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U.S. cancer centers embroiled in Chinese research thefts
Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.
The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.
On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.
The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.
“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.
Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”
The FBI said it is investigating China-related cases in all 50 states.
Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.
“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.
He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.
The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.
For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.
“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
Moffitt story still unfolding
The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.
In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”
New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.
The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.
Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.
All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.
According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.
Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.
The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.
Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.
The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”
No charges have been filed against any of the former Moffitt employees.
However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.
AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.
The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.
“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.
The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
Lack of oversight?
Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.
But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”
Federal investigators have said that Thousand Talents has been one of the biggest threats.
The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”
The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
Widening dragnet
In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.
Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.
Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.
The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
This article first appeared on Medscape.com.
Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.
The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.
On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.
The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.
“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.
Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”
The FBI said it is investigating China-related cases in all 50 states.
Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.
“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.
He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.
The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.
For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.
“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
Moffitt story still unfolding
The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.
In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”
New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.
The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.
Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.
All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.
According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.
Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.
The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.
Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.
The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”
No charges have been filed against any of the former Moffitt employees.
However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.
AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.
The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.
“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.
The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
Lack of oversight?
Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.
But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”
Federal investigators have said that Thousand Talents has been one of the biggest threats.
The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”
The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
Widening dragnet
In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.
Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.
Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.
The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
This article first appeared on Medscape.com.
Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.
The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.
On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.
The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.
“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.
Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”
The FBI said it is investigating China-related cases in all 50 states.
Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.
“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.
He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.
The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.
For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.
“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
Moffitt story still unfolding
The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.
In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”
New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.
The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.
Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.
All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.
According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.
Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.
The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.
Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.
The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”
No charges have been filed against any of the former Moffitt employees.
However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.
AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.
The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.
“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.
The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
Lack of oversight?
Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.
But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”
Federal investigators have said that Thousand Talents has been one of the biggest threats.
The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”
The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
Widening dragnet
In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.
Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.
Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.
The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
This article first appeared on Medscape.com.
Deferiprone noninferior to deferoxamine for iron overload in SCD, rare anemias
ORLANDO – The oral iron chelator deferiprone showed noninferiority to deferoxamine for treating iron overload in patients with sickle cell disease and other rare anemias in a randomized open-label trial.
The least squares mean change from baseline in liver iron concentration (LIC) – the primary study endpoint – was –4.04 mg/g dry weight (dw) in 152 patients randomized to receive deferiprone, and –4.45 mg/g dw in 76 who received deferoxamine, Janet L. Kwiatkowski, MD, of the Children’s Hospital of Philadelphia reported at the annual meeting of the American Society of Hematology.
The upper limit of the stringent 96.01% confidence interval used for the evaluation of noninferiority in the study was 1.57, thus the findings demonstrated noninferiority of deferiprone, Dr. Kwiatkowski said.
Deferiprone also showed noninferiority for the secondary endpoints of change in cardiac iron (about –0.02 ms on T2* MRI, log-transformed for both groups) and serum ferritin levels (–415 vs. –750 mcg/L for deferiprone vs. deferoxamine) at 12 months. The difference between the groups was not statistically significant for either endpoint.
Study participants, who had a mean age of 16.9 years, were aged 2 years and older with LIC between 7 and 30 mg/g dw. They were recruited from 33 sites in nine countries and randomized 2:1 to receive deferiprone or deferoxamine for up to 12 months; in patients with lower transfusional iron input and/or less severe iron load, deferiprone was dosed at 75 mg/kg daily and deferoxamine was dosed at 20 mg/kg for children and 40 mg/kg for adults. In those with higher iron input and/or more severe iron load, the deferiprone dose was 99 mg/kg daily and the deferoxamine doses were up to 40 mg/kg in children and up to 50 mg/kg for adults.
“Over the course of the treatment period, the dosage could be adjusted downward if there were side effects, or upward if there was no improvement in iron burden,” Dr Kwiatkowski said, adding that after 12 months, patients had the option of continuing on to a 2-year extension trial in which everyone received deferiprone.
No significant demographic differences were noted between the groups; 84% in both groups had sickle cell disease, and the remaining patients had other, rarer forms of transfusion-dependent anemia. Baseline iron burden was similar in the groups.
The rates of acceptable compliance over the course of the study were also similar at 69% and 79% in the deferiprone and deferoxamine arms, respectively, she noted.
No statistically significant difference between the groups was seen in the overall rate of adverse events, treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis occurred in one deferiprone patient and zero deferoxamine patients, and mild or moderate neutropenia occurred in four patients and one patient in the groups, respectively.
All episodes resolved, no difference was seen in the rates of any of the serious AEs, and no unexpected serious adverse events occurred, she said.
Patients with sickle cell disease or other rare anemias whose care includes chronic blood transfusions require iron chelation to prevent iron overload. Currently, only deferoxamine and deferasirox are approved chelators in these patient populations, she said, noting that in 2011 deferiprone received accelerated Food and Drug Administration approval for the treatment of thalassemia.
The current study was conducted because of an FDA requirement for postmarket assessment of deferiprone’s efficacy and safety in patients with sickle cell disease and other anemias who develop transfusional iron overload. It was initiated prior to the approval of deferasirox for the first-line treatment of SCD, therefore it was compared only with deferoxamine, she explained.
Dr. Kwiatkowski reported research funding from Apopharma, bluebird bio, Novartis, and Terumo, and consultancy for Agios, bluebird bio, Celgene, and Imara.
ORLANDO – The oral iron chelator deferiprone showed noninferiority to deferoxamine for treating iron overload in patients with sickle cell disease and other rare anemias in a randomized open-label trial.
The least squares mean change from baseline in liver iron concentration (LIC) – the primary study endpoint – was –4.04 mg/g dry weight (dw) in 152 patients randomized to receive deferiprone, and –4.45 mg/g dw in 76 who received deferoxamine, Janet L. Kwiatkowski, MD, of the Children’s Hospital of Philadelphia reported at the annual meeting of the American Society of Hematology.
The upper limit of the stringent 96.01% confidence interval used for the evaluation of noninferiority in the study was 1.57, thus the findings demonstrated noninferiority of deferiprone, Dr. Kwiatkowski said.
Deferiprone also showed noninferiority for the secondary endpoints of change in cardiac iron (about –0.02 ms on T2* MRI, log-transformed for both groups) and serum ferritin levels (–415 vs. –750 mcg/L for deferiprone vs. deferoxamine) at 12 months. The difference between the groups was not statistically significant for either endpoint.
Study participants, who had a mean age of 16.9 years, were aged 2 years and older with LIC between 7 and 30 mg/g dw. They were recruited from 33 sites in nine countries and randomized 2:1 to receive deferiprone or deferoxamine for up to 12 months; in patients with lower transfusional iron input and/or less severe iron load, deferiprone was dosed at 75 mg/kg daily and deferoxamine was dosed at 20 mg/kg for children and 40 mg/kg for adults. In those with higher iron input and/or more severe iron load, the deferiprone dose was 99 mg/kg daily and the deferoxamine doses were up to 40 mg/kg in children and up to 50 mg/kg for adults.
“Over the course of the treatment period, the dosage could be adjusted downward if there were side effects, or upward if there was no improvement in iron burden,” Dr Kwiatkowski said, adding that after 12 months, patients had the option of continuing on to a 2-year extension trial in which everyone received deferiprone.
No significant demographic differences were noted between the groups; 84% in both groups had sickle cell disease, and the remaining patients had other, rarer forms of transfusion-dependent anemia. Baseline iron burden was similar in the groups.
The rates of acceptable compliance over the course of the study were also similar at 69% and 79% in the deferiprone and deferoxamine arms, respectively, she noted.
No statistically significant difference between the groups was seen in the overall rate of adverse events, treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis occurred in one deferiprone patient and zero deferoxamine patients, and mild or moderate neutropenia occurred in four patients and one patient in the groups, respectively.
All episodes resolved, no difference was seen in the rates of any of the serious AEs, and no unexpected serious adverse events occurred, she said.
Patients with sickle cell disease or other rare anemias whose care includes chronic blood transfusions require iron chelation to prevent iron overload. Currently, only deferoxamine and deferasirox are approved chelators in these patient populations, she said, noting that in 2011 deferiprone received accelerated Food and Drug Administration approval for the treatment of thalassemia.
The current study was conducted because of an FDA requirement for postmarket assessment of deferiprone’s efficacy and safety in patients with sickle cell disease and other anemias who develop transfusional iron overload. It was initiated prior to the approval of deferasirox for the first-line treatment of SCD, therefore it was compared only with deferoxamine, she explained.
Dr. Kwiatkowski reported research funding from Apopharma, bluebird bio, Novartis, and Terumo, and consultancy for Agios, bluebird bio, Celgene, and Imara.
ORLANDO – The oral iron chelator deferiprone showed noninferiority to deferoxamine for treating iron overload in patients with sickle cell disease and other rare anemias in a randomized open-label trial.
The least squares mean change from baseline in liver iron concentration (LIC) – the primary study endpoint – was –4.04 mg/g dry weight (dw) in 152 patients randomized to receive deferiprone, and –4.45 mg/g dw in 76 who received deferoxamine, Janet L. Kwiatkowski, MD, of the Children’s Hospital of Philadelphia reported at the annual meeting of the American Society of Hematology.
The upper limit of the stringent 96.01% confidence interval used for the evaluation of noninferiority in the study was 1.57, thus the findings demonstrated noninferiority of deferiprone, Dr. Kwiatkowski said.
Deferiprone also showed noninferiority for the secondary endpoints of change in cardiac iron (about –0.02 ms on T2* MRI, log-transformed for both groups) and serum ferritin levels (–415 vs. –750 mcg/L for deferiprone vs. deferoxamine) at 12 months. The difference between the groups was not statistically significant for either endpoint.
Study participants, who had a mean age of 16.9 years, were aged 2 years and older with LIC between 7 and 30 mg/g dw. They were recruited from 33 sites in nine countries and randomized 2:1 to receive deferiprone or deferoxamine for up to 12 months; in patients with lower transfusional iron input and/or less severe iron load, deferiprone was dosed at 75 mg/kg daily and deferoxamine was dosed at 20 mg/kg for children and 40 mg/kg for adults. In those with higher iron input and/or more severe iron load, the deferiprone dose was 99 mg/kg daily and the deferoxamine doses were up to 40 mg/kg in children and up to 50 mg/kg for adults.
“Over the course of the treatment period, the dosage could be adjusted downward if there were side effects, or upward if there was no improvement in iron burden,” Dr Kwiatkowski said, adding that after 12 months, patients had the option of continuing on to a 2-year extension trial in which everyone received deferiprone.
No significant demographic differences were noted between the groups; 84% in both groups had sickle cell disease, and the remaining patients had other, rarer forms of transfusion-dependent anemia. Baseline iron burden was similar in the groups.
The rates of acceptable compliance over the course of the study were also similar at 69% and 79% in the deferiprone and deferoxamine arms, respectively, she noted.
No statistically significant difference between the groups was seen in the overall rate of adverse events, treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis occurred in one deferiprone patient and zero deferoxamine patients, and mild or moderate neutropenia occurred in four patients and one patient in the groups, respectively.
All episodes resolved, no difference was seen in the rates of any of the serious AEs, and no unexpected serious adverse events occurred, she said.
Patients with sickle cell disease or other rare anemias whose care includes chronic blood transfusions require iron chelation to prevent iron overload. Currently, only deferoxamine and deferasirox are approved chelators in these patient populations, she said, noting that in 2011 deferiprone received accelerated Food and Drug Administration approval for the treatment of thalassemia.
The current study was conducted because of an FDA requirement for postmarket assessment of deferiprone’s efficacy and safety in patients with sickle cell disease and other anemias who develop transfusional iron overload. It was initiated prior to the approval of deferasirox for the first-line treatment of SCD, therefore it was compared only with deferoxamine, she explained.
Dr. Kwiatkowski reported research funding from Apopharma, bluebird bio, Novartis, and Terumo, and consultancy for Agios, bluebird bio, Celgene, and Imara.
REPORTING FROM ASH 2019
Novel mutations contribute to progression of venetoclax-treated CLL
Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.
“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.
Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.
With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.
Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.
“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.
The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.
In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.
“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.
Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.
The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.
Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.
“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.
Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.
With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.
Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.
“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.
The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.
In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.
“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.
Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.
The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.
Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.
“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.
Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.
With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.
Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.
“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.
The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.
In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.
“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.
Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.
The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.
FROM BLOOD
ECHELON-1 update: A+AVD bests ABVD in Hodgkin lymphoma
Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) provides “robust, sustained efficacy” in patients with Hodgkin lymphoma, according to investigators.
In the ECHELON-1 trial, investigators compared A+AVD to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for stage III or IV Hodgkin lymphoma. The 3-year progression-free survival (PFS) was superior in patients who received A+AVD, and this benefit was seen across most subgroups.
David J. Straus, MD, of Memorial Sloan Kettering Cancer Center in New York and his colleagues detailed these findings in Blood.
The phase 3 trial (NCT01712490) enrolled 1,334 patients with stage III or IV classical Hodgkin lymphoma. They were randomized to receive A+AVD (n = 664) or ABVD (n = 670). Baseline characteristics were similar between the treatment arms.
Positron emission tomography status after cycle 2 (PET2) was similar between the treatment arms as well. Most patients – 89% of the A+AVD arm and 86% of the ABVD arm – were PET2 negative. Treating physicians used PET2 status as a guide to potentially switch patients to an alternative regimen (radiotherapy or chemotherapy with or without transplant).
In a prior analysis, the study’s primary endpoint was modified PFS (time to progression, death, or noncomplete response after frontline therapy) per an independent review committee (N Engl J Med. 2018;378:331-44). The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm (hazard ratio, 0.77; P = .04).
PFS update
In the current analysis, the main exploratory endpoint was PFS per investigator. The 3-year PFS rate was significantly higher in the A+AVD arm than in the ABVD arm – 83.1% and 76.0%, respectively (HR, 0.704; P = .005).
The investigators observed a “consistent improvement in PFS” in the A+AVD arm, regardless of disease stage, International Prognostic score, Eastern Cooperative Oncology Group status, sex, or age. There was a significant improvement in PFS with A+AVD in PET2-negative patients and a trend toward improvement in PET2-positive patients. In the PET2-negative patients, the 3-year PFS was 85.8% in the A+AVD arm and 79.5% in the ABVD arm (HR, 0.69; P = .009). In PET2-positive patients, the 3-year PFS was 67.7% and 51.5%, respectively (HR, 0.59; P = .077).
“These data highlight that A+AVD provides a durable efficacy benefit, compared with ABVD, for frontline stage III/IV cHL [classical Hodgkin lymphoma], which is consistent across key subgroups regardless of patient status at PET2,” Dr. Straus and his colleagues wrote.
Safety update
In both treatment arms, peripheral neuropathy continued to improve or resolve with longer follow-up. Among patients who developed peripheral neuropathy, 78% in the A+AVD arm and 83% in the ABVD arm had improvement or resolution of the condition at 3 years.
Most patients had complete resolution of peripheral neuropathy; 62% in the A+AVD arm and 73% in the ABVD arm. The median time to complete resolution was 28 weeks (range, 0-167 weeks) after stopping A+AVD and 14 weeks (range, 0-188 weeks) after stopping ABVD.
The incidence of secondary malignancies was similar between the treatment arms. There were 14 secondary malignancies in the A+AVD arm (6 solid tumors, 8 hematologic malignancies) and 20 in the ABVD arm (9 solid tumors, 11 hematologic malignancies).
“A+AVD provided a sustained PFS benefit with a predictable and manageable safety profile,” Dr. Straus and colleagues wrote. “These data further support the advantages of A+AVD versus ABVD as frontline treatment of patients with advanced stage III or IV cHL [classical Hodgkin lymphoma].”
The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a subsidiary of Takeda) and Seattle Genetics. The investigators disclosed relationships with Millennium, Takeda, Seattle Genetics, and a range of other companies.
SOURCE: Straus DJ et al. Blood. 2020 Jan 16. pii: blood.2019003127. doi: 10.1182/blood.2019003127.
Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) provides “robust, sustained efficacy” in patients with Hodgkin lymphoma, according to investigators.
In the ECHELON-1 trial, investigators compared A+AVD to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for stage III or IV Hodgkin lymphoma. The 3-year progression-free survival (PFS) was superior in patients who received A+AVD, and this benefit was seen across most subgroups.
David J. Straus, MD, of Memorial Sloan Kettering Cancer Center in New York and his colleagues detailed these findings in Blood.
The phase 3 trial (NCT01712490) enrolled 1,334 patients with stage III or IV classical Hodgkin lymphoma. They were randomized to receive A+AVD (n = 664) or ABVD (n = 670). Baseline characteristics were similar between the treatment arms.
Positron emission tomography status after cycle 2 (PET2) was similar between the treatment arms as well. Most patients – 89% of the A+AVD arm and 86% of the ABVD arm – were PET2 negative. Treating physicians used PET2 status as a guide to potentially switch patients to an alternative regimen (radiotherapy or chemotherapy with or without transplant).
In a prior analysis, the study’s primary endpoint was modified PFS (time to progression, death, or noncomplete response after frontline therapy) per an independent review committee (N Engl J Med. 2018;378:331-44). The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm (hazard ratio, 0.77; P = .04).
PFS update
In the current analysis, the main exploratory endpoint was PFS per investigator. The 3-year PFS rate was significantly higher in the A+AVD arm than in the ABVD arm – 83.1% and 76.0%, respectively (HR, 0.704; P = .005).
The investigators observed a “consistent improvement in PFS” in the A+AVD arm, regardless of disease stage, International Prognostic score, Eastern Cooperative Oncology Group status, sex, or age. There was a significant improvement in PFS with A+AVD in PET2-negative patients and a trend toward improvement in PET2-positive patients. In the PET2-negative patients, the 3-year PFS was 85.8% in the A+AVD arm and 79.5% in the ABVD arm (HR, 0.69; P = .009). In PET2-positive patients, the 3-year PFS was 67.7% and 51.5%, respectively (HR, 0.59; P = .077).
“These data highlight that A+AVD provides a durable efficacy benefit, compared with ABVD, for frontline stage III/IV cHL [classical Hodgkin lymphoma], which is consistent across key subgroups regardless of patient status at PET2,” Dr. Straus and his colleagues wrote.
Safety update
In both treatment arms, peripheral neuropathy continued to improve or resolve with longer follow-up. Among patients who developed peripheral neuropathy, 78% in the A+AVD arm and 83% in the ABVD arm had improvement or resolution of the condition at 3 years.
Most patients had complete resolution of peripheral neuropathy; 62% in the A+AVD arm and 73% in the ABVD arm. The median time to complete resolution was 28 weeks (range, 0-167 weeks) after stopping A+AVD and 14 weeks (range, 0-188 weeks) after stopping ABVD.
The incidence of secondary malignancies was similar between the treatment arms. There were 14 secondary malignancies in the A+AVD arm (6 solid tumors, 8 hematologic malignancies) and 20 in the ABVD arm (9 solid tumors, 11 hematologic malignancies).
“A+AVD provided a sustained PFS benefit with a predictable and manageable safety profile,” Dr. Straus and colleagues wrote. “These data further support the advantages of A+AVD versus ABVD as frontline treatment of patients with advanced stage III or IV cHL [classical Hodgkin lymphoma].”
The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a subsidiary of Takeda) and Seattle Genetics. The investigators disclosed relationships with Millennium, Takeda, Seattle Genetics, and a range of other companies.
SOURCE: Straus DJ et al. Blood. 2020 Jan 16. pii: blood.2019003127. doi: 10.1182/blood.2019003127.
Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) provides “robust, sustained efficacy” in patients with Hodgkin lymphoma, according to investigators.
In the ECHELON-1 trial, investigators compared A+AVD to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for stage III or IV Hodgkin lymphoma. The 3-year progression-free survival (PFS) was superior in patients who received A+AVD, and this benefit was seen across most subgroups.
David J. Straus, MD, of Memorial Sloan Kettering Cancer Center in New York and his colleagues detailed these findings in Blood.
The phase 3 trial (NCT01712490) enrolled 1,334 patients with stage III or IV classical Hodgkin lymphoma. They were randomized to receive A+AVD (n = 664) or ABVD (n = 670). Baseline characteristics were similar between the treatment arms.
Positron emission tomography status after cycle 2 (PET2) was similar between the treatment arms as well. Most patients – 89% of the A+AVD arm and 86% of the ABVD arm – were PET2 negative. Treating physicians used PET2 status as a guide to potentially switch patients to an alternative regimen (radiotherapy or chemotherapy with or without transplant).
In a prior analysis, the study’s primary endpoint was modified PFS (time to progression, death, or noncomplete response after frontline therapy) per an independent review committee (N Engl J Med. 2018;378:331-44). The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm (hazard ratio, 0.77; P = .04).
PFS update
In the current analysis, the main exploratory endpoint was PFS per investigator. The 3-year PFS rate was significantly higher in the A+AVD arm than in the ABVD arm – 83.1% and 76.0%, respectively (HR, 0.704; P = .005).
The investigators observed a “consistent improvement in PFS” in the A+AVD arm, regardless of disease stage, International Prognostic score, Eastern Cooperative Oncology Group status, sex, or age. There was a significant improvement in PFS with A+AVD in PET2-negative patients and a trend toward improvement in PET2-positive patients. In the PET2-negative patients, the 3-year PFS was 85.8% in the A+AVD arm and 79.5% in the ABVD arm (HR, 0.69; P = .009). In PET2-positive patients, the 3-year PFS was 67.7% and 51.5%, respectively (HR, 0.59; P = .077).
“These data highlight that A+AVD provides a durable efficacy benefit, compared with ABVD, for frontline stage III/IV cHL [classical Hodgkin lymphoma], which is consistent across key subgroups regardless of patient status at PET2,” Dr. Straus and his colleagues wrote.
Safety update
In both treatment arms, peripheral neuropathy continued to improve or resolve with longer follow-up. Among patients who developed peripheral neuropathy, 78% in the A+AVD arm and 83% in the ABVD arm had improvement or resolution of the condition at 3 years.
Most patients had complete resolution of peripheral neuropathy; 62% in the A+AVD arm and 73% in the ABVD arm. The median time to complete resolution was 28 weeks (range, 0-167 weeks) after stopping A+AVD and 14 weeks (range, 0-188 weeks) after stopping ABVD.
The incidence of secondary malignancies was similar between the treatment arms. There were 14 secondary malignancies in the A+AVD arm (6 solid tumors, 8 hematologic malignancies) and 20 in the ABVD arm (9 solid tumors, 11 hematologic malignancies).
“A+AVD provided a sustained PFS benefit with a predictable and manageable safety profile,” Dr. Straus and colleagues wrote. “These data further support the advantages of A+AVD versus ABVD as frontline treatment of patients with advanced stage III or IV cHL [classical Hodgkin lymphoma].”
The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a subsidiary of Takeda) and Seattle Genetics. The investigators disclosed relationships with Millennium, Takeda, Seattle Genetics, and a range of other companies.
SOURCE: Straus DJ et al. Blood. 2020 Jan 16. pii: blood.2019003127. doi: 10.1182/blood.2019003127.
FROM BLOOD
Occult HCV infection is correlated to unfavorable genotypes in hemophilia patients
The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.
This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.
The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.
“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.
The authors reported that they had no disclosures.
SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.
The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.
This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.
The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.
“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.
The authors reported that they had no disclosures.
SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.
The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.
This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.
The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.
“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.
The authors reported that they had no disclosures.
SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.
FROM INFECTION, GENETICS AND EVOLUTION
FDA approves first treatment for advanced epithelioid sarcoma
The Food and Drug Administration has granted accelerated approval to tazemetostat (Tazverik) for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Approval was based on overall response rate in a trial enrolling 62 patients with metastatic or locally advanced epithelioid sarcoma. The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the nine patients that had a response, six (67%) had a response lasting 6 months or longer, the FDA said in a press statement.
The most common side effects for patients taking tazemetostat were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Patients treated with tazemetostat are at increased risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.
“Epithelioid sarcoma accounts for less than 1% of all soft-tissue sarcomas,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease.”
Tazemetostat must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks, the FDA said.
The Food and Drug Administration has granted accelerated approval to tazemetostat (Tazverik) for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Approval was based on overall response rate in a trial enrolling 62 patients with metastatic or locally advanced epithelioid sarcoma. The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the nine patients that had a response, six (67%) had a response lasting 6 months or longer, the FDA said in a press statement.
The most common side effects for patients taking tazemetostat were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Patients treated with tazemetostat are at increased risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.
“Epithelioid sarcoma accounts for less than 1% of all soft-tissue sarcomas,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease.”
Tazemetostat must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks, the FDA said.
The Food and Drug Administration has granted accelerated approval to tazemetostat (Tazverik) for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Approval was based on overall response rate in a trial enrolling 62 patients with metastatic or locally advanced epithelioid sarcoma. The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the nine patients that had a response, six (67%) had a response lasting 6 months or longer, the FDA said in a press statement.
The most common side effects for patients taking tazemetostat were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Patients treated with tazemetostat are at increased risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.
“Epithelioid sarcoma accounts for less than 1% of all soft-tissue sarcomas,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease.”
Tazemetostat must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks, the FDA said.
DOACs for treatment of cancer-associated venous thromboembolism
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Bleeding risk may determine best option
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Experts break down latest CAR T-cell advances in lymphoma
ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.
The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.
Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.
Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.
Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.
In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.
The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.
The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”
“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.
The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).
Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.
ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.
The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.
Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.
Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.
Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.
In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.
The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.
The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”
“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.
The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).
Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.
ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.
The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.
Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.
Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.
Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.
In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.
The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.
The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”
“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.
The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).
Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.
EXPERT ANALYSIS FROM ASH 2019
Start of myeloma therapy may be delayed for women, minorities
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
FROM JCO ONCOLOGY PRACTICE
Key clinical point:
Major finding: Patients with delays in treatment were more likely to be women (odds ratio, 1.15) and more likely to be non-Hispanic blacks (OR, 1.21).
Study details: Retrospective analysis of 74,722 patients in the National Cancer Database diagnosed with multiple myeloma between 2004 and 2015.
Disclosures: Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
Source: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Adult survivors of childhood cancer are experiencing fewer major cardiac events
Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.
“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”
Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.
Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.
When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.
“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.
In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.
“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”
This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.
SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.
Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.
“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”
Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.
Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.
When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.
“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.
In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.
“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”
This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.
SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.
Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.
“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”
Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.
Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.
When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.
“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.
In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.
“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”
This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.
SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.
FROM BMJ