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Whole-genome sequencing demonstrates clinical relevance
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
REPORTING FROM BSH 2019
Cost-Effective Treatment Option for von Willebrand Disease
Click here to read the supplement.
What can be done to provide a cost-effective treatment option for von Willebrand Disease?
Topics include:
- Review of Key Clinical Studies and Surgical Procedures
- Pharmacokinetics Comparison
- Pharmacoeconomic Comparisons
Click here to read the supplement.
Click here to read the supplement.
What can be done to provide a cost-effective treatment option for von Willebrand Disease?
Topics include:
- Review of Key Clinical Studies and Surgical Procedures
- Pharmacokinetics Comparison
- Pharmacoeconomic Comparisons
Click here to read the supplement.
Click here to read the supplement.
What can be done to provide a cost-effective treatment option for von Willebrand Disease?
Topics include:
- Review of Key Clinical Studies and Surgical Procedures
- Pharmacokinetics Comparison
- Pharmacoeconomic Comparisons
Click here to read the supplement.
FDA panel leans toward more robust breast implant surveillance
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
FDA halts enrollment in trial of venetoclax for multiple myeloma
The Food and Drug Administration has halted enrollment in trials of venetoclax (Venclexta) for multiple myeloma.
The move comes after a review of data from the phase 3 BELLINI trial, which pitted venetoclax against placebo in relapsed and refractory multiple myeloma patients on a background of bortezomib and low-dose dexamethasone. Venetoclax is not approved for the treatment of multiple myeloma; the agency said that patients using the drug for approved indications should continue use of the drug.
There were 41/194 deaths (21.1%) in the venetoclax arm, versus 11/97 (11.3%) in the placebo group; 13 of the deaths in the venetoclax arm (32%) and 1 death in the placebo arm (9%) were treatment related. Sepsis, pneumonia, and cardiac arrest were the most common treatment-related causes of death in the venetoclax group; 8 of the 13 deaths (62%) were due to infection.
The FDA estimated that the drug doubled the risk of death compared to placebo.
The agency warned against off-label use of venetoclax for multiple myeloma, and noted that the drug “is safe and effective for its approved uses,” which include second-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma in adults, as well as newly-diagnosed acute myeloid leukemia in adults age 75 years or older or who have contraindications to standard chemotherapy.
There are more than 10 trials in the United States of venetoclax for multiple myeloma, and most of them have been suspended, including BELLINI.
Patients already enrolled in the trial can remain on treatment, but they must re-consent to the trial. The FDA “will be working directly with sponsors of Venclexta, as well as other investigators conducting clinical trials in patients with multiple myeloma, to determine the extent of the safety issue,” the agency said in a statement.
Abbvie, which is developing venetoclax in partnership with Roche, noted in its own press release that the drug otherwise outperformed placebo in BELLINI, both in progression-free survival (22.4 months versus 11.5 months), and in overall (82% versus 68%) and partial (59% versus 36%) response rates.
Severe grade 3-5 toxicity and serious adverse event rates were similar in the two study arms, as was the overall incidence of infections (79.8% versus 77.1%). However, the incidence of pneumonia was 20.7% with venetoclax, versus 15.6% with placebo.
“We will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Michael Severino, MD, AbbVie vice chairman and president, said in the press release.
Venetoclax binds and inhibits the B-cell lymphoma-2 protein, which prevents some blood cancer cells from undergoing programmed cell death.
The Food and Drug Administration has halted enrollment in trials of venetoclax (Venclexta) for multiple myeloma.
The move comes after a review of data from the phase 3 BELLINI trial, which pitted venetoclax against placebo in relapsed and refractory multiple myeloma patients on a background of bortezomib and low-dose dexamethasone. Venetoclax is not approved for the treatment of multiple myeloma; the agency said that patients using the drug for approved indications should continue use of the drug.
There were 41/194 deaths (21.1%) in the venetoclax arm, versus 11/97 (11.3%) in the placebo group; 13 of the deaths in the venetoclax arm (32%) and 1 death in the placebo arm (9%) were treatment related. Sepsis, pneumonia, and cardiac arrest were the most common treatment-related causes of death in the venetoclax group; 8 of the 13 deaths (62%) were due to infection.
The FDA estimated that the drug doubled the risk of death compared to placebo.
The agency warned against off-label use of venetoclax for multiple myeloma, and noted that the drug “is safe and effective for its approved uses,” which include second-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma in adults, as well as newly-diagnosed acute myeloid leukemia in adults age 75 years or older or who have contraindications to standard chemotherapy.
There are more than 10 trials in the United States of venetoclax for multiple myeloma, and most of them have been suspended, including BELLINI.
Patients already enrolled in the trial can remain on treatment, but they must re-consent to the trial. The FDA “will be working directly with sponsors of Venclexta, as well as other investigators conducting clinical trials in patients with multiple myeloma, to determine the extent of the safety issue,” the agency said in a statement.
Abbvie, which is developing venetoclax in partnership with Roche, noted in its own press release that the drug otherwise outperformed placebo in BELLINI, both in progression-free survival (22.4 months versus 11.5 months), and in overall (82% versus 68%) and partial (59% versus 36%) response rates.
Severe grade 3-5 toxicity and serious adverse event rates were similar in the two study arms, as was the overall incidence of infections (79.8% versus 77.1%). However, the incidence of pneumonia was 20.7% with venetoclax, versus 15.6% with placebo.
“We will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Michael Severino, MD, AbbVie vice chairman and president, said in the press release.
Venetoclax binds and inhibits the B-cell lymphoma-2 protein, which prevents some blood cancer cells from undergoing programmed cell death.
The Food and Drug Administration has halted enrollment in trials of venetoclax (Venclexta) for multiple myeloma.
The move comes after a review of data from the phase 3 BELLINI trial, which pitted venetoclax against placebo in relapsed and refractory multiple myeloma patients on a background of bortezomib and low-dose dexamethasone. Venetoclax is not approved for the treatment of multiple myeloma; the agency said that patients using the drug for approved indications should continue use of the drug.
There were 41/194 deaths (21.1%) in the venetoclax arm, versus 11/97 (11.3%) in the placebo group; 13 of the deaths in the venetoclax arm (32%) and 1 death in the placebo arm (9%) were treatment related. Sepsis, pneumonia, and cardiac arrest were the most common treatment-related causes of death in the venetoclax group; 8 of the 13 deaths (62%) were due to infection.
The FDA estimated that the drug doubled the risk of death compared to placebo.
The agency warned against off-label use of venetoclax for multiple myeloma, and noted that the drug “is safe and effective for its approved uses,” which include second-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma in adults, as well as newly-diagnosed acute myeloid leukemia in adults age 75 years or older or who have contraindications to standard chemotherapy.
There are more than 10 trials in the United States of venetoclax for multiple myeloma, and most of them have been suspended, including BELLINI.
Patients already enrolled in the trial can remain on treatment, but they must re-consent to the trial. The FDA “will be working directly with sponsors of Venclexta, as well as other investigators conducting clinical trials in patients with multiple myeloma, to determine the extent of the safety issue,” the agency said in a statement.
Abbvie, which is developing venetoclax in partnership with Roche, noted in its own press release that the drug otherwise outperformed placebo in BELLINI, both in progression-free survival (22.4 months versus 11.5 months), and in overall (82% versus 68%) and partial (59% versus 36%) response rates.
Severe grade 3-5 toxicity and serious adverse event rates were similar in the two study arms, as was the overall incidence of infections (79.8% versus 77.1%). However, the incidence of pneumonia was 20.7% with venetoclax, versus 15.6% with placebo.
“We will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Michael Severino, MD, AbbVie vice chairman and president, said in the press release.
Venetoclax binds and inhibits the B-cell lymphoma-2 protein, which prevents some blood cancer cells from undergoing programmed cell death.
AUGUSTUS: Dual surpasses triple therapy when AFib patients have PCI or ACS
NEW ORLEANS – For patients with atrial fibrillation and either a recent acute coronary syndrome or percutaneous coronary intervention, combined treatment for 6 months with the anticoagulant apixaban and a P2Y12 inhibitor antiplatelet drug, but without aspirin, was safer than and as effective as a regimen that either also included aspirin or that substituted a vitamin K antagonist, such as warfarin, for the direct-acting oral anticoagulant, based on results from a multicenter, randomized trial with more than 4,600 patients.
The apixaban plus P2Y12 inhibitor (typically, clopidogrel) combination “resulted in less bleeding and fewer hospitalizations without significant differences in ischemic events than regimens that included a vitamin K antagonist, aspirin, or both,” Renato D. Lopes, MD, said at the annual meeting of the American College of Cardiology. Concurrently, his report of the results also appeared in an online article.
This finding in the AUGUSTUS trial gives clinicians more guidance for the long-standing dilemma of how to best prevent arterial thrombus formation in patients with atrial fibrillation (AFib). To prevent a stroke, these patients routinely receive treatment with an anticoagulant when they have an acute coronary syndrome (ACS) event or undergo percutaneous coronary intervention (PCI). Typically, they receive several months of dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor to prevent a clot from forming in the stented or unstable region of a coronary artery.
These patients are not uncommon; this circumstance occurs for about 20% of all AFib patients, and poses the question of what is the safest and most effective way to treat them. Should they get triple therapy with an anticoagulant, aspirin, and a P2Y12 inhibitor, an option that could cause excess bleeding; or should one of the three drugs drop out with the potential for an increased rate of ischemic events? The AUGUSTUS findings suggest that one solution is treatment with a combination of the direct-acting oral anticoagulant apixaban (Eliquis) and the P2Y12 inhibitor clopidogrel (Plavix) but without aspirin.
For the majority of patients like the ones enrolled, “less is more.” By dropping aspirin from the treatment mix, patients did better, said Dr. Lopes, a professor of medicine at Duke University in Durham, N.C.
Dr. Lopes and his associates designed AUGUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis [Blood Clots] Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart) as a two-by-two factorial study to address two different questions: During 6 months of treatment, how did apixaban compare with a vitamin K antagonist (usually warfarin) in these patients for safety and efficacy, and how did aspirin compare with placebo in this setting for the same endpoints?
The trial enrolled 4,614 patients at 492 sites in 33 countries. All patients in the study received a P2Y12 inhibitor, with 93% treated with clopidogrel. The study had roughly as many patients as the combined total of patients enrolled in two smaller, prior studies that had looked at roughly the same questions in similar patients.
“The aspirin part is the more interesting, and probably more unique and important finding,” John H. Alexander, MD, a coinvestigator on the study, said in a video interview. Regardless of the anticoagulant used, patients who received aspirin had a 16% rate of major bleeds or clinically relevant non-major bleeds, compared with a 9% rate among those on placebo, a statistically significant result that underscored the bleeding risk posed by adding aspirin to an anticoagulant and a P2Y12 inhibitor.
The results also showed no statistically significant difference in any efficacy measure with or without aspirin, including the rate of death or hospitalization, or of any individual ischemic endpoint. However the results showed a signal of a small increase in the rates of each of three types of ischemic events – stent thrombosis, MI, and need for urgent revascularization, each of which showed a numerical increase when aspirin was dropped. But the increase was small.
Dr. Lopes calculated that, for example, to prevent one episode of stent thrombosis by treating with aspirin also would cause 15 major or clinically relevant non-major bleeds, which makes inclusion of aspirin something of a judgment call for each patient, said Dr. Alexander, a professor of medicine at Duke. An AFib patient with a high risk for thrombosis but a low risk for bleeding following PCI or an ACS event might be a reasonable patient to treat with aspirin along with apixaban and a P2Y12 inhibitor, he explained.
The rate of major or clinically relevant bleeds was 11% with apixaban and 15% with a vitamin K antagonist, a statistically significant difference. Patients treated with apixaban also had a significantly reduced rate of death or hospitalization, 24%, compared with 27% among those on the vitamin K antagonist, as well as a significantly lower rate of stroke.
Overall the lowest bleeding rate was in patients on apixaban but no aspirin, a 7% rate, while the highest rate was in patients on a vitamin K antagonist plus aspirin, a 19% rate.
Dr. Alexander said that it would be an overreach to extrapolate these findings to other direct-acting oral anticoagulants, compared with a vitamin K antagonist, but he believed that the findings the study generated about aspirin were probably relevant regardless of the anticoagulant used.
mzoler@mdedge.com
On Twitter @mitchelzoler
It’s very reassuring to see that you can use a direct-acting oral anticoagulant like apixaban along with a P2Y12 inhibitor, but with no aspirin, and have no statistically significant increase in ischemic events. This is a fantastic finding. The finding shows once again that warfarin is a problematic drug. As the cost for direct-acting oral anticoagulants has decreased, their use has increased.
These results were not unexpected and also are probably the final nail in the coffin for using a combination of warfarin and aspirin. Prior findings from the PIONEER AF-PCI study that used rivaroxaban (N Engl J Med. 2016 Dec 22;375[25]:2423-34) and from the RE-DUAL PCI study that used dabigatran (N Engl J Med. 2017 Oct 19;377[16]:1513-24) also showed the advantages of using a direct-acting oral anticoagulant when compared with a vitamin K antagonist in this setting, The AUGUSTUS trial, with just over 4,600 patients, had nearly as many patients as the roughly 4,850 enrolled in these two prior studies put together.
Dhanunjaya Lakkireddy, MD , is medical director of the Kansas City Heart Rhythm Institute in Overland Park. He had no disclosures. He made these comments as the designated discussant during a press briefing.
It’s very reassuring to see that you can use a direct-acting oral anticoagulant like apixaban along with a P2Y12 inhibitor, but with no aspirin, and have no statistically significant increase in ischemic events. This is a fantastic finding. The finding shows once again that warfarin is a problematic drug. As the cost for direct-acting oral anticoagulants has decreased, their use has increased.
These results were not unexpected and also are probably the final nail in the coffin for using a combination of warfarin and aspirin. Prior findings from the PIONEER AF-PCI study that used rivaroxaban (N Engl J Med. 2016 Dec 22;375[25]:2423-34) and from the RE-DUAL PCI study that used dabigatran (N Engl J Med. 2017 Oct 19;377[16]:1513-24) also showed the advantages of using a direct-acting oral anticoagulant when compared with a vitamin K antagonist in this setting, The AUGUSTUS trial, with just over 4,600 patients, had nearly as many patients as the roughly 4,850 enrolled in these two prior studies put together.
Dhanunjaya Lakkireddy, MD , is medical director of the Kansas City Heart Rhythm Institute in Overland Park. He had no disclosures. He made these comments as the designated discussant during a press briefing.
It’s very reassuring to see that you can use a direct-acting oral anticoagulant like apixaban along with a P2Y12 inhibitor, but with no aspirin, and have no statistically significant increase in ischemic events. This is a fantastic finding. The finding shows once again that warfarin is a problematic drug. As the cost for direct-acting oral anticoagulants has decreased, their use has increased.
These results were not unexpected and also are probably the final nail in the coffin for using a combination of warfarin and aspirin. Prior findings from the PIONEER AF-PCI study that used rivaroxaban (N Engl J Med. 2016 Dec 22;375[25]:2423-34) and from the RE-DUAL PCI study that used dabigatran (N Engl J Med. 2017 Oct 19;377[16]:1513-24) also showed the advantages of using a direct-acting oral anticoagulant when compared with a vitamin K antagonist in this setting, The AUGUSTUS trial, with just over 4,600 patients, had nearly as many patients as the roughly 4,850 enrolled in these two prior studies put together.
Dhanunjaya Lakkireddy, MD , is medical director of the Kansas City Heart Rhythm Institute in Overland Park. He had no disclosures. He made these comments as the designated discussant during a press briefing.
NEW ORLEANS – For patients with atrial fibrillation and either a recent acute coronary syndrome or percutaneous coronary intervention, combined treatment for 6 months with the anticoagulant apixaban and a P2Y12 inhibitor antiplatelet drug, but without aspirin, was safer than and as effective as a regimen that either also included aspirin or that substituted a vitamin K antagonist, such as warfarin, for the direct-acting oral anticoagulant, based on results from a multicenter, randomized trial with more than 4,600 patients.
The apixaban plus P2Y12 inhibitor (typically, clopidogrel) combination “resulted in less bleeding and fewer hospitalizations without significant differences in ischemic events than regimens that included a vitamin K antagonist, aspirin, or both,” Renato D. Lopes, MD, said at the annual meeting of the American College of Cardiology. Concurrently, his report of the results also appeared in an online article.
This finding in the AUGUSTUS trial gives clinicians more guidance for the long-standing dilemma of how to best prevent arterial thrombus formation in patients with atrial fibrillation (AFib). To prevent a stroke, these patients routinely receive treatment with an anticoagulant when they have an acute coronary syndrome (ACS) event or undergo percutaneous coronary intervention (PCI). Typically, they receive several months of dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor to prevent a clot from forming in the stented or unstable region of a coronary artery.
These patients are not uncommon; this circumstance occurs for about 20% of all AFib patients, and poses the question of what is the safest and most effective way to treat them. Should they get triple therapy with an anticoagulant, aspirin, and a P2Y12 inhibitor, an option that could cause excess bleeding; or should one of the three drugs drop out with the potential for an increased rate of ischemic events? The AUGUSTUS findings suggest that one solution is treatment with a combination of the direct-acting oral anticoagulant apixaban (Eliquis) and the P2Y12 inhibitor clopidogrel (Plavix) but without aspirin.
For the majority of patients like the ones enrolled, “less is more.” By dropping aspirin from the treatment mix, patients did better, said Dr. Lopes, a professor of medicine at Duke University in Durham, N.C.
Dr. Lopes and his associates designed AUGUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis [Blood Clots] Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart) as a two-by-two factorial study to address two different questions: During 6 months of treatment, how did apixaban compare with a vitamin K antagonist (usually warfarin) in these patients for safety and efficacy, and how did aspirin compare with placebo in this setting for the same endpoints?
The trial enrolled 4,614 patients at 492 sites in 33 countries. All patients in the study received a P2Y12 inhibitor, with 93% treated with clopidogrel. The study had roughly as many patients as the combined total of patients enrolled in two smaller, prior studies that had looked at roughly the same questions in similar patients.
“The aspirin part is the more interesting, and probably more unique and important finding,” John H. Alexander, MD, a coinvestigator on the study, said in a video interview. Regardless of the anticoagulant used, patients who received aspirin had a 16% rate of major bleeds or clinically relevant non-major bleeds, compared with a 9% rate among those on placebo, a statistically significant result that underscored the bleeding risk posed by adding aspirin to an anticoagulant and a P2Y12 inhibitor.
The results also showed no statistically significant difference in any efficacy measure with or without aspirin, including the rate of death or hospitalization, or of any individual ischemic endpoint. However the results showed a signal of a small increase in the rates of each of three types of ischemic events – stent thrombosis, MI, and need for urgent revascularization, each of which showed a numerical increase when aspirin was dropped. But the increase was small.
Dr. Lopes calculated that, for example, to prevent one episode of stent thrombosis by treating with aspirin also would cause 15 major or clinically relevant non-major bleeds, which makes inclusion of aspirin something of a judgment call for each patient, said Dr. Alexander, a professor of medicine at Duke. An AFib patient with a high risk for thrombosis but a low risk for bleeding following PCI or an ACS event might be a reasonable patient to treat with aspirin along with apixaban and a P2Y12 inhibitor, he explained.
The rate of major or clinically relevant bleeds was 11% with apixaban and 15% with a vitamin K antagonist, a statistically significant difference. Patients treated with apixaban also had a significantly reduced rate of death or hospitalization, 24%, compared with 27% among those on the vitamin K antagonist, as well as a significantly lower rate of stroke.
Overall the lowest bleeding rate was in patients on apixaban but no aspirin, a 7% rate, while the highest rate was in patients on a vitamin K antagonist plus aspirin, a 19% rate.
Dr. Alexander said that it would be an overreach to extrapolate these findings to other direct-acting oral anticoagulants, compared with a vitamin K antagonist, but he believed that the findings the study generated about aspirin were probably relevant regardless of the anticoagulant used.
mzoler@mdedge.com
On Twitter @mitchelzoler
NEW ORLEANS – For patients with atrial fibrillation and either a recent acute coronary syndrome or percutaneous coronary intervention, combined treatment for 6 months with the anticoagulant apixaban and a P2Y12 inhibitor antiplatelet drug, but without aspirin, was safer than and as effective as a regimen that either also included aspirin or that substituted a vitamin K antagonist, such as warfarin, for the direct-acting oral anticoagulant, based on results from a multicenter, randomized trial with more than 4,600 patients.
The apixaban plus P2Y12 inhibitor (typically, clopidogrel) combination “resulted in less bleeding and fewer hospitalizations without significant differences in ischemic events than regimens that included a vitamin K antagonist, aspirin, or both,” Renato D. Lopes, MD, said at the annual meeting of the American College of Cardiology. Concurrently, his report of the results also appeared in an online article.
This finding in the AUGUSTUS trial gives clinicians more guidance for the long-standing dilemma of how to best prevent arterial thrombus formation in patients with atrial fibrillation (AFib). To prevent a stroke, these patients routinely receive treatment with an anticoagulant when they have an acute coronary syndrome (ACS) event or undergo percutaneous coronary intervention (PCI). Typically, they receive several months of dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor to prevent a clot from forming in the stented or unstable region of a coronary artery.
These patients are not uncommon; this circumstance occurs for about 20% of all AFib patients, and poses the question of what is the safest and most effective way to treat them. Should they get triple therapy with an anticoagulant, aspirin, and a P2Y12 inhibitor, an option that could cause excess bleeding; or should one of the three drugs drop out with the potential for an increased rate of ischemic events? The AUGUSTUS findings suggest that one solution is treatment with a combination of the direct-acting oral anticoagulant apixaban (Eliquis) and the P2Y12 inhibitor clopidogrel (Plavix) but without aspirin.
For the majority of patients like the ones enrolled, “less is more.” By dropping aspirin from the treatment mix, patients did better, said Dr. Lopes, a professor of medicine at Duke University in Durham, N.C.
Dr. Lopes and his associates designed AUGUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis [Blood Clots] Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart) as a two-by-two factorial study to address two different questions: During 6 months of treatment, how did apixaban compare with a vitamin K antagonist (usually warfarin) in these patients for safety and efficacy, and how did aspirin compare with placebo in this setting for the same endpoints?
The trial enrolled 4,614 patients at 492 sites in 33 countries. All patients in the study received a P2Y12 inhibitor, with 93% treated with clopidogrel. The study had roughly as many patients as the combined total of patients enrolled in two smaller, prior studies that had looked at roughly the same questions in similar patients.
“The aspirin part is the more interesting, and probably more unique and important finding,” John H. Alexander, MD, a coinvestigator on the study, said in a video interview. Regardless of the anticoagulant used, patients who received aspirin had a 16% rate of major bleeds or clinically relevant non-major bleeds, compared with a 9% rate among those on placebo, a statistically significant result that underscored the bleeding risk posed by adding aspirin to an anticoagulant and a P2Y12 inhibitor.
The results also showed no statistically significant difference in any efficacy measure with or without aspirin, including the rate of death or hospitalization, or of any individual ischemic endpoint. However the results showed a signal of a small increase in the rates of each of three types of ischemic events – stent thrombosis, MI, and need for urgent revascularization, each of which showed a numerical increase when aspirin was dropped. But the increase was small.
Dr. Lopes calculated that, for example, to prevent one episode of stent thrombosis by treating with aspirin also would cause 15 major or clinically relevant non-major bleeds, which makes inclusion of aspirin something of a judgment call for each patient, said Dr. Alexander, a professor of medicine at Duke. An AFib patient with a high risk for thrombosis but a low risk for bleeding following PCI or an ACS event might be a reasonable patient to treat with aspirin along with apixaban and a P2Y12 inhibitor, he explained.
The rate of major or clinically relevant bleeds was 11% with apixaban and 15% with a vitamin K antagonist, a statistically significant difference. Patients treated with apixaban also had a significantly reduced rate of death or hospitalization, 24%, compared with 27% among those on the vitamin K antagonist, as well as a significantly lower rate of stroke.
Overall the lowest bleeding rate was in patients on apixaban but no aspirin, a 7% rate, while the highest rate was in patients on a vitamin K antagonist plus aspirin, a 19% rate.
Dr. Alexander said that it would be an overreach to extrapolate these findings to other direct-acting oral anticoagulants, compared with a vitamin K antagonist, but he believed that the findings the study generated about aspirin were probably relevant regardless of the anticoagulant used.
mzoler@mdedge.com
On Twitter @mitchelzoler
REPORTING FROM ACC 19
Andexanet alfa effectively reverses factor Xa inhibition
HONOLULU – according to a study presented at the International Stroke Conference sponsored by the American Heart Association. The medication is associated with a low rate of mortality resulting from intracerebral hemorrhage (ICH), compared with the general population of patients with ICH receiving anticoagulation.
Factor Xa inhibitors such as apixaban and rivaroxaban effectively prevent thromboembolic events but may cause or exacerbate acute major bleeding. Andexanet alfa, a modified, recombinant, inactive form of human factor Xa, was developed and approved as a reversal agent for factor Xa inhibitors. In a 2015 study, andexanet rapidly and safely reversed anti–factor Xa activity in large cohorts of patients without bleeding.
A single-cohort study
Truman John Milling Jr., MD, an emergency medicine physician at Dell Seton Medical Center at the University of Texas in Austin, and his colleagues conducted the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study to evaluate the drug’s safety and efficacy in patients with acute major bleeding associated with treatment with a factor Xa inhibitor. For participants to be eligible, their bleeding had to be life threatening with signs of hemodynamic compromise, be associated with a decrease in hemoglobin level of at least 2 g/dL, or occur in a critical organ such as the brain. An independent academic committee determined whether patients met these criteria.
The trial’s primary efficacy outcomes were change from baseline in anti–factor Xa activity and the percentage of patients with excellent or good hemostatic efficacy at 12 hours. The primary safety endpoints were death, thrombotic events, and the development of neutralizing antibodies to andexanet or to native factor X and factor Xa. The efficacy population included patients with major bleeding and baseline anti–factor Xa activity of at least 75 ng/mL. The safety population included all patients who received a dose of andexanet. The independent committee adjudicated the efficacy and safety outcomes.
Hemostasis was sustained for 12 hours
The investigators enrolled 352 participants into the study, all of whom received andexanet and were followed for at least 30 days or until death. The population’s mean age was 77 years. “These were older and sicker patients with a significant amount of comorbid disease,” said Dr. Milling. The primary indication for anticoagulation was atrial fibrillation in 80% of patients. The primary site of bleeding was intracranial in 64% of patients and gastrointestinal in 26% of patients. The remaining 10% of patients had bleeding affecting other areas (such as pericardial or intramuscular bleeding).
The investigators included 254 patients in the efficacy population. At the end of the administration of the andexanet bolus, the median value for anti–factor Xa activity decreased by 92% among participants receiving apixaban, 92% among participants receiving rivaroxaban, and 75% among patients receiving enoxaparin. Among patients receiving apixaban, the median value for anti–factor Xa activity was decreased by 32% at 4 hours, 34% at 8 hours, and 38% at 12 hours. Among patients receiving rivaroxaban, the median value for anti–factor Xa activity was decreased by 42% at 4 hours, 48% at 8 hours, and 62% at 12 hours.
Dr. Milling and his colleagues assessed hemostatic efficacy in 249 patients. Of this group, 82% achieved good or excellent hemostasis. Among participants with good or excellent hemostasis, 84% had excellent results, and 16% had good results. Subanalysis by factor Xa inhibitor, type of bleed, age, and dose of andexanet did not alter the findings significantly.
To determine whether hemostasis had been sustained sufficiently to prevent clinical deterioration, the investigators examined 71 patients with ICH and a single-compartment bleed. From 1 hour to 12 hours, one patient’s outcome changed from excellent/good to poor/none, and one patient’s outcome changed from excellent to good. For the majority of these patients, however, good hemostasis was sustained from 1 to 12 hours.
The rate of thromboembolic events was 9.7%, which is in the expected range for this population, said Dr. Milling. These events were distributed evenly among the 4 weeks of the study. Stroke and deep vein thrombosis accounted for most of these events, and pulmonary emboli and heart attacks occurred as well. “Once we restarted oral anticoagulation ... there were no more thrombotic events,” said Dr. Milling. No patient developed neutralizing antibodies to factor X or factor Xa, nor did any patient develop neutralizing antibodies to andexanet.
The overall mortality rate was 13.9%. The rate of mortality resulting from ICH was 15%, and the rate of mortality resulting from gastrointestinal bleeding was 11%. These results are impressive, considering that patients had received anticoagulants, said Dr. Milling.
Portola Pharmaceuticals, the maker of andexanet alfa, funded the study. Dr. Milling reported receiving funding and honoraria from the Population Health Research Institute at McMasters University, Janssen, CSL Behring, and Octapharma. He also received a small research payment from Portola Pharmaceuticals. Several of the investigators reported receiving funding from Portola Pharmaceuticals.
SOURCE: Milling TJ et al. ISC 2019, Abstract LB7.
HONOLULU – according to a study presented at the International Stroke Conference sponsored by the American Heart Association. The medication is associated with a low rate of mortality resulting from intracerebral hemorrhage (ICH), compared with the general population of patients with ICH receiving anticoagulation.
Factor Xa inhibitors such as apixaban and rivaroxaban effectively prevent thromboembolic events but may cause or exacerbate acute major bleeding. Andexanet alfa, a modified, recombinant, inactive form of human factor Xa, was developed and approved as a reversal agent for factor Xa inhibitors. In a 2015 study, andexanet rapidly and safely reversed anti–factor Xa activity in large cohorts of patients without bleeding.
A single-cohort study
Truman John Milling Jr., MD, an emergency medicine physician at Dell Seton Medical Center at the University of Texas in Austin, and his colleagues conducted the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study to evaluate the drug’s safety and efficacy in patients with acute major bleeding associated with treatment with a factor Xa inhibitor. For participants to be eligible, their bleeding had to be life threatening with signs of hemodynamic compromise, be associated with a decrease in hemoglobin level of at least 2 g/dL, or occur in a critical organ such as the brain. An independent academic committee determined whether patients met these criteria.
The trial’s primary efficacy outcomes were change from baseline in anti–factor Xa activity and the percentage of patients with excellent or good hemostatic efficacy at 12 hours. The primary safety endpoints were death, thrombotic events, and the development of neutralizing antibodies to andexanet or to native factor X and factor Xa. The efficacy population included patients with major bleeding and baseline anti–factor Xa activity of at least 75 ng/mL. The safety population included all patients who received a dose of andexanet. The independent committee adjudicated the efficacy and safety outcomes.
Hemostasis was sustained for 12 hours
The investigators enrolled 352 participants into the study, all of whom received andexanet and were followed for at least 30 days or until death. The population’s mean age was 77 years. “These were older and sicker patients with a significant amount of comorbid disease,” said Dr. Milling. The primary indication for anticoagulation was atrial fibrillation in 80% of patients. The primary site of bleeding was intracranial in 64% of patients and gastrointestinal in 26% of patients. The remaining 10% of patients had bleeding affecting other areas (such as pericardial or intramuscular bleeding).
The investigators included 254 patients in the efficacy population. At the end of the administration of the andexanet bolus, the median value for anti–factor Xa activity decreased by 92% among participants receiving apixaban, 92% among participants receiving rivaroxaban, and 75% among patients receiving enoxaparin. Among patients receiving apixaban, the median value for anti–factor Xa activity was decreased by 32% at 4 hours, 34% at 8 hours, and 38% at 12 hours. Among patients receiving rivaroxaban, the median value for anti–factor Xa activity was decreased by 42% at 4 hours, 48% at 8 hours, and 62% at 12 hours.
Dr. Milling and his colleagues assessed hemostatic efficacy in 249 patients. Of this group, 82% achieved good or excellent hemostasis. Among participants with good or excellent hemostasis, 84% had excellent results, and 16% had good results. Subanalysis by factor Xa inhibitor, type of bleed, age, and dose of andexanet did not alter the findings significantly.
To determine whether hemostasis had been sustained sufficiently to prevent clinical deterioration, the investigators examined 71 patients with ICH and a single-compartment bleed. From 1 hour to 12 hours, one patient’s outcome changed from excellent/good to poor/none, and one patient’s outcome changed from excellent to good. For the majority of these patients, however, good hemostasis was sustained from 1 to 12 hours.
The rate of thromboembolic events was 9.7%, which is in the expected range for this population, said Dr. Milling. These events were distributed evenly among the 4 weeks of the study. Stroke and deep vein thrombosis accounted for most of these events, and pulmonary emboli and heart attacks occurred as well. “Once we restarted oral anticoagulation ... there were no more thrombotic events,” said Dr. Milling. No patient developed neutralizing antibodies to factor X or factor Xa, nor did any patient develop neutralizing antibodies to andexanet.
The overall mortality rate was 13.9%. The rate of mortality resulting from ICH was 15%, and the rate of mortality resulting from gastrointestinal bleeding was 11%. These results are impressive, considering that patients had received anticoagulants, said Dr. Milling.
Portola Pharmaceuticals, the maker of andexanet alfa, funded the study. Dr. Milling reported receiving funding and honoraria from the Population Health Research Institute at McMasters University, Janssen, CSL Behring, and Octapharma. He also received a small research payment from Portola Pharmaceuticals. Several of the investigators reported receiving funding from Portola Pharmaceuticals.
SOURCE: Milling TJ et al. ISC 2019, Abstract LB7.
HONOLULU – according to a study presented at the International Stroke Conference sponsored by the American Heart Association. The medication is associated with a low rate of mortality resulting from intracerebral hemorrhage (ICH), compared with the general population of patients with ICH receiving anticoagulation.
Factor Xa inhibitors such as apixaban and rivaroxaban effectively prevent thromboembolic events but may cause or exacerbate acute major bleeding. Andexanet alfa, a modified, recombinant, inactive form of human factor Xa, was developed and approved as a reversal agent for factor Xa inhibitors. In a 2015 study, andexanet rapidly and safely reversed anti–factor Xa activity in large cohorts of patients without bleeding.
A single-cohort study
Truman John Milling Jr., MD, an emergency medicine physician at Dell Seton Medical Center at the University of Texas in Austin, and his colleagues conducted the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study to evaluate the drug’s safety and efficacy in patients with acute major bleeding associated with treatment with a factor Xa inhibitor. For participants to be eligible, their bleeding had to be life threatening with signs of hemodynamic compromise, be associated with a decrease in hemoglobin level of at least 2 g/dL, or occur in a critical organ such as the brain. An independent academic committee determined whether patients met these criteria.
The trial’s primary efficacy outcomes were change from baseline in anti–factor Xa activity and the percentage of patients with excellent or good hemostatic efficacy at 12 hours. The primary safety endpoints were death, thrombotic events, and the development of neutralizing antibodies to andexanet or to native factor X and factor Xa. The efficacy population included patients with major bleeding and baseline anti–factor Xa activity of at least 75 ng/mL. The safety population included all patients who received a dose of andexanet. The independent committee adjudicated the efficacy and safety outcomes.
Hemostasis was sustained for 12 hours
The investigators enrolled 352 participants into the study, all of whom received andexanet and were followed for at least 30 days or until death. The population’s mean age was 77 years. “These were older and sicker patients with a significant amount of comorbid disease,” said Dr. Milling. The primary indication for anticoagulation was atrial fibrillation in 80% of patients. The primary site of bleeding was intracranial in 64% of patients and gastrointestinal in 26% of patients. The remaining 10% of patients had bleeding affecting other areas (such as pericardial or intramuscular bleeding).
The investigators included 254 patients in the efficacy population. At the end of the administration of the andexanet bolus, the median value for anti–factor Xa activity decreased by 92% among participants receiving apixaban, 92% among participants receiving rivaroxaban, and 75% among patients receiving enoxaparin. Among patients receiving apixaban, the median value for anti–factor Xa activity was decreased by 32% at 4 hours, 34% at 8 hours, and 38% at 12 hours. Among patients receiving rivaroxaban, the median value for anti–factor Xa activity was decreased by 42% at 4 hours, 48% at 8 hours, and 62% at 12 hours.
Dr. Milling and his colleagues assessed hemostatic efficacy in 249 patients. Of this group, 82% achieved good or excellent hemostasis. Among participants with good or excellent hemostasis, 84% had excellent results, and 16% had good results. Subanalysis by factor Xa inhibitor, type of bleed, age, and dose of andexanet did not alter the findings significantly.
To determine whether hemostasis had been sustained sufficiently to prevent clinical deterioration, the investigators examined 71 patients with ICH and a single-compartment bleed. From 1 hour to 12 hours, one patient’s outcome changed from excellent/good to poor/none, and one patient’s outcome changed from excellent to good. For the majority of these patients, however, good hemostasis was sustained from 1 to 12 hours.
The rate of thromboembolic events was 9.7%, which is in the expected range for this population, said Dr. Milling. These events were distributed evenly among the 4 weeks of the study. Stroke and deep vein thrombosis accounted for most of these events, and pulmonary emboli and heart attacks occurred as well. “Once we restarted oral anticoagulation ... there were no more thrombotic events,” said Dr. Milling. No patient developed neutralizing antibodies to factor X or factor Xa, nor did any patient develop neutralizing antibodies to andexanet.
The overall mortality rate was 13.9%. The rate of mortality resulting from ICH was 15%, and the rate of mortality resulting from gastrointestinal bleeding was 11%. These results are impressive, considering that patients had received anticoagulants, said Dr. Milling.
Portola Pharmaceuticals, the maker of andexanet alfa, funded the study. Dr. Milling reported receiving funding and honoraria from the Population Health Research Institute at McMasters University, Janssen, CSL Behring, and Octapharma. He also received a small research payment from Portola Pharmaceuticals. Several of the investigators reported receiving funding from Portola Pharmaceuticals.
SOURCE: Milling TJ et al. ISC 2019, Abstract LB7.
REPORTING FROM ISC 2019
Repeat VTE risk heightened in HIV patients
SEATTLE – HIV infection is associated with increased risk of recurrent venous thromboembolism, especially within 1 year of the initial episode. The finding, presented during a poster session at the Conference on Retroviruses & Opportunistic Infections, follows up on an earlier study that found that first-time VTE risk also is higher among HIV-positive individuals than in the general population.
The conclusion about first-time VTE risk, published earlier this year in Lancet HIV, came from a comparison between the ATHENA (AIDS Therapy Evaluation in the Netherlands) cohort and European population-level of studies of VTE. It found a crude incidence of 2.33 VTE events per 1,000 person-years In HIV patients, with heightened odds when CD4 cell counts were below 200 cells/mcL (adjusted hazard ratio, 3.40).
The new work represents a follow-up and compared results from ATHENA (153 patients with HIV and first VTE) and the Dutch MEGA cohort (4,005 patients without HIV, with first VTE), which includes the general population. Overall, 26% of patients in the ATHENA cohort experienced a second VTE event, compared with 16% of the general population. At 1 year after anticoagulation withdrawal, HIV-positive individuals were at 67% increased risk (HR, 1.67). At 6-years after withdrawal, the relationship was not statistically significant (HR, 1.22).
Researchers also found that CD4 cell-count recovery was associated with lowered risk, with every 100 cell-count increase between initial VTE diagnosis and anticoagulant withdrawal linked to a 20% reduction in risk (HR, 0.80).
“The clinical question is: If it’s true you have an increased risk of recurrence, should you be continuing anticoagulant therapy longer in people with HIV? This poster doesn’t answer that question and you probably need a randomized, controlled trial to look at that,” Peter Reiss, MD, professor of medicine at Amsterdam University Medical Center, said in an interview during the conference.
In the absence of a clear answer, it’s sensible for clinicians to be aware of the potential increased risk, much as clinicians have internalized the increased risk of atherosclerotic vascular disease in HIV patients. “I think the publication [in Lancet HIV] as well as this poster suggest that on the venous side of things there may also be an accentuated risk,” said Dr. Reiss.
Heidi Crane, MD, a professor of medicine at the University of Washington, Seattle, presented a poster examining the underlying factors that may predispose HIV patients to first-time VTE events. Her team performed an adjudicated review of VTE cases among HIV patients at six institutions and found that the risk factors appeared to be distinct from those seen in the general population.
The traditional long plane ride was less common in this population, while factors such as injected drug use and pneumonia were more common. The VTE events occurred at a median age of 49 years; 30% of the patients had a detectable viral load. “We’re seeing a little more (VTE) than you might expect, and in a younger population than you might have guessed,” said Dr. Crane in an interview.
The most frequent predisposing risk factors were recent hospitalization (40%), infection (40%), or immobilization/bed rest (24%) within the past 90 days, and injectable drug use (22%). “It’s not just the traditional risk factors. Some HIV-specific risk factors are driving this,” said Dr. Crane.
She also aims to learn more about the specifics of risk factors, such as catheter-associated thromboses. The team is working to increase the sample size in order to parse out the relationships with specific outcomes.
In the meantime, the data further characterize the health challenges facing people living with HIV. “This is another example demonstrating that comorbid conditions among patients with HIV that are often considered age related occur at much younger ages in our population,” said Dr. Crane.
SOURCE: Rokx C et al. CROI 2019, Abstract 636; and Tenforde MW et al. CROI 2019, Abstract 637.
.
SEATTLE – HIV infection is associated with increased risk of recurrent venous thromboembolism, especially within 1 year of the initial episode. The finding, presented during a poster session at the Conference on Retroviruses & Opportunistic Infections, follows up on an earlier study that found that first-time VTE risk also is higher among HIV-positive individuals than in the general population.
The conclusion about first-time VTE risk, published earlier this year in Lancet HIV, came from a comparison between the ATHENA (AIDS Therapy Evaluation in the Netherlands) cohort and European population-level of studies of VTE. It found a crude incidence of 2.33 VTE events per 1,000 person-years In HIV patients, with heightened odds when CD4 cell counts were below 200 cells/mcL (adjusted hazard ratio, 3.40).
The new work represents a follow-up and compared results from ATHENA (153 patients with HIV and first VTE) and the Dutch MEGA cohort (4,005 patients without HIV, with first VTE), which includes the general population. Overall, 26% of patients in the ATHENA cohort experienced a second VTE event, compared with 16% of the general population. At 1 year after anticoagulation withdrawal, HIV-positive individuals were at 67% increased risk (HR, 1.67). At 6-years after withdrawal, the relationship was not statistically significant (HR, 1.22).
Researchers also found that CD4 cell-count recovery was associated with lowered risk, with every 100 cell-count increase between initial VTE diagnosis and anticoagulant withdrawal linked to a 20% reduction in risk (HR, 0.80).
“The clinical question is: If it’s true you have an increased risk of recurrence, should you be continuing anticoagulant therapy longer in people with HIV? This poster doesn’t answer that question and you probably need a randomized, controlled trial to look at that,” Peter Reiss, MD, professor of medicine at Amsterdam University Medical Center, said in an interview during the conference.
In the absence of a clear answer, it’s sensible for clinicians to be aware of the potential increased risk, much as clinicians have internalized the increased risk of atherosclerotic vascular disease in HIV patients. “I think the publication [in Lancet HIV] as well as this poster suggest that on the venous side of things there may also be an accentuated risk,” said Dr. Reiss.
Heidi Crane, MD, a professor of medicine at the University of Washington, Seattle, presented a poster examining the underlying factors that may predispose HIV patients to first-time VTE events. Her team performed an adjudicated review of VTE cases among HIV patients at six institutions and found that the risk factors appeared to be distinct from those seen in the general population.
The traditional long plane ride was less common in this population, while factors such as injected drug use and pneumonia were more common. The VTE events occurred at a median age of 49 years; 30% of the patients had a detectable viral load. “We’re seeing a little more (VTE) than you might expect, and in a younger population than you might have guessed,” said Dr. Crane in an interview.
The most frequent predisposing risk factors were recent hospitalization (40%), infection (40%), or immobilization/bed rest (24%) within the past 90 days, and injectable drug use (22%). “It’s not just the traditional risk factors. Some HIV-specific risk factors are driving this,” said Dr. Crane.
She also aims to learn more about the specifics of risk factors, such as catheter-associated thromboses. The team is working to increase the sample size in order to parse out the relationships with specific outcomes.
In the meantime, the data further characterize the health challenges facing people living with HIV. “This is another example demonstrating that comorbid conditions among patients with HIV that are often considered age related occur at much younger ages in our population,” said Dr. Crane.
SOURCE: Rokx C et al. CROI 2019, Abstract 636; and Tenforde MW et al. CROI 2019, Abstract 637.
.
SEATTLE – HIV infection is associated with increased risk of recurrent venous thromboembolism, especially within 1 year of the initial episode. The finding, presented during a poster session at the Conference on Retroviruses & Opportunistic Infections, follows up on an earlier study that found that first-time VTE risk also is higher among HIV-positive individuals than in the general population.
The conclusion about first-time VTE risk, published earlier this year in Lancet HIV, came from a comparison between the ATHENA (AIDS Therapy Evaluation in the Netherlands) cohort and European population-level of studies of VTE. It found a crude incidence of 2.33 VTE events per 1,000 person-years In HIV patients, with heightened odds when CD4 cell counts were below 200 cells/mcL (adjusted hazard ratio, 3.40).
The new work represents a follow-up and compared results from ATHENA (153 patients with HIV and first VTE) and the Dutch MEGA cohort (4,005 patients without HIV, with first VTE), which includes the general population. Overall, 26% of patients in the ATHENA cohort experienced a second VTE event, compared with 16% of the general population. At 1 year after anticoagulation withdrawal, HIV-positive individuals were at 67% increased risk (HR, 1.67). At 6-years after withdrawal, the relationship was not statistically significant (HR, 1.22).
Researchers also found that CD4 cell-count recovery was associated with lowered risk, with every 100 cell-count increase between initial VTE diagnosis and anticoagulant withdrawal linked to a 20% reduction in risk (HR, 0.80).
“The clinical question is: If it’s true you have an increased risk of recurrence, should you be continuing anticoagulant therapy longer in people with HIV? This poster doesn’t answer that question and you probably need a randomized, controlled trial to look at that,” Peter Reiss, MD, professor of medicine at Amsterdam University Medical Center, said in an interview during the conference.
In the absence of a clear answer, it’s sensible for clinicians to be aware of the potential increased risk, much as clinicians have internalized the increased risk of atherosclerotic vascular disease in HIV patients. “I think the publication [in Lancet HIV] as well as this poster suggest that on the venous side of things there may also be an accentuated risk,” said Dr. Reiss.
Heidi Crane, MD, a professor of medicine at the University of Washington, Seattle, presented a poster examining the underlying factors that may predispose HIV patients to first-time VTE events. Her team performed an adjudicated review of VTE cases among HIV patients at six institutions and found that the risk factors appeared to be distinct from those seen in the general population.
The traditional long plane ride was less common in this population, while factors such as injected drug use and pneumonia were more common. The VTE events occurred at a median age of 49 years; 30% of the patients had a detectable viral load. “We’re seeing a little more (VTE) than you might expect, and in a younger population than you might have guessed,” said Dr. Crane in an interview.
The most frequent predisposing risk factors were recent hospitalization (40%), infection (40%), or immobilization/bed rest (24%) within the past 90 days, and injectable drug use (22%). “It’s not just the traditional risk factors. Some HIV-specific risk factors are driving this,” said Dr. Crane.
She also aims to learn more about the specifics of risk factors, such as catheter-associated thromboses. The team is working to increase the sample size in order to parse out the relationships with specific outcomes.
In the meantime, the data further characterize the health challenges facing people living with HIV. “This is another example demonstrating that comorbid conditions among patients with HIV that are often considered age related occur at much younger ages in our population,” said Dr. Crane.
SOURCE: Rokx C et al. CROI 2019, Abstract 636; and Tenforde MW et al. CROI 2019, Abstract 637.
.
REPORTING FROM CROI 2019
Novel transplant regimen improves survival in primary immunodeficiency
HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.
At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.
GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.
All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.
The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m2 along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.
All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.
Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.
An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.
Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.
“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”
Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.
Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.
“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.
Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.
“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.
All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.
The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.
“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.
For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.
The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.
“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Dimitrova reported having no financial disclosures.
SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.
HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.
At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.
GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.
All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.
The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m2 along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.
All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.
Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.
An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.
Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.
“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”
Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.
Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.
“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.
Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.
“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.
All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.
The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.
“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.
For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.
The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.
“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Dimitrova reported having no financial disclosures.
SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.
HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.
At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.
GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.
All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.
The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m2 along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.
All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.
Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.
An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.
Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.
“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”
Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.
Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.
“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.
Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.
“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.
All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.
The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.
“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.
For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.
The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.
“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Dimitrova reported having no financial disclosures.
SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.
REPORTING FROM TCT 2019
Gene therapy in hemophilia is just version 1.0
PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.
“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.
Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.
“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”
A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.
Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”
When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.
Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).
In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.
“This has stepped up the game hugely,” Dr. Pasi said.
The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.
Gene modification is also not coming anytime soon.
“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”
Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.
“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”
Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.
Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.
“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”
The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.
Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”
Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.
“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”
PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.
“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.
Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.
“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”
A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.
Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”
When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.
Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).
In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.
“This has stepped up the game hugely,” Dr. Pasi said.
The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.
Gene modification is also not coming anytime soon.
“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”
Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.
“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”
Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.
Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.
“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”
The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.
Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”
Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.
“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”
PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.
“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.
Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.
“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”
A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.
Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”
When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.
Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).
In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.
“This has stepped up the game hugely,” Dr. Pasi said.
The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.
Gene modification is also not coming anytime soon.
“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”
Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.
“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”
Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.
Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.
“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”
The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.
Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”
Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.
“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”
EXPERT ANALYSIS FROM EAHAD 2019
Myeloma therapies raise cardiovascular risks
WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.
In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.
In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.
The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.
The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.
The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).
In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.
“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
IMiDs and thromboembolism
In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.
“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.
There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.
Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.
“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.
He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.
WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.
In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.
In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.
The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.
The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.
The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).
In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.
“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
IMiDs and thromboembolism
In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.
“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.
There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.
Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.
“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.
He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.
WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.
In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.
In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.
The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.
The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.
The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).
In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.
“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
IMiDs and thromboembolism
In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.
“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.
There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.
Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.
“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.
He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.
REPORTING FROM ACC CARDIO-ONCOLOGY