my own experience that [in] those calcified long lesions where I didn’t use the Rotablator, I regretted it in a fair number of cases,” Dr. Kern said. “So my view is that we probably don’t use it enough. This trial suggests that you can get away [without it], but I think ultimately, we are going to need this tool, even though it’s not used in a huge number of patients.”
Trial details
Patients enrolled in PREPARE-CALC had severely calcified coronary lesions according to angiographic criteria. For lesion preparation, half underwent high-speed rotational atherectomy (Rotablator), and half underwent treatment with either a cutting balloon (Flextome, Boston Scientific) or a scoring balloon (AngioSculpt, AngioScore, or Scoreflex, OrbusNeich Medical). Thereafter, all received sirolimus-eluting stents (Orsiro, Biotronik).
Results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that, compared with the modified balloons, rotational atherectomy yielded a higher rate of strategy success, defined as successful stent delivery and expansion with less than 20% in-stent residual stenosis and TIMI 3 flow, without crossover to the other arm or stent failure. The rotational atherectomy patients had a success rate of 98%, compared with 81% for the balloon patients (P = .0001).
“This difference was mainly driven by a high rate of crossovers from balloon to rotablation,” Dr. Richardt, noted, with 16% of patients assigned to the former modality ultimately receiving the latter. “These crossovers were due to noncrossable or nondilated lesions.”
Analyses suggested three subgroups did not benefit from rotational atherectomy when it came to strategy success: women, patients in whom the left anterior descending artery was the target, and patients not having type C lesions.
Quantitative coronary analysis showed that the acute lumen gain, whether in-stent or in-segment, did not differ significantly between the two preparation methods. “This is different from what we know from historical studies where the Rotablator was always achieving more acute gain than standard balloons,” Dr. Richardt commented.
Rotational atherectomy and modified balloons were similar with respect to the magnitude of in-stent late lumen loss (0.22 vs. 0.16 mm, P = .021 for superiority; P = .01 for noninferiority) and the rate of target-vessel failure (6% vs. 8%) at 9 months. Those failure rates were lower than the 10% expected from previous trials, he pointed out. “This might increase over time, but it’s not so far away from what we see in contemporary drug-eluting stent trials.”
Fluoroscopy time was about 4 minutes longer with rotational atherectomy than with modified balloons. “You may say that’s a lot. I would say in these 75-year-old patients, it is acceptable,” Dr. Richardt commented. “But to be honest, we had some cases where we had to place a pacemaker, and this increases the duration of the fluoroscopy time.”
The PREPARE-CALC findings should improve the rate of rotational atherectomy use in Europe, he said. “If you believe my data, then the rate should go up to 10% or 12%.”
Dr. Richardt disclosed that he receives speaker’s honoraria from Boston Scientific and Biotronik. The trial was sponsored by the Herz-Kreislauf-Zentrum Segeberger Kliniken GmbH.
SAN DIEGO – When it comes to preparing highly calcified coronary lesions for drug-eluting stents, rotational atherectomy has an early procedural advantage over modified balloons that cut or score the lesion, but yields similar clinical outcomes over time, according to results of the randomized PREPARE-CALC trial.
“Because severe calcification is mostly excluded from randomized PCI [percutaneous coronary intervention] trials, there is poor evidence for best PCI practice,” commented presenter Gert Richardt, MD, PhD, chief of cardiology and angiology at the Heart Center Segeberger Kliniken, Bad Segeberg, Germany. “Most interventional cardiologists will agree it is essential to facilitate stent delivery and adequate stent expansion in severely calcified lesions.”
Compared with standard balloon preparation, rotational atherectomy (rotablation) achieves a higher stenting success rate and better acute luminal gain, but its stimulatory effect leads to neointima formation that translates to late lumen loss, he noted. New balloons and drug-eluting stents may alter that calculus, however.
The 200 patients in PREPARE-CALC were randomized evenly to undergo preparation of their severely calcified coronary lesions with rotational atherectomy or a modified cutting/scoring balloon, each followed by placement of drug-eluting stents.
Compared with modified balloons, rotational atherectomy yielded a higher rate of successful stent delivery and expansion, according to data reported at the Transcatheter Cardiovascular Therapeutics annual meeting and simultaneously published online (Circ Cardiovasc Interv. 2018;11:e007415). The two methods did not differ significantly with respect to the 9-month magnitude of restenosis or rate of target vessel failure, at 6% with rotational atherectomy and 8% with modified balloons.
Importantly, about one in six patients in the modified balloon group had to cross over to rotational atherectomy because the balloon could not pass or sufficiently dilate the lesion.
“In patients with severely calcified coronary lesions, elective rotablation is feasible in nearly all patients, and the acute success rate is superior to modified balloons. Both approaches, elective rotational atherectomy and balloon plus bailout rotational atherectomy, are equally safe and effective,” Dr. Richardt summarized at the meeting sponsored by the Cardiovascular Research Foundation. “Use of rotablation is no longer associated with excessive late lumen loss in the era of modern drug-eluting stents.”
An underused tool
“This is a little bit ‘back to the future’ for me,” commented press conference panelist Mark Reisman, MD, director of the Center for Emerging Cardiovascular Therapies and head of UW Cardiology, Seattle. The PREPARE-CALC results are not surprising, but low uptake of rotablation in Europe, at just 1%-2%, is surprising and unexplained.
Importantly, the trial allows a sound comparison of rotational atherectomy with the best available alternatives, he said. “This may significantly impact the behavior and maybe some of the reimbursement in Europe. ... I’m sure that drives a lot of the decisions: cost as well as technique.”
Many of the original rotational atherectomy studies used larger burrs and multiple burrs, whereas the trial investigators applied less aggressive, more refined parameters. It will be interesting to look at their technique as it may have contributed to the favorable findings, according to Dr. Reisman.
“Based on what we just heard, there are very complex lesions that were maybe not being approached historically, which now people will feel a lot more confident in approaching, looking at the durable outcome with the Rotablator [Boston Scientific],” he summarized.
“From the practice of a clinician, it’s very frustrating to hit a calcified lesion and attempt to work on it up front and find you can’t cross it,” commented press conference panelist Morton J. Kern, MD, professor of medicine at the school of medicine and chief of medicine, VA Long Beach Health Care System, University of California, Irvine Medical Center. The high rate of crossover to rotablation in PREPARE-CALC speaks to this problem. Having to resort to this tool after failure of other lesional interventions often translates to a rockier overall procedure and clinical course.
“Lesion preparation is underestimated. I know from my own experience that [in] those calcified long lesions where I didn’t use the Rotablator, I regretted it in a fair number of cases,” Dr. Kern said. “So my view is that we probably don’t use it enough. This trial suggests that you can get away [without it], but I think ultimately, we are going to need this tool, even though it’s not used in a huge number of patients.”
Trial details
Patients enrolled in PREPARE-CALC had severely calcified coronary lesions according to angiographic criteria. For lesion preparation, half underwent high-speed rotational atherectomy (Rotablator), and half underwent treatment with either a cutting balloon (Flextome, Boston Scientific) or a scoring balloon (AngioSculpt, AngioScore, or Scoreflex, OrbusNeich Medical). Thereafter, all received sirolimus-eluting stents (Orsiro, Biotronik).
Results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that, compared with the modified balloons, rotational atherectomy yielded a higher rate of strategy success, defined as successful stent delivery and expansion with less than 20% in-stent residual stenosis and TIMI 3 flow, without crossover to the other arm or stent failure. The rotational atherectomy patients had a success rate of 98%, compared with 81% for the balloon patients (P = .0001).
“This difference was mainly driven by a high rate of crossovers from balloon to rotablation,” Dr. Richardt, noted, with 16% of patients assigned to the former modality ultimately receiving the latter. “These crossovers were due to noncrossable or nondilated lesions.”
Analyses suggested three subgroups did not benefit from rotational atherectomy when it came to strategy success: women, patients in whom the left anterior descending artery was the target, and patients not having type C lesions.
Quantitative coronary analysis showed that the acute lumen gain, whether in-stent or in-segment, did not differ significantly between the two preparation methods. “This is different from what we know from historical studies where the Rotablator was always achieving more acute gain than standard balloons,” Dr. Richardt commented.
Rotational atherectomy and modified balloons were similar with respect to the magnitude of in-stent late lumen loss (0.22 vs. 0.16 mm, P = .021 for superiority; P = .01 for noninferiority) and the rate of target-vessel failure (6% vs. 8%) at 9 months. Those failure rates were lower than the 10% expected from previous trials, he pointed out. “This might increase over time, but it’s not so far away from what we see in contemporary drug-eluting stent trials.”
Fluoroscopy time was about 4 minutes longer with rotational atherectomy than with modified balloons. “You may say that’s a lot. I would say in these 75-year-old patients, it is acceptable,” Dr. Richardt commented. “But to be honest, we had some cases where we had to place a pacemaker, and this increases the duration of the fluoroscopy time.”
The PREPARE-CALC findings should improve the rate of rotational atherectomy use in Europe, he said. “If you believe my data, then the rate should go up to 10% or 12%.”
Dr. Richardt disclosed that he receives speaker’s honoraria from Boston Scientific and Biotronik. The trial was sponsored by the Herz-Kreislauf-Zentrum Segeberger Kliniken GmbH.
REPORTING FROM TCT 2018
Key clinical point:
Major finding: Rotational atherectomy preparation and cutting/scoring balloon preparation did not differ significantly with respect to 9-month in-stent late lumen loss (0.22 vs. 0.16 mm) and target vessel failure (6% vs. 8%).
Study details: PREPARE-CALC, an open-label, randomized, controlled trial in 200 patients with severely calcified coronary lesions undergoing implantation of drug-eluting stents.
Disclosures: Dr. Richardt disclosed that he receives speaker’s honoraria from Boston Scientific and Biotronik. The trial was sponsored by the Herz-Kreislauf-Zentrum Segeberger Kliniken GmbH.
Eluvia drug-eluting vascular stent approved on heels of TCT presentation
Boston Scientific announced the was presented at the Transcatheter Cardiovascular Therapeutics annual meeting in San Diego.
The Eluvia Drug-Eluting Vascular Stent System is designed to restore blood flow in the peripheral arteries above the knee – specifically, the superficial femoral artery and proximal popliteal artery, according to the company.
Lead investigator William A. Gray, MD, a cardiologist at the Lankenau Heart Institute, Wynnewood, Pa., presented the results of IMPERIAL at TCT 2018. The randomized, head-to-head trial compared the performance of Eluvia with the paclitaxel-eluting Zilver PTX, which at the time was the only drug-releasing stent approved in the United States for the indication. Patients had occlusive lesions of the superficial femoral and/or proximal popliteal arteries.
At 12 months, primary patency was 86.8% in the Eluvia group versus 81.5% among those randomized to Zilver PTX, meeting the threshold for noninferiority.
For the endpoint of target lesion revascularization, Eluvia was superior to Zilver PTX, with 4.5% and 9% of patients, respectively, requiring it (Lancet. 2018 Sep 22. doi: 10.1016/S0140-6736[18]32262-1).
According to Boston Scientific’s announcement of the approval, the drug-polymer combination used in the Eluvia stent offers sustained release of paclitaxel over 1 year to prevent tissue regrowth.
Eluvia was approved in Europe in early 2016.
Boston Scientific announced the was presented at the Transcatheter Cardiovascular Therapeutics annual meeting in San Diego.
The Eluvia Drug-Eluting Vascular Stent System is designed to restore blood flow in the peripheral arteries above the knee – specifically, the superficial femoral artery and proximal popliteal artery, according to the company.
Lead investigator William A. Gray, MD, a cardiologist at the Lankenau Heart Institute, Wynnewood, Pa., presented the results of IMPERIAL at TCT 2018. The randomized, head-to-head trial compared the performance of Eluvia with the paclitaxel-eluting Zilver PTX, which at the time was the only drug-releasing stent approved in the United States for the indication. Patients had occlusive lesions of the superficial femoral and/or proximal popliteal arteries.
At 12 months, primary patency was 86.8% in the Eluvia group versus 81.5% among those randomized to Zilver PTX, meeting the threshold for noninferiority.
For the endpoint of target lesion revascularization, Eluvia was superior to Zilver PTX, with 4.5% and 9% of patients, respectively, requiring it (Lancet. 2018 Sep 22. doi: 10.1016/S0140-6736[18]32262-1).
According to Boston Scientific’s announcement of the approval, the drug-polymer combination used in the Eluvia stent offers sustained release of paclitaxel over 1 year to prevent tissue regrowth.
Eluvia was approved in Europe in early 2016.
Boston Scientific announced the was presented at the Transcatheter Cardiovascular Therapeutics annual meeting in San Diego.
The Eluvia Drug-Eluting Vascular Stent System is designed to restore blood flow in the peripheral arteries above the knee – specifically, the superficial femoral artery and proximal popliteal artery, according to the company.
Lead investigator William A. Gray, MD, a cardiologist at the Lankenau Heart Institute, Wynnewood, Pa., presented the results of IMPERIAL at TCT 2018. The randomized, head-to-head trial compared the performance of Eluvia with the paclitaxel-eluting Zilver PTX, which at the time was the only drug-releasing stent approved in the United States for the indication. Patients had occlusive lesions of the superficial femoral and/or proximal popliteal arteries.
At 12 months, primary patency was 86.8% in the Eluvia group versus 81.5% among those randomized to Zilver PTX, meeting the threshold for noninferiority.
For the endpoint of target lesion revascularization, Eluvia was superior to Zilver PTX, with 4.5% and 9% of patients, respectively, requiring it (Lancet. 2018 Sep 22. doi: 10.1016/S0140-6736[18]32262-1).
According to Boston Scientific’s announcement of the approval, the drug-polymer combination used in the Eluvia stent offers sustained release of paclitaxel over 1 year to prevent tissue regrowth.
Eluvia was approved in Europe in early 2016.
Pediatric data on novel axillary hyperhidrosis treatment reported
PARIS – Two compelling reasons exist to take excessive sweating in children and adolescents more seriously, Lawrence J. Green, MD, asserted at the annual congress of the European Academy of Dermatology and Venereology.
One is that this is a surprisingly common and embarrassing medical condition that can have a profound adverse developmental impact in young people at a time when they are engaged in forming their self-image.
The other reason to get serious about addressing primary axillary hyperhidrosis in pediatric patients is the recent approval of glycopyrronium tosylate as a topical therapy, Dr. Green, a dermatologist at George Washington University, Washington. The treatment, glycopyrronium pads (Qbrexza), was approved by the Food and Drug Administration for the topical treatment of primary axillary hyperhidrosis in patients aged 9 years and older in June 2018, and will be available in October 2018.
He presented new data from a 44-week, open-label extension of two pivotal 4-week, phase 3, randomized, double-blind, placebo-controlled trials known as ATMOS-1 and ATMOS-2. The new post hoc analysis from the extension study, known as the ARIDO study, provides reassurance that the product remains both safe and durably effective with longterm use.
Dr. Green’s analysis focused on the 44 pediatric participants aged 9-16 years. That’s because even though primary axillary hyperhidrosis affects people of all ages, with an estimated 4.8% prevalence in the U.S. population – 5.3 million people – it is more common in children and adolescents than adults. And it hits them particularly hard.
“Hyperhidrosis is largely underdiagnosed and undertreated, particularly among pediatric patients,” he said. “The impact on quality of life is comparable to or greater than acne, psoriasis, or eczema.”
The glycopyrronium pad is self-applied as a once-daily wipe. Glycopyrronium is an anticholinergic agent, which blocks sweat production by inhibiting the receptors that activate sweat glands.
Dr. Green noted several key findings from the 44-week ARIDO analysis, presented for the first time at the EADV congress.
The median absolute decrease in sweat production in pediatric patients at 44 weeks as measured gravimetrically was 50.3 mg per 5 minutes from a baseline of 150 mg per 5 minutes, comparable with the mean 75 mg reduction from a baseline of 175 mg in the 507-patient older cohort. However, Dr. Green advised not to make too much of this endpoint, as sweat production is notoriously difficult to measure accurately. In addition, an individual’s sweat rate can vary widely depending upon a multitude of factors, including ambient temperature and even what a patient is thinking about. The FDA recognizes this and therefore elevated several validated patient-reported outcomes to the status of coprimary endpoints in the clinical trials.
A positive result on one such patient-reported outcome, the Hyperhidrosis Severity Scale, was achieved in 57% of pediatric patients and 64% of adults at week 44 of open-label therapy. This required at least a 2-grade improvement from baseline, when roughly 60% of youths had a score of 3 and the remainder scored 4 on the 1-4 point scale.
From a mean baseline score of 9.2 on the Children’s Dermatology Life Quality Index, the pediatric group averaged a mean 6.2-point improvement at week 44, while adults experienced a mean 8.7-point improvement on the Dermatology Life Quality Index from a baseline of 11.25.
There was no diminution in treatment efficacy through 44 weeks, Dr. Green noted. Treatment-emergent adverse events consisted largely of transient mild to moderate anticholinergic effects, which seldom led to study discontinuation.
Dilated pupils and blurred vision were more common in children than adults (7.9% and 10.5% vs. 5.1% and 6.4%, respectively). “Why that is I can only speculate. Kids do tend to touch their eyes more often than adults. Pretty much everything else was the same. The adverse events can be worked around by educating people to use the pads appropriately. We saw the anticholinergic side effects more often in the first 4 weeks of the double-blind trials than in the longterm extension because once patients learned how to use the pad and not touch themselves afterwards, the adverse events came down,” he said.
The studies were sponsored by Dermira. Dr. Green has received research funding from and been a consultant to the company.
PARIS – Two compelling reasons exist to take excessive sweating in children and adolescents more seriously, Lawrence J. Green, MD, asserted at the annual congress of the European Academy of Dermatology and Venereology.
One is that this is a surprisingly common and embarrassing medical condition that can have a profound adverse developmental impact in young people at a time when they are engaged in forming their self-image.
The other reason to get serious about addressing primary axillary hyperhidrosis in pediatric patients is the recent approval of glycopyrronium tosylate as a topical therapy, Dr. Green, a dermatologist at George Washington University, Washington. The treatment, glycopyrronium pads (Qbrexza), was approved by the Food and Drug Administration for the topical treatment of primary axillary hyperhidrosis in patients aged 9 years and older in June 2018, and will be available in October 2018.
He presented new data from a 44-week, open-label extension of two pivotal 4-week, phase 3, randomized, double-blind, placebo-controlled trials known as ATMOS-1 and ATMOS-2. The new post hoc analysis from the extension study, known as the ARIDO study, provides reassurance that the product remains both safe and durably effective with longterm use.
Dr. Green’s analysis focused on the 44 pediatric participants aged 9-16 years. That’s because even though primary axillary hyperhidrosis affects people of all ages, with an estimated 4.8% prevalence in the U.S. population – 5.3 million people – it is more common in children and adolescents than adults. And it hits them particularly hard.
“Hyperhidrosis is largely underdiagnosed and undertreated, particularly among pediatric patients,” he said. “The impact on quality of life is comparable to or greater than acne, psoriasis, or eczema.”
The glycopyrronium pad is self-applied as a once-daily wipe. Glycopyrronium is an anticholinergic agent, which blocks sweat production by inhibiting the receptors that activate sweat glands.
Dr. Green noted several key findings from the 44-week ARIDO analysis, presented for the first time at the EADV congress.
The median absolute decrease in sweat production in pediatric patients at 44 weeks as measured gravimetrically was 50.3 mg per 5 minutes from a baseline of 150 mg per 5 minutes, comparable with the mean 75 mg reduction from a baseline of 175 mg in the 507-patient older cohort. However, Dr. Green advised not to make too much of this endpoint, as sweat production is notoriously difficult to measure accurately. In addition, an individual’s sweat rate can vary widely depending upon a multitude of factors, including ambient temperature and even what a patient is thinking about. The FDA recognizes this and therefore elevated several validated patient-reported outcomes to the status of coprimary endpoints in the clinical trials.
A positive result on one such patient-reported outcome, the Hyperhidrosis Severity Scale, was achieved in 57% of pediatric patients and 64% of adults at week 44 of open-label therapy. This required at least a 2-grade improvement from baseline, when roughly 60% of youths had a score of 3 and the remainder scored 4 on the 1-4 point scale.
From a mean baseline score of 9.2 on the Children’s Dermatology Life Quality Index, the pediatric group averaged a mean 6.2-point improvement at week 44, while adults experienced a mean 8.7-point improvement on the Dermatology Life Quality Index from a baseline of 11.25.
There was no diminution in treatment efficacy through 44 weeks, Dr. Green noted. Treatment-emergent adverse events consisted largely of transient mild to moderate anticholinergic effects, which seldom led to study discontinuation.
Dilated pupils and blurred vision were more common in children than adults (7.9% and 10.5% vs. 5.1% and 6.4%, respectively). “Why that is I can only speculate. Kids do tend to touch their eyes more often than adults. Pretty much everything else was the same. The adverse events can be worked around by educating people to use the pads appropriately. We saw the anticholinergic side effects more often in the first 4 weeks of the double-blind trials than in the longterm extension because once patients learned how to use the pad and not touch themselves afterwards, the adverse events came down,” he said.
The studies were sponsored by Dermira. Dr. Green has received research funding from and been a consultant to the company.
PARIS – Two compelling reasons exist to take excessive sweating in children and adolescents more seriously, Lawrence J. Green, MD, asserted at the annual congress of the European Academy of Dermatology and Venereology.
One is that this is a surprisingly common and embarrassing medical condition that can have a profound adverse developmental impact in young people at a time when they are engaged in forming their self-image.
The other reason to get serious about addressing primary axillary hyperhidrosis in pediatric patients is the recent approval of glycopyrronium tosylate as a topical therapy, Dr. Green, a dermatologist at George Washington University, Washington. The treatment, glycopyrronium pads (Qbrexza), was approved by the Food and Drug Administration for the topical treatment of primary axillary hyperhidrosis in patients aged 9 years and older in June 2018, and will be available in October 2018.
He presented new data from a 44-week, open-label extension of two pivotal 4-week, phase 3, randomized, double-blind, placebo-controlled trials known as ATMOS-1 and ATMOS-2. The new post hoc analysis from the extension study, known as the ARIDO study, provides reassurance that the product remains both safe and durably effective with longterm use.
Dr. Green’s analysis focused on the 44 pediatric participants aged 9-16 years. That’s because even though primary axillary hyperhidrosis affects people of all ages, with an estimated 4.8% prevalence in the U.S. population – 5.3 million people – it is more common in children and adolescents than adults. And it hits them particularly hard.
“Hyperhidrosis is largely underdiagnosed and undertreated, particularly among pediatric patients,” he said. “The impact on quality of life is comparable to or greater than acne, psoriasis, or eczema.”
The glycopyrronium pad is self-applied as a once-daily wipe. Glycopyrronium is an anticholinergic agent, which blocks sweat production by inhibiting the receptors that activate sweat glands.
Dr. Green noted several key findings from the 44-week ARIDO analysis, presented for the first time at the EADV congress.
The median absolute decrease in sweat production in pediatric patients at 44 weeks as measured gravimetrically was 50.3 mg per 5 minutes from a baseline of 150 mg per 5 minutes, comparable with the mean 75 mg reduction from a baseline of 175 mg in the 507-patient older cohort. However, Dr. Green advised not to make too much of this endpoint, as sweat production is notoriously difficult to measure accurately. In addition, an individual’s sweat rate can vary widely depending upon a multitude of factors, including ambient temperature and even what a patient is thinking about. The FDA recognizes this and therefore elevated several validated patient-reported outcomes to the status of coprimary endpoints in the clinical trials.
A positive result on one such patient-reported outcome, the Hyperhidrosis Severity Scale, was achieved in 57% of pediatric patients and 64% of adults at week 44 of open-label therapy. This required at least a 2-grade improvement from baseline, when roughly 60% of youths had a score of 3 and the remainder scored 4 on the 1-4 point scale.
From a mean baseline score of 9.2 on the Children’s Dermatology Life Quality Index, the pediatric group averaged a mean 6.2-point improvement at week 44, while adults experienced a mean 8.7-point improvement on the Dermatology Life Quality Index from a baseline of 11.25.
There was no diminution in treatment efficacy through 44 weeks, Dr. Green noted. Treatment-emergent adverse events consisted largely of transient mild to moderate anticholinergic effects, which seldom led to study discontinuation.
Dilated pupils and blurred vision were more common in children than adults (7.9% and 10.5% vs. 5.1% and 6.4%, respectively). “Why that is I can only speculate. Kids do tend to touch their eyes more often than adults. Pretty much everything else was the same. The adverse events can be worked around by educating people to use the pads appropriately. We saw the anticholinergic side effects more often in the first 4 weeks of the double-blind trials than in the longterm extension because once patients learned how to use the pad and not touch themselves afterwards, the adverse events came down,” he said.
The studies were sponsored by Dermira. Dr. Green has received research funding from and been a consultant to the company.
REPORTING FROM THE EADV CONGRESS
Key clinical point: Glycopyrronium tosylate pads address a common and undertreated medical condition in children: primary axillary hyperhidrosis.
Major finding: Mean scores on the Children’s Dermatology Life Quality Index improved by an average of 6.2 points from a baseline of 9.2 in children aged 9-16 years with primary axillary hyperhidrosis treated with once-daily glycopyrronium tosylate pads during an open-label, 44-week study.
Study details: This was a post hoc analysis of 44 patients aged 9-16 years and 507 patients aged 17 years and older who participated in a 44-week, open-label extension study of once-daily glycopyrronium tosylate pads for treatment of primary axillary hyperhidrosis.
Disclosures: The study was sponsored by Dermira. The presenter has received research funding from and been a consultant to the company.
Congenital syphilis rates continue skyrocketing alongside other STDs
Rapidly increasing cases of newborn syphilis have reached their highest prevalence in 2 decades, according to a new report by the Centers for Disease Control and Prevention on sexually transmitted disease surveillance in 2017.
Newborn syphilis incidence has more than doubled, from 362 cases in 2013 to 918 cases in 2017, resulting in 64 syphilitic stillbirths and 13 infant deaths that year, according to data published in Sexually Transmitted Disease Surveillance 2017.
At least one case was reported in 37 states last year, and the greatest burden of cases occurred in California, Arizona, Texas, Louisiana, and Florida, together accounting for 70% of all 2017 cases.
“The resurgence of syphilis, and particularly congenital syphilis, is not an arbitrary event, but rather a symptom of a deteriorating public health infrastructure and lack of access to health care,” wrote Gail Bolan, MD, director of the Division of STD Prevention at the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. “It is exposing hidden, fragile populations in need that are not getting the health care and preventive services they deserve.”
Dr. Bolan recommends modernizing surveillance to capture more of the cases in populations without ready access to diagnosis and treatment and in those choosing not to access care.
“It is imperative that federal, state, and local programs employ strategies that maximize long-term population impact by reducing STD incidence and promoting sexual, reproductive, maternal, and infant health,” she wrote. “Further, it will be important for us to measure and monitor the adverse health consequences of STDs, such as ocular and neurosyphilis, pelvic inflammatory disease, ectopic pregnancy, infertility, HIV, congenital syphilis, and neonatal herpes.”
Multiple sources contributed data to the report: state and local STD programs’ notifiable disease reporting, private and federal national surveys, and specific projects that collect STD prevalence data, including the National Job Training Program, the STD Surveillance Network and the Gonococcal Isolate Surveillance Project.
The four nationally notifiable STDs are chlamydia, gonorrhea, syphilis, and chancroid.
The rise in newborn syphilis cases, currently at 23.3 cases per 100,000 live births, mirrors the increased U.S. prevalence of both primary and secondary syphilis in 2017, with 9.5 cases per 100,000 people. Syphilis has increased every year since 2000-2001, when prevalence was at a record low.
Chlamydia and gonorrhea rates climb too
The report also noted increases in the prevalence of other STDs. Chlamydia, the most common STD, increased 6.9% as compared to 2016, with 528.8 cases per 100,000 people. This increase occurred in all U.S. regions and independently of sex, race, or ethnicity, though rates were highest in teens and young adults. Nearly two-thirds of chlamydia cases in 2017 occurred in people ages 15-24 years old.
Reported rates were higher in women than in men, likely due to women’s increased likelihood of undergoing screening, the report suggested. Better surveillance may also partly explain the climb in men’s cases.
“Increases in rates among men may reflect an increased number of men, including gay, bisexual and other men who have sex with men (collectively referred to as MSM) being tested and diagnosed with a chlamydial infection due to increased availability of urine testing and extragenital screening,” according to the report.
The CDC received reports of more than a half million gonorrhea infections in 2017 (555,608 cases), an increase of 18.6% since the previous year, including a 19.3% increase among men and a 17.8% increase among women.
“The magnitude of the increase among men suggests either increased transmission, increased case ascertainment (e.g., through increased extra-genital screening among MSM), or both,” the authors wrote. “The concurrent increase in cases reported among women suggests parallel increases in heterosexual transmission, increased screening among women, or both.”
Overall, gonorrhea cases have skyrocketed 75.2% since their historic low in 2009, compounding the problem of antibiotic resistance that has limited CDC-recommended treatment to just ceftriaxone and azithromycin.
The report was supported by the Centers for Disease Control and Prevention. The authors did not report having any disclosures.
SOURCE: Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2017; https://www.cdc.gov/std/stats
Rapidly increasing cases of newborn syphilis have reached their highest prevalence in 2 decades, according to a new report by the Centers for Disease Control and Prevention on sexually transmitted disease surveillance in 2017.
Newborn syphilis incidence has more than doubled, from 362 cases in 2013 to 918 cases in 2017, resulting in 64 syphilitic stillbirths and 13 infant deaths that year, according to data published in Sexually Transmitted Disease Surveillance 2017.
At least one case was reported in 37 states last year, and the greatest burden of cases occurred in California, Arizona, Texas, Louisiana, and Florida, together accounting for 70% of all 2017 cases.
“The resurgence of syphilis, and particularly congenital syphilis, is not an arbitrary event, but rather a symptom of a deteriorating public health infrastructure and lack of access to health care,” wrote Gail Bolan, MD, director of the Division of STD Prevention at the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. “It is exposing hidden, fragile populations in need that are not getting the health care and preventive services they deserve.”
Dr. Bolan recommends modernizing surveillance to capture more of the cases in populations without ready access to diagnosis and treatment and in those choosing not to access care.
“It is imperative that federal, state, and local programs employ strategies that maximize long-term population impact by reducing STD incidence and promoting sexual, reproductive, maternal, and infant health,” she wrote. “Further, it will be important for us to measure and monitor the adverse health consequences of STDs, such as ocular and neurosyphilis, pelvic inflammatory disease, ectopic pregnancy, infertility, HIV, congenital syphilis, and neonatal herpes.”
Multiple sources contributed data to the report: state and local STD programs’ notifiable disease reporting, private and federal national surveys, and specific projects that collect STD prevalence data, including the National Job Training Program, the STD Surveillance Network and the Gonococcal Isolate Surveillance Project.
The four nationally notifiable STDs are chlamydia, gonorrhea, syphilis, and chancroid.
The rise in newborn syphilis cases, currently at 23.3 cases per 100,000 live births, mirrors the increased U.S. prevalence of both primary and secondary syphilis in 2017, with 9.5 cases per 100,000 people. Syphilis has increased every year since 2000-2001, when prevalence was at a record low.
Chlamydia and gonorrhea rates climb too
The report also noted increases in the prevalence of other STDs. Chlamydia, the most common STD, increased 6.9% as compared to 2016, with 528.8 cases per 100,000 people. This increase occurred in all U.S. regions and independently of sex, race, or ethnicity, though rates were highest in teens and young adults. Nearly two-thirds of chlamydia cases in 2017 occurred in people ages 15-24 years old.
Reported rates were higher in women than in men, likely due to women’s increased likelihood of undergoing screening, the report suggested. Better surveillance may also partly explain the climb in men’s cases.
“Increases in rates among men may reflect an increased number of men, including gay, bisexual and other men who have sex with men (collectively referred to as MSM) being tested and diagnosed with a chlamydial infection due to increased availability of urine testing and extragenital screening,” according to the report.
The CDC received reports of more than a half million gonorrhea infections in 2017 (555,608 cases), an increase of 18.6% since the previous year, including a 19.3% increase among men and a 17.8% increase among women.
“The magnitude of the increase among men suggests either increased transmission, increased case ascertainment (e.g., through increased extra-genital screening among MSM), or both,” the authors wrote. “The concurrent increase in cases reported among women suggests parallel increases in heterosexual transmission, increased screening among women, or both.”
Overall, gonorrhea cases have skyrocketed 75.2% since their historic low in 2009, compounding the problem of antibiotic resistance that has limited CDC-recommended treatment to just ceftriaxone and azithromycin.
The report was supported by the Centers for Disease Control and Prevention. The authors did not report having any disclosures.
SOURCE: Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2017; https://www.cdc.gov/std/stats
Rapidly increasing cases of newborn syphilis have reached their highest prevalence in 2 decades, according to a new report by the Centers for Disease Control and Prevention on sexually transmitted disease surveillance in 2017.
Newborn syphilis incidence has more than doubled, from 362 cases in 2013 to 918 cases in 2017, resulting in 64 syphilitic stillbirths and 13 infant deaths that year, according to data published in Sexually Transmitted Disease Surveillance 2017.
At least one case was reported in 37 states last year, and the greatest burden of cases occurred in California, Arizona, Texas, Louisiana, and Florida, together accounting for 70% of all 2017 cases.
“The resurgence of syphilis, and particularly congenital syphilis, is not an arbitrary event, but rather a symptom of a deteriorating public health infrastructure and lack of access to health care,” wrote Gail Bolan, MD, director of the Division of STD Prevention at the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. “It is exposing hidden, fragile populations in need that are not getting the health care and preventive services they deserve.”
Dr. Bolan recommends modernizing surveillance to capture more of the cases in populations without ready access to diagnosis and treatment and in those choosing not to access care.
“It is imperative that federal, state, and local programs employ strategies that maximize long-term population impact by reducing STD incidence and promoting sexual, reproductive, maternal, and infant health,” she wrote. “Further, it will be important for us to measure and monitor the adverse health consequences of STDs, such as ocular and neurosyphilis, pelvic inflammatory disease, ectopic pregnancy, infertility, HIV, congenital syphilis, and neonatal herpes.”
Multiple sources contributed data to the report: state and local STD programs’ notifiable disease reporting, private and federal national surveys, and specific projects that collect STD prevalence data, including the National Job Training Program, the STD Surveillance Network and the Gonococcal Isolate Surveillance Project.
The four nationally notifiable STDs are chlamydia, gonorrhea, syphilis, and chancroid.
The rise in newborn syphilis cases, currently at 23.3 cases per 100,000 live births, mirrors the increased U.S. prevalence of both primary and secondary syphilis in 2017, with 9.5 cases per 100,000 people. Syphilis has increased every year since 2000-2001, when prevalence was at a record low.
Chlamydia and gonorrhea rates climb too
The report also noted increases in the prevalence of other STDs. Chlamydia, the most common STD, increased 6.9% as compared to 2016, with 528.8 cases per 100,000 people. This increase occurred in all U.S. regions and independently of sex, race, or ethnicity, though rates were highest in teens and young adults. Nearly two-thirds of chlamydia cases in 2017 occurred in people ages 15-24 years old.
Reported rates were higher in women than in men, likely due to women’s increased likelihood of undergoing screening, the report suggested. Better surveillance may also partly explain the climb in men’s cases.
“Increases in rates among men may reflect an increased number of men, including gay, bisexual and other men who have sex with men (collectively referred to as MSM) being tested and diagnosed with a chlamydial infection due to increased availability of urine testing and extragenital screening,” according to the report.
The CDC received reports of more than a half million gonorrhea infections in 2017 (555,608 cases), an increase of 18.6% since the previous year, including a 19.3% increase among men and a 17.8% increase among women.
“The magnitude of the increase among men suggests either increased transmission, increased case ascertainment (e.g., through increased extra-genital screening among MSM), or both,” the authors wrote. “The concurrent increase in cases reported among women suggests parallel increases in heterosexual transmission, increased screening among women, or both.”
Overall, gonorrhea cases have skyrocketed 75.2% since their historic low in 2009, compounding the problem of antibiotic resistance that has limited CDC-recommended treatment to just ceftriaxone and azithromycin.
The report was supported by the Centers for Disease Control and Prevention. The authors did not report having any disclosures.
SOURCE: Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2017; https://www.cdc.gov/std/stats
Key clinical point: Newborn syphilis cases have more than doubled in 5 years along with substantial increases in chlamydia, gonorrhea, and syphilis.
Major finding: 918 cases of newborn syphilis were reported in 37 states in 2017.
Study details: The findings are based on data from public health notifiable disease reports and multiple federal and private surveillance projects.
Disclosures: The report was supported by the Centers for Disease Control and Prevention. The authors did not report having any disclosures.
Source: Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2017.